Compositions, Kits, And Methods For Identification, Assessment, Prevention, And Therapy Of Breast Cancer

Abstract

The invention relates to nucleic acid molecules and proteins associated with breast cancer. Compositions, kits, and methods for detecting, characterizing, preventing, and treating human breast cancers are provided.

Description

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation of U.S. patent application Ser. No. 10/855,588, filed on May 26, 2004, the entire contents of which are expressly incorporated herein by reference. This application also claims the benefit of U.S. Provisional Application No. 60/474,281, filed May 29, 2003, and U.S. Provisional Application No. 60/555,557, filed Mar. 23, 2004, the entire contents of each of which are expressly incorporated herein by reference.

FIELD OF THE INVENTION

[0002] The field of the invention is breast cancer, including diagnosis, characterization, management, and therapy of breast cancer.

BACKGROUND OF THE INVENTION

[0003] The increased number of cancer cases reported in the United States, and, indeed, around the world, is a major concern. Currently there are only a handful of treatments available for specific types of cancer, and these provide no absolute guarantee of success. In order to be most effective, these treatments require not only an early detection of the malignancy, but a reliable assessment of the severity of the malignancy.

[0004] The incidence of breast cancer, a leading cause of death in women, has been gradually increasing in the United States over the last thirty years. In 1997, it was estimated that 181,000 new cases were reported in the U.S., and that 44,000 people would die of breast cancer (Parker et al., 1997, CA Cancer J. Clin. 47:5-27; Chu et al., 1996, J. Nat. Cancer Inst. 88:1571-1579). While the pathogenesis of breast cancer is unclear, transformation of normal breast epithelium to a malignant phenotype may be the result of genetic factors, especially in women under 30 (Mild et al., 1994, Science, 266:66-71). The discovery and characterization of BRCA1 and BRCA2 has recently expanded our knowledge of genetic factors which can contribute to familial breast cancer. Germ-line mutations within these two loci are associated with a 50 to 85% lifetime risk of breast and/or ovarian cancer (Casey, 1997, Curr. Opin. Oncol. 9:88-93; Marcus et al., 1996, Cancer 77:697-709). However, it is likely that other, non-genetic factors also have a significant effect on the etiology of the disease. Regardless of its origin, breast cancer morbidity and mortality increases significantly if it is not detected early in its progression. Thus, considerable effort has focused on the early detection of cellular transformation and tumor formation in breast tissue.

[0005] Currently, the principal manner of identifying breast cancer is through detection of the presence of dense tumorous tissue. This may be accomplished to varying degrees of effectiveness by direct examination of the outside of the breast, or through mammography or other X-ray imaging methods (Jatoi, 1999, Am. J. Surg. 177:518-524). The latter approach is not without considerable cost, however. Every time a mammogram is taken, the patient incurs a small risk of having a breast tumor induced by the ionizing properties of the radiation used during the test. In addition, the process is expensive and the subjective interpretations of a technician can lead to imprecision, e.g., one study showed major clinical disagreements for about one-third of a set of mammograms that were interpreted individually by a surveyed group of radiologists. Moreover, many women find that undergoing a mammogram is a painful experience. Accordingly, the National Cancer Institute has not recommended mammograms for women under fifty years of age, since this group is not as likely to develop breast cancers as are older women. It is compelling to note, however, that while only about 22% of breast cancers occur in women under fifty, data suggests that breast cancer is more aggressive in pre-menopausal women.

[0006] It would therefore be beneficial to provide specific methods and reagents for the diagnosis, staging, prognosis, monitoring, and treatment of diseases associated with breast cancer, or to indicate a predisposition to such for preventative measures.

SUMMARY OF THE INVENTION

[0007] The invention relates to cancer markers (hereinafter "markers" or "markers of the inventions"), which are listed in Table 1 and Table 2. The invention provides nucleic acids and proteins that are encoded by or correspond to the markers (hereinafter "marker nucleic acids" and "marker proteins," respectively). The invention further provides antibodies, antibody derivatives and antibody fragments which bind specifically with such marker proteins and/or fragments of the marker proteins.

[0008] The invention also relates to various methods, reagents and kits for diagnosing, staging, prognosing, monitoring and treating breast cancer. In one embodiment, the invention provides a diagnostic method of assessing whether a patient has breast cancer or has higher than normal risk for developing breast cancer, comprising comparing the level of expression of at least one marker of the invention in a patient sample and the normal level of expression of the marker or markers in a control, e.g., a sample from a patient without breast cancer. Elevated expression of the marker or markers in the patient sample can be indicative of a patient having or at risk for developing breast cancer.

[0009] In another embodiment, the invention provides a diagnostic method of assessing whether a patient has an aggressive breast tumor or is likely to develop an aggressive breast tumor, comprising comparing the level of expression of at least one marker of the invention in a patient sample and the level of expression of the marker in a sample from a control subject having an indolent breast tumor or no breast tumor. Elevated expression of the marker can be indicative of aggressive breast cancer.

[0010] Thus, the methods of the present invention can be of use in identifying patients having an enhanced risk of developing breast cancer (e.g., patients having a familial history of breast cancer, patients identified as having a mutant oncogene). The methods are also useful diagnostics for assessing whether a patient has an aggressive breast cancer or is likely to develop an aggressive breast tumor.

[0011] The methods of the present invention may be useful in predicting the specific stage of breast cancer, as well as in assessing whether the cancer has metastasized (e.g., metastasis to the lymph nodes). Still further, the methods of the present invention are also useful in predicting the clinical outcome for a patient with breast cancer, or for a patient who has undergone therapy to eradicate breast cancer. Additionally, the methods of the present invention are also useful in assessing the efficacy of treatment of a breast cancer patient (e.g., the efficacy of chemotherapy).

[0012] According to the invention, the markers are selected such that the positive predictive value of the methods of the invention is at least about 10%, preferably about 25%, more preferably about 50% and most preferably about 90%. Also preferred are embodiments of the method wherein the marker is over-expressed by at least five-fold in at least about 15% of breast cancer patients (including, e.g., stage 0 breast cancer patients, stage I breast cancer patients, stage IIA breast cancer patients, stage IIB breast cancer patients, stage IIIA breast cancer patients, stage IIIB breast cancer patients, stage IV breast cancer patients, grade I breast cancer patients, grade II breast cancer patients, grade III breast cancer patients, malignant breast cancer patients, ductal carcinoma breast cancer patients, and lobular carcinoma breast cancer patients, and any other types of cancers, malignancies and transformations associated with the breast) as compared to normal non-breast cancer patients.

[0013] In one aspect, a diagnostic method of assessing whether a patient is afflicted with breast cancer (e.g., new detection "screening," detection of recurrence, reflex testing) is provided. Such method comprises comparing the level of expression of at least one marker listed in Table 1 in a sample from the patient, and the level of expression of the marker or markers in a control subject not having breast cancer. A significantly higher level of expression of the marker in the patient sample, as compared to the level in the control subject, is an indication that the patient is afflicted with breast cancer.

[0014] The invention additionally provides a diagnostic method for assessing whether a patient is afflicted with an aggressive breast cancer, comprising the steps of:

[0015] determining the level of expression of at least one marker in a patient sample, wherein the marker is selected from the group consisting of the markers listed in Table 2;

[0016] determining the level of expression of the marker or markers in a sample from a control subject having an indolent breast tumor or no breast tumor; and

[0017] comparing the level of expression of the marker in the patient sample and in the sample from a control subject. A significantly higher level of expression of the marker or markers in the patient sample, as compared to the level in the sample from the control subject, is an indication that the patient has an aggressive breast cancer or is likely to develop an aggressive breast tumor. No difference in expression between the patient sample and the control sample, or a significantly lower level of expression in the patient sample, as compared to the control level, indicates that the patient has an indolent breast cancer.

[0018] The invention further provides a diagnostic method of assessing whether a patient is afflicted with a breast cancer which has metastasized or is likely to metastasize, the method comprising comparing the level of expression of at least one marker listed in Table 2 in a sample from the patient, and the level of expression of the marker or markers in a sample from a control subject having a non-metastasized breast tumor or no breast tumor. A significantly higher level of expression in the patient sample as compared to the level in the sample from the control subject is an indication that the breast cancer has metastasized or is likely to metastasize.

[0019] In another embodiment, the present invention includes a method for determining whether a patient has breast cancer that has metastasized to lymph nodes, or is likely to metastasize to lymph nodes, the method comprising comparing the level of expression of a marker listed in Table 2 in a sample from the patient, and the level of expression in a sample from a control subject having a non-metastasized breast tumor or no breast tumor. A significantly higher level of expression in the patient sample as compared to the level in the sample from the control subject, is an indication that the patient is afflicted with metastatic breast cancer that has metastasized to lymph nodes, or is likely to metastasize to lymph nodes.

[0020] The invention also provides a method for predicting the clinical outcome of a breast cancer patient, comprising comparing the level of expression of at least one marker listed in Table 2 in a sample from the patient and the level of expression of the marker or markers in a sample for a control subject having a good clinical outcome (e.g., a former breast cancer patient having greater than five years of disease free survival level). A significantly higher level of expression in the patient sample as compared to the expression level in the sample from the control subject is an indication that the patient has a poor outcome (e.g., less than three years of disease free survival).

[0021] The invention also provides methods for assessing the efficacy of a therapy for inhibiting breast cancer in a patient. Such methods comprise comparing expression of at least one marker of the invention in a first sample obtained from the patient prior to providing at least a portion of the therapy to the patient, and expression of the marker or markers in a second sample obtained from the patient following provision of the portion of the therapy. A significantly lower level of expression of the marker or markers in the second sample relative to that in the first sample is an indication that the therapy is efficacious for inhibiting breast cancer in the patient.

[0022] It will be appreciated that in these methods the "therapy" may be any therapy for treating breast cancer including, but not limited to, chemotherapy, radiation therapy, surgical removal of tumor tissue, gene therapy and biologic therapy, such as the administering of antibodies and chemokines. Thus, the methods of the invention may be used to evaluate a patient before, during and after therapy, for example, to evaluate the reduction in tumor burden.

[0023] In a preferred embodiment, the methods are directed to therapy using a chemical or biologic agent. These methods comprise comparing expression of at least one marker of the invention in a first sample obtained from the patient and maintained in the presence of the chemical or biologic agent, and expression of the marker in a second sample obtained from the patient and maintained in the absence of the agent. A significantly lower level of expression of the marker or markers in the second sample relative to that in the first sample is an indication that the agent is efficacious for inhibiting breast cancer, in the patient. In certain embodiments, the first and second samples can be portions of a single sample obtained from the patient, or portions of pooled samples obtained from the patient.

[0024] The invention additionally provides a monitoring method for assessing progression of breast cancer in a patient, the method comprising:

[0025] detecting in a sample from the patient at a first time point, the expression of at least one marker of the invention;

[0026] repeating the detection of expression step at a subsequent time point in time; and

[0027] comparing the level of expression detected in the first and second detection steps, thereby monitoring the progression of breast cancer in the patient. A significantly higher level of expression of the marker in the sample at the subsequent time point from that of the sample at the first time point is an indication that the breast cancer has progressed in the patient, whereas a significantly lower level of expression is an indication that the breast cancer has regressed. In one embodiment, the patient has undergone surgery to remove a tumor between the first point in time and the subsequent point in time.

[0028] The invention moreover provides a test method for selecting a candidate composition for inhibiting breast cancer in a patient. This method comprises the steps of:

[0029] obtaining a sample comprising cancer cells from the patient;

[0030] separately maintaining at least one sample comprising cancer cells from the patient in the presence of at least one test composition;

[0031] comparing expression of at least one marker of the invention in each of the aliquots; and

[0032] selecting a test composition as a candidate composition for inhibition of breast cancer where the composition significantly reduces the level of expression of at least one marker of the invention in the aliquot containing that test composition, relative to the levels of expression of the marker in the presence of the other test compositions.

[0033] The invention additionally provides a test method of assessing the breast carcinogenic potential of a compound. This method comprises the steps of: maintaining separate aliquots of breast cells in the presence and absence of a compound; and comparing expression of a marker of the invention in each of the aliquots. A significantly higher level of expression of the marker in the aliquot maintained in the presence of the compound, relative to that of the aliquot maintained in the absence of the compound, is an indication that the compound possesses breast carcinogenic potential.

[0034] In addition, the invention further provides a method of inhibiting breast cancer in a patient. This method comprises the steps of:

[0035] obtaining a sample comprising cancer cells from a patient;

[0036] separately maintaining at least one sample comprising cancer cells from a patient in the presence of a test composition;

[0037] comparing expression of a marker of the invention in each of the aliquots;

[0038] identifying a composition as an inhibitor of breast cancer where the composition significantly lowers the level of expression of a marker of the invention in the aliquot containing the composition relative to the levels of expression of the marker in the presence of the other compositions; and

[0039] administering to the patient at least one of the compositions which are identified as an inhibitor of breast cancer.

[0040] According to the invention, the level of expression of a marker of the invention in a sample can be assessed, for example, by detecting the presence in the sample of:

[0041] the corresponding marker protein (e.g., a protein having any one of the sequences of SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 20, SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 26, SEQ ID NO: 28, SEQ ID NO: 30, SEQ ID NO: 32, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 38, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 50, SEQ ID NO: 52, SEQ ID NO: 54, SEQ ID NO: 56, SEQ ID NO: 58, SEQ ID NO: 60, SEQ ID NO: 62, SEQ ID NO: 64, SEQ ID NO: 66, SEQ ID NO: 68, SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 74, SEQ ID NO: 76, SEQ ID NO: 78, SEQ ID NO: 80, SEQ ID NO: 82, SEQ ID NO: 84, SEQ ID NO: 86, SEQ ID NO: 88, SEQ ID NO: 90, SEQ ID NO: 92, SEQ ID NO: 94, and SEQ ID NO: 96) or a fragment of the protein (e.g., by using a reagent, such as an antibody, an antibody derivative, an antibody fragment or single-chain antibody, which binds specifically with the protein or protein fragment);

[0042] the corresponding marker nucleic acid (e.g., a nucleotide transcript having one of the sequences of the SEQ ID NOs (e.g., SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 5, SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 19, SEQ ID NO: 21, SEQ ID NO: 23, SEQ ID NO: 25, SEQ ID NO: 27, SEQ ID NO: 29, SEQ ID NO: 31, SEQ ID NO: 33, SEQ ID NO: 35, SEQ ID NO: 37, SEQ ID NO: 39, SEQ ID NO: 41, SEQ ID NO: 43, SEQ ID NO: 45, SEQ ID NO: 47, SEQ ID NO: 49, SEQ ID NO: 51, SEQ ID NO: 53, SEQ ID NO: 55, SEQ ID NO: 57, SEQ ID NO: 59, SEQ ID NO: 61, SEQ ID NO: 63, SEQ ID NO: 65, SEQ ID NO: 67, SEQ ID NO: 69, SEQ ID NO: 71, SEQ ID NO: 73, SEQ ID NO: 75, SEQ ID NO: 77, SEQ ID NO: 79, SEQ ID NO: 81, SEQ ID NO: 83, SEQ ID NO: 85, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 91, SEQ ID NO: 93, and SEQ ID NO: 95), or a complement thereof), or a fragment of the nucleic acid (e.g., by contacting transcribed polynucleotides obtained from the sample with a substrate having affixed thereto one or more nucleic acids having the entire or a segment of the sequence of any of the SEQ ID NOs (e.g., SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 5, SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 19, SEQ ID NO: 21, SEQ ID NO: 23, SEQ ID NO: 25, SEQ ID NO: 27, SEQ ID NO: 29, SEQ ID NO: 31, SEQ ID NO: 33, SEQ ID NO: 35, SEQ ID NO: 37, SEQ ID NO: 39, SEQ ID NO: 41, SEQ ID NO: 43, SEQ ID NO: 45, SEQ ID NO: 47, SEQ ID NO: 49, SEQ ID NO: 51, SEQ ID NO: 53, SEQ ID NO: 55, SEQ ID NO: 57, SEQ ID NO: 59, SEQ ID NO: 61, SEQ ID NO: 63, SEQ ID NO: 65, SEQ ID NO: 67, SEQ ID NO: 69, SEQ ID NO: 71, SEQ ID NO: 73, SEQ ID NO: 75, SEQ ID NO: 77, SEQ ID NO: 79, SEQ ID NO: 81, SEQ ID NO: 83, SEQ ID NO: 85, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 91, SEQ ID NO: 93, and SEQ ID NO: 95)), or a complement thereof, or a metabolite which is produced directly (i.e., catalyzed) or indirectly by the corresponding marker protein.

[0043] According to the invention, any of the aforementioned methods may be performed using or detecting a plurality (e.g., 2, 3, 5, or 10 or more) of breast cancer markers, including a combination of the provided markers of the invention with additional breast cancer markers known in the art. In such methods, the level of expression in the sample of each of a plurality of markers, at least one of which is a marker of the invention, is compared with the normal level of expression of each of the plurality of markers in samples of the same type obtained from control humans not afflicted with breast cancer. A significantly altered (i.e., increased or decreased as specified in the described methods using a single marker) level of expression in the sample of one or more markers of the invention, or some combination thereof, relative to that marker's corresponding normal or control level, is an indication that the patient is afflicted with breast cancer. For all of the aforementioned methods, the marker(s) are preferably selected such that the positive predictive value of the method is at least about 10%.

[0044] In a further aspect, the invention provides an antibody, an antibody derivative, or an antibody fragment, which binds specifically with a marker protein (e.g., a protein having the sequence of any of SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 20, SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 26, SEQ ID NO: 28, SEQ ID NO: 30, SEQ ID NO: 32, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 38, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 50, SEQ ID NO: 52, SEQ ID NO: 54, SEQ ID NO: 56, SEQ ID NO: 58, SEQ ID NO: 60, SEQ ID NO: 62, SEQ ID NO: 64, SEQ ID NO: 66, SEQ ID NO: 68, SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 74, SEQ ID NO: 76, SEQ ID NO: 78, SEQ ID NO: 80, SEQ ID NO: 82, SEQ ID NO: 84, SEQ ID NO: 86, SEQ ID NO: 88, SEQ ID NO: 90, SEQ ID NO: 92, SEQ ID NO: 94, and SEQ ID NO: 96) or a fragment of the protein. The invention also provides methods for making such antibody, antibody derivative, and antibody fragment. Such methods may comprise immunizing a mammal with a protein or peptide comprising the entirety, or a segment of 10 or more amino acids, of a marker protein (e.g., a protein having the sequence of any of SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 20, SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 26, SEQ ID NO: 28, SEQ ID NO: 30, SEQ ID NO: 32, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 38, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 50, SEQ ID NO: 52, SEQ ID NO: 54, SEQ ID NO: 56, SEQ ID NO: 58, SEQ ID NO: 60, SEQ ID NO: 62, SEQ ID NO: 64, SEQ ID NO: 66, SEQ ID NO: 68, SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 74, SEQ ID NO: 76, SEQ ID NO: 78, SEQ ID NO: 80, SEQ ID NO: 82, SEQ ID NO: 84, SEQ ID NO: 86, SEQ ID NO: 88, SEQ ID NO: 90, SEQ ID NO: 92, SEQ ID NO: 94, and SEQ ID NO: 96), wherein the protein or peptide may be obtained from a cell or by chemical synthesis. The methods of the invention also encompass producing monoclonal and single-chain antibodies, which would further comprise isolating splenocytes from the immunized mammal, fusing the isolated splenocytes with an immortalized cell line to form hybridomas, and screening individual hybridomas for those that produce an antibody that binds specifically with a marker protein or a fragment of the protein.

[0045] In another aspect, the invention relates to various diagnostic and test kits. In one embodiment, the invention provides a kit for assessing whether a patient is afflicted with a breast tumor. In another aspect, the kit may be used for assessing whether a patient is at risk of developing a breast tumor. The kit comprises a reagent for assessing expression of at least one marker of the invention. Yet another embodiment provides a kit which may be used for assessing whether a patient is afflicted with an aggressive breast tumor. The kit comprises a reagent for assessing expression of at least one marker of the invention. In another embodiment, the invention provides a kit for assessing the suitability of a chemical or biologic agent for inhibiting breast cancer in a patient. Such a kit comprises reagents for assessing expression of at least one marker of the invention, and may also comprise one or more of such agents. In a further embodiment, the invention provides kits for assessing the presence of breast cancer cells or treating breast cancers. Such kits may comprise an antibody, an antibody derivative, or an antibody fragment, which binds specifically with a marker protein, or a fragment of the protein. Such kits may also comprise a plurality of antibodies, antibody derivatives, or antibody fragments wherein the plurality of such antibody agents binds specifically with a marker protein, or a fragment of the protein.

[0046] In an additional embodiment, the invention provides a kit for assessing the presence of breast cancer cells, wherein the kit comprises at least one nucleic acid probe that binds specifically with at least one marker nucleic acid or a fragment of the nucleic acid. The kit may further comprise a plurality of probes, wherein each of the probes binds specifically with a marker nucleic acid, or a fragment of the nucleic acid.

[0047] In a further aspect, the invention relates to methods for treating a patient afflicted with breast cancer or at risk of developing breast cancer. Such methods may comprise reducing the expression and/or interfering with the biological function of at least one marker of the invention. In one embodiment, the method comprises providing to the patient an antisense oligonucleotide or polynucleotide complementary to a marker nucleic acid, or a segment thereof. For example, an antisense polynucleotide may be provided to the patient through the delivery of a vector that expresses an anti-sense polynucleotide of a marker nucleic acid or a fragment thereof. In another embodiment, the method comprises providing to the patient an antibody, an antibody derivative, or antibody fragment, which binds specifically with a marker protein or a fragment of the protein. In a preferred embodiment, the antibody, antibody derivative or antibody fragment binds specifically with a protein having the sequence of SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 20, SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 26, SEQ ID NO: 28, SEQ ID NO: 30, SEQ ID NO: 32, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 38, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 50, SEQ ID NO: 52, SEQ ID NO: 54, SEQ ID NO: 56, SEQ ID NO: 58, SEQ ID NO: 60, SEQ ID NO: 62, SEQ ID NO: 64, SEQ ID NO: 66, SEQ ID NO: 68, SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 74, SEQ ID NO: 76, SEQ ID NO: 78, SEQ ID NO: 80, SEQ ID NO: 82, SEQ ID NO: 84, SEQ ID NO: 86, SEQ ID NO: 88, SEQ ID NO: 90, SEQ ID NO: 92, SEQ ID NO: 94, and SEQ ID NO: 96, or a fragment of the protein.

[0048] It will be appreciated that the methods and kits of the present invention may also include known cancer markers including known breast cancer markers. It will further be appreciated that the methods and kits may be used to identify cancers other than breast cancer.

[0049] In another aspect the invention features nucleic acid molecules which encode marker proteins or marker polypeptides, e.g., a biologically active portion of the marker protein. In a preferred embodiment, the isolated nucleic acid molecules encode marker polypeptides having the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 20, SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 26, SEQ ID NO: 28, SEQ ID NO: 30, SEQ ID NO: 32, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 38, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 50, SEQ ID NO: 52, SEQ ID NO: 54, SEQ ID NO: 56, SEQ ID NO: 58, SEQ ID NO: 60, SEQ ID NO: 62, SEQ ID NO: 64, SEQ ID NO: 66, SEQ ID NO: 68, SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 74, SEQ ID NO: 76, SEQ ID NO: 78, SEQ ID NO: 80, SEQ ID NO: 82, SEQ ID NO: 84, SEQ ID NO: 86, SEQ ID NO: 88, SEQ ID NO: 90, SEQ ID NO: 92, SEQ ID NO: 94, and SEQ ID NO: 96. In other embodiments, the invention provides isolated marker nucleic acid molecules having the nucleotide sequences shown in any one selected from SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 5, SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 19, SEQ ID NO: 21, SEQ ID NO: 23, SEQ ID NO: 25, SEQ ID NO: 27, SEQ ID NO: 29, SEQ ID NO: 31, SEQ ID NO: 33, SEQ ID NO: 35, SEQ ID NO: 37, SEQ ID NO: 39, SEQ ID NO: 41, SEQ ID NO: 43, SEQ ID NO: 45, SEQ ID NO: 47, SEQ ID NO: 49, SEQ ID NO: 51, SEQ ID NO: 53, SEQ ID NO: 55, SEQ ID NO: 57, SEQ ID NO: 59, SEQ ID NO: 61, SEQ ID NO: 63, SEQ ID NO: 65, SEQ ID NO: 67, SEQ ID NO: 69, SEQ ID NO: 71, SEQ ID NO: 73, SEQ ID NO: 75, SEQ ID NO: 77, SEQ ID NO: 79, SEQ ID NO: 81, SEQ ID NO: 83, SEQ ID NO: 85, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 91, SEQ ID NO: 93, or SEQ ID NO: 95. In still other embodiments, the invention provides nucleic acid molecules that are substantially identical (e.g., naturally occurring allelic variants) to the nucleotide sequences shown in SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 5, SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 19, SEQ ID NO: 21, SEQ ID NO: 23, SEQ ID NO: 25, SEQ ID NO: 27, SEQ ID NO: 29, SEQ ID NO: 31, SEQ ID NO: 33, SEQ ID NO: 35, SEQ ID NO: 37, SEQ ID NO: 39, SEQ ID NO: 41, SEQ ID NO: 43, SEQ ID NO: 45, SEQ ID NO: 47, SEQ ID NO: 49, SEQ ID NO: 51, SEQ ID NO: 53, SEQ ID NO: 55, SEQ ID NO: 57, SEQ ID NO: 59, SEQ ID NO: 61, SEQ ID NO: 63, SEQ ID NO: 65, SEQ ID NO: 67, SEQ ID NO: 69, SEQ ID NO: 71, SEQ ID NO: 73, SEQ ID NO: 75, SEQ ID NO: 77, SEQ ID NO: 79, SEQ ID NO: 81, SEQ ID NO: 83, SEQ ID NO: 85, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 91, SEQ ID NO: 93, or SEQ ID NO: 95. In other embodiments, the invention provides nucleic acid molecules which hybridize under stringent hybridization conditions as described herein to nucleic acid molecules comprising the nucleotide sequence of SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 5, SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 19, SEQ ID NO: 21, SEQ ID NO: 23, SEQ ID NO: 25, SEQ ID NO: 27, SEQ ID NO: 29, SEQ ID NO: 31, SEQ ID NO: 33, SEQ ID NO: 35, SEQ ID NO: 37, SEQ ID NO: 39, SEQ ID NO: 41, SEQ ID NO: 43, SEQ ID NO: 45, SEQ ID NO: 47, SEQ ID NO: 49, SEQ ID NO: 51, SEQ ID NO: 53, SEQ ID NO: 55, SEQ ID NO: 57, SEQ ID NO: 59, SEQ ID NO: 61, SEQ ID NO: 63, SEQ ID NO: 65, SEQ ID NO: 67, SEQ ID NO: 69, SEQ ID NO: 71, SEQ ID NO: 73, SEQ ID NO: 75, SEQ ID NO: 77, SEQ ID NO: 79, SEQ ID NO: 81, SEQ ID NO: 83, SEQ ID NO: 85, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 91, SEQ ID NO: 93, and SEQ ID NO: 95, wherein the nucleic acid encodes a full length marker protein or an active fragment thereof.

[0050] In a related aspect, the invention further provides nucleic acid constructs which include marker nucleic acid molecules described herein. In certain embodiments, the nucleic acid molecules of the invention are operatively linked to native or heterologous regulatory sequences. Also included are vectors and host cells containing marker nucleic acid molecules of the invention e.g., vectors and host cells suitable for producing polypeptides.

[0051] In another related aspect, the invention provides nucleic acid fragments suitable as primers or hybridization probes for the detection of marker-encoding nucleic acids.

[0052] In still another related aspect, isolated nucleic acid molecules that are antisense to a marker encoding nucleic acid molecule are provided.

[0053] In other embodiments, the invention provides marker polypeptides, e.g., marker polypeptides having the amino acid sequences shown in SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 20, SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 26, SEQ ID NO: 28, SEQ ID NO: 30, SEQ ID NO: 32, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 38, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 50, SEQ ID NO: 52, SEQ ID NO: 54, SEQ ID NO: 56, SEQ ID NO: 58, SEQ ID NO: 60, SEQ ID NO: 62, SEQ ID NO: 64, SEQ ID NO: 66, SEQ ID NO: 68, SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 74, SEQ ID NO: 76, SEQ ID NO: 78, SEQ ID NO: 80, SEQ ID NO: 82, SEQ ID NO: 84, SEQ ID NO: 86, SEQ ID NO: 88, SEQ ID NO: 90, SEQ ID NO: 92, SEQ ID NO: 94, and SEQ ID NO: 96; an amino acid sequence that is substantially identical to the amino acid sequences shown in SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 20, SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 26, SEQ ID NO: 28, SEQ ID NO: 30, SEQ ID NO: 32, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 38, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 50, SEQ ID NO: 52, SEQ ID NO: 54, SEQ ID NO: 56, SEQ ID NO: 58, SEQ ID NO: 60, SEQ ID NO: 62, SEQ ID NO: 64, SEQ ID NO: 66, SEQ ID NO: 68, SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 74, SEQ ID NO: 76, SEQ ID NO: 78, SEQ ID NO: 80, SEQ ID NO: 82, SEQ ID NO: 84, SEQ ID NO: 86, SEQ ID NO: 88, SEQ ID NO: 90, SEQ ID NO: 92, SEQ ID NO: 94, and SEQ ID NO: 96; or amino acid sequences encoded by nucleic acid molecules having a nucleotide sequence which hybridizes under a stringent hybridization condition as described herein to nucleic acid molecules comprising the nucleotide sequences of SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 5, SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 19, SEQ ID NO: 21, SEQ ID NO: 23, SEQ ID NO: 25, SEQ ID NO: 27, SEQ ID NO: 29, SEQ ID NO: 31, SEQ ID NO: 33, SEQ ID NO: 35, SEQ ID NO: 37, SEQ ID NO: 39, SEQ ID NO: 41, SEQ ID NO: 43, SEQ ID NO: 45, SEQ ID NO: 47, SEQ ID NO: 49, SEQ ID NO: 51, SEQ ID NO: 53, SEQ ID NO: 55, SEQ ID NO: 57, SEQ ID NO: 59, SEQ ID NO: 61, SEQ ID NO: 63, SEQ ID NO: 65, SEQ ID NO: 67, SEQ ID NO: 69, SEQ ID NO: 71, SEQ ID NO: 73, SEQ ID NO: 75, SEQ ID NO: 77, SEQ ID NO: 79, SEQ ID NO: 81, SEQ ID NO: 83, SEQ ID NO: 85, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 91, SEQ ID NO: 93, and SEQ ID NO: 95, wherein the nucleic acid encodes a full length marker protein or an active fragment thereof.

[0054] In a related aspect, the invention further provides protein or peptide constructs which include polypeptide molecules described herein. In certain embodiments, the marker polypeptides or fragments of the invention are operatively linked to native or heterologous non-marker polypeptide sequences to form fusion protein sequences.

[0055] In yet another aspect, the invention features antibodies and antigen-binding fragments thereof, that react with, or more preferably specifically or selectively bind marker polypeptides.

DETAILED DESCRIPTION OF THE INVENTION

[0056] The invention relates to newly discovered breast cancer markers set forth in Table 1, associated with the cancerous state of breast cells. It has been discovered that a higher than normal level of expression of any of these markers or combination of these markers correlates with breast cancer in a patient. Additionally, the invention relates to newly discovered breast cancer markers set forth in Table 2, associated with the cancerous state of breast cells. It has been discovered that a higher than normal level of expression of any of these markers or combination of these markers correlates with aggressiveness of breast cancer in a patient. Methods are provided for detecting the presence of breast cancer in a sample, the absence of breast cancer in a sample, the stage of breast cancer, assessing whether a breast cancer has metastasized, predicting the likely clinical outcome of a breast cancer patient, and with other characteristics of breast cancer that are relevant to prevention, diagnosis, characterization, and therapy of breast cancer in a patient. Methods of treating breast cancer are also provided.

[0057] Table 1 lists markers of the invention which are over-expressed in breast cancer patient samples compared to non-breast cancer patient samples (e.g., non-breast cancer patient samples, non-cancerous breast cells, other non-breast cancer patient samples). Table 1 lists markers particularly useful in screening for the presence of breast cancer ("screening markers"). Table 2 lists markers of the invention, which are over-expressed in poor outcome breast cancer patient samples compared to normal samples (e.g., good outcome breast cancer patient samples, non-breast cancer patient samples, non-cancerous breast cells). Table 2 lists markers particularly useful in assessing the stage of the breast cancer ("staging markers"). Table 1 and Table 2 provide the sequence listing identifiers of the cDNA sequence of a nucleotide transcript and the amino acid sequence of a protein encoded by or corresponding to each marker, as well as the location of the protein coding sequence within the cDNA sequence. Tables 1 identifies markers of the invention (SEQ ID NOS:1-66) and Table 2 identifies markers of the invention (SEQ ID NOS: 67-96), which are designated with a name ("Marker"), the name the gene is commonly known by, if applicable ("Gene Name"), the Sequence Listing identifier of the cDNA sequence of the nucleotide transcript encoded by or corresponding to the marker ("SEQ ID NO (nts)"), the Sequence Listing identifier of the amino acid sequence of the protein encoded by the nucleotide transcript ("SEQ ID NO (AAs)"), and the location of the protein coding sequence within the cDNA sequence ("CDS").

TABLE-US-00001 TABLE 1 Breast Cancer Screening Markers SEQ SEQ ID NO ID NO Marker Gene Name (nts) (AAs) CDS M196A BCMP11: breast cancer membrane protein 11, variant 1 1 2 48 . . . 548 M725 BCMP11: breast cancer membrane protein 11, variant 2 3 4 49 . . . 501 M726 BCMP11: breast cancer membrane protein 11, variant 3 5 6 98 . . . 412 M727 BCMP11: breast cancer membrane protein 11, variant 4 7 8 49 . . . 465 M156 CXCL9: chemokine (C-X-C motif) ligand 9 9 10 40 . . . 417 M419 CXCL10: chemokine (C-X-C motif) ligand 10 11 12 67 . . . 363 M728 DNAJC1: DNAJ (hsp40) homolog, subfamily C, 13 14 244 . . . 1152 member 1, variant 1 M729 DNAJC1: DNAJ (hsp40) homolog, subfamily C, 15 16 244 . . . 1134 member 1, variant 2 M111 DNAJC1: DNAJ (hsp40) homolog, subfamily C, 17 18 108 . . . 1772 member 1, variant 3 M428A FLJ22774: hypothetical protein FLJ22774 19 20 528 . . . 3053 M149A LIV-1: LIV-1 protein, estrogen regulated, variant 1 21 22 282 . . . 2549 M730 LIV-1: LIV-1 protein, estrogen regulated, variant 2 23 24 309 . . . 1751 M158A MMP11: matrix metalloproteinase 11 (stromelysin 3) 25 26 23 . . . 1489 M165A NPY1R: neuropeptide Y receptor Y1, variant 1 27 28 272 . . . 1426 M731 NPY1R: neuropeptide Y receptor Y1, variant 2 29 30 241 . . . 1005 M732 NPY1R: neuropeptide Y receptor Y1, variant 3 31 32 272 . . . 700 M235 NY-BR-1: breast cancer antigen NY-BR-1 33 34 100 . . . 4125 M56A OSF-2: osteoblast specific factor 2 (fasciclin I-like), 35 36 12 . . . 2522 variant 1 M733 OSF-2: osteoblast specific factor 2 (fasciclin I-like), 37 38 12 . . . 2438 variant 2 M734 OSF-2: osteoblast specific factor 2 (fasciclin I-like), 39 40 12 . . . 2441 variant 3 M735 OSF-2: osteoblast specific factor 2 (fasciclin I-like), 41 42 12 . . . 2357 variant 4 M491A OSF-2: osteoblast specific factor 2 (fasciclin I-like), 43 44 12 . . . 2351 variant 5 M736 OSF-2: osteoblast specific factor 2 (fasciclin I-like), 45 46 12 . . . 2267 variant 6 M737 OSF-2: osteoblast specific factor 2 (fasciclin I-like), 47 48 12 . . . 2261 variant 7 M738 OSF-2: osteoblast specific factor 2 (fasciclin I-like), 49 50 12 . . . 2177 variant 8 M562 PIP: prolactin-induced protein 51 52 37 . . . 477 M96A SCUBE2: signal peptide, CUB domain, EGF-like 2, 53 54 81 . . . 3077 variant 1 M739 SCUBE2: signal peptide, CUB domain, EGF-like 2, 55 56 81 . . . 2837 variant 2 M740 SCUBE2: signal peptide, CUB domain, EGF-like 2, 57 58 81 . . . 2699 variant 3 M741 SCUBE2: signal peptide, CUB domain, EGF-like 2, 59 60 81 . . . 3164 variant 4 M242 TFF1: trefoil factor 1 (breast cancer, estrogen-inducible 61 62 41 . . . 295 sequence expressed in) M716 WFDC2: WAP four-desulfide core domain 2, variant 1 63 64 28 . . . 402 M717 WFDC2: WAP four-desulfide core domain 2, variant 2 65 66 67 . . . 288

TABLE-US-00002 TABLE 2 Breast Cancer Staging Markers SEQ ID SEQ ID NO NO Marker Gene Name (nts) (AAs) CDS M672A ASS: argininosuccinate synthetase 67 68 81 . . . 1319 M675A CAB2: hypothetical protein MGC9753 69 70 18 . . . 980 M367 CD24: CD24 antigen (small cell lung carcinoma 71 72 57 . . . 299 cluster 4 antigen) M514 DARPP-32: dopamine and cAMP regulated 73 74 236 . . . 742 phosphoprotein, (PPP1R1B: protein phosphatase 1, regulatory (inhibitor) subunit 1B), variant 1 M708 DARPP-32: dopamine and cAMP regulated 75 76 468 . . . 1082 phosphoprotein, (PPP1R1B: protein phosphatase 1, regulatory (inhibitor) subunit 1B), variant 2 M709 FACL2: fatty-acid-Coenzyme A ligase, long-chain 77 78 124 . . . 2220 2, variant 1 M710 FACL2: fatty-acid-Coenzyme A ligase, long-chain 79 80 188 . . . 2284 2, variant 2 M495 GSTP1: glutathione S-transferase pi 81 82 30 . . . 662 M674 HN1: hematological and neurological expressed 1 83 84 104 . . . 568 M234A MGC14832: hypothetical protein MGC14832 85 86 8 . . . 355 M408 NDRG1: N-myc downstream regulated protein 87 88 111 . . . 1295 M711 ORMDL3: ORM1-like 3 (S. cerevisiae) 89 90 301 . . . 762 M678A PSMB9: proteasome subunit, beta type, 9 91 92 52 . . . 711 M421A SERHL: kraken-like 93 94 103 . . . 1047 M185A SLPI: secretory leukocyte protease inhibitor 95 96 23 . . . 421 (antileukoproteinase)

DEFINITIONS

[0058] As used herein, each of the following terms has the meaning associated with it in this section.

[0059] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0060] A "marker" is a gene whose altered level of expression in a tissue or cell from its expression level in normal or healthy tissue or cell is associated with a disease state, such as cancer. A "marker nucleic acid" is a nucleic acid (e.g., mRNA, cDNA) encoded by or corresponding to a marker of the invention. Such marker nucleic acids include DNA (e.g., cDNA) comprising the entire or a partial sequence of any of SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 5, SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 19, SEQ ID NO: 21, SEQ ID NO: 23, SEQ ID NO: 25, SEQ ID NO: 27, SEQ ID NO: 29, SEQ ID NO: 31, SEQ ID NO: 33, SEQ ID NO: 35, SEQ ID NO: 37, SEQ ID NO: 39, SEQ ID NO: 41, SEQ ID NO: 43, SEQ ID NO: 45, SEQ ID NO: 47, SEQ ID NO: 49, SEQ ID NO: 51, SEQ ID NO: 53, SEQ ID NO: 55, SEQ ID NO: 57, SEQ ID NO: 59, SEQ ID NO: 61, SEQ ID NO: 63, SEQ ID NO: 65, SEQ ID NO: 67, SEQ ID NO: 69, SEQ ID NO: 71, SEQ ID NO: 73, SEQ ID NO: 75, SEQ ID NO: 77, SEQ ID NO: 79, SEQ ID NO: 81, SEQ ID NO: 83, SEQ ID NO: 85, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 91, SEQ ID NO: 93, or SEQ ID NO: 95 or the complement of such a sequence. The marker nucleic acids also include RNA comprising the entire or a partial sequence of any of SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 5, SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 19, SEQ ID NO: 21, SEQ ID NO: 23, SEQ ID NO: 25, SEQ ID NO: 27, SEQ ID NO: 29, SEQ ID NO: 31, SEQ ID NO: 33, SEQ ID NO: 35, SEQ ID NO: 37, SEQ ID NO: 39, SEQ ID NO: 41, SEQ ID NO: 43, SEQ ID NO: 45, SEQ ID NO: 47, SEQ ID NO: 49, SEQ ID NO: 51, SEQ ID NO: 53, SEQ ID NO: 55, SEQ ID NO: 57, SEQ ID NO: 59, SEQ ID NO: 61, SEQ ID NO: 63, SEQ ID NO: 65, SEQ ID NO: 67, SEQ ID NO: 69, SEQ ID NO: 71, SEQ ID NO: 73, SEQ ID NO: 75, SEQ ID NO: 77, SEQ ID NO: 79, SEQ ID NO: 81, SEQ ID NO: 83, SEQ ID NO: 85, SEQ ID NO: 87, SEQ ID NO: 89, SEQ ID NO: 91, SEQ ID NO: 93, or SEQ ID NO: 95 or the complement of such a sequence, wherein all thymidine residues are replaced with uridine residues. A "marker protein" is a protein encoded by or corresponding to a marker of the invention. A marker protein comprises the entire or a partial sequence of any of SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 20, SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 26, SEQ ID NO: 28, SEQ ID NO: 30, SEQ ID NO: 32, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 38, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 50, SEQ ID NO: 52, SEQ ID NO: 54, SEQ ID NO: 56, SEQ ID NO: 58, SEQ ID NO: 60, SEQ ID NO: 62, SEQ ID NO: 64, SEQ ID NO: 66, SEQ ID NO: 68, SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 74, SEQ ID NO: 76, SEQ ID NO: 78, SEQ ID NO: 80, SEQ ID NO: 82, SEQ ID NO: 84, SEQ ID NO: 86, SEQ ID NO: 88, SEQ ID NO: 90, SEQ ID NO: 92, SEQ ID NO: 94, and SEQ ID NO: 96. The terms "protein" and "polypeptide` are used interchangeably.

[0061] A "marker set" is a group of more than one marker.

[0062] The term "probe" refers to any molecule which is capable of selectively binding to a specifically intended target molecule, for example, a nucleotide transcript or protein encoded by or corresponding to a marker. Probes can be either synthesized by one skilled in the art, or derived from appropriate biological preparations. For purposes of detection of the target molecule, probes may be specifically designed to be labeled, as described herein. Examples of molecules that can be utilized as probes include, but are not limited to, RNA, DNA, proteins, antibodies, and organic molecules.

[0063] "Breast cancer" as used herein includes carcinomas, (e.g., carcinoma in situ, invasive carcinoma, metastatic carcinoma) and pre-malignant conditions.

[0064] A "breast-associated" body fluid is a fluid which, when in the body of a patient, contacts or passes through breast cells or into which cells, nucleic acids or proteins shed from breast cells are capable of passing. Exemplary breast-associated body fluids include blood fluids, lymph, cystic fluid, and nipple aspirates.

[0065] A "sample" or "patient sample" comprises cells obtained from the patient, e.g., a lump biopsy, body fluids including blood fluids, lymph and cystic fluids, as well as nipple aspirates. In a further embodiment, the patient sample is in vivo.

[0066] The "normal" level of expression of a marker is the level of expression of the marker in breast cells of a human subject or patient not afflicted with breast cancer.

[0067] An "over-expression" or "significantly higher level of expression" of a marker refers to an expression level in a test sample that is greater than the standard error of the assay employed to assess expression, and is preferably at least twice, and more preferably three, four, five or ten times the expression level of the marker in a control sample (e.g., sample from a healthy subjects not having the marker associated disease) and preferably, the average expression level of the marker in several control samples.

[0068] A "significantly lower level of expression" of a marker refers to an expression level in a test sample that is at least twice, and more preferably three, four, five or ten times lower than the expression level of the marker in a control sample (e.g., sample from a healthy subjects not having the marker associated disease) and preferably, the average expression level of the marker in several control samples.

[0069] As used herein, the term "promoter/regulatory sequence" means a nucleic acid sequence which is required for expression of a gene product operably linked to the promoter/regulatory sequence. In some instances, this sequence may be the core promoter sequence and in other instances, this sequence may also include an enhancer sequence and other regulatory elements which are required for expression of the gene product. The promoter/regulatory sequence may, for example, be one which expresses the gene product in a tissue-specific manner.

[0070] A "constitutive" promoter is a nucleotide sequence which, when operably linked with a polynucleotide which encodes or specifies a gene product, causes the gene product to be produced in a living human cell under most or all physiological conditions of the cell.

[0071] An "inducible" promoter is a nucleotide sequence which, when operably linked with a polynucleotide which encodes or specifies a gene product, causes the gene product to be produced in a living human cell substantially only when an inducer which corresponds to the promoter is present in the cell.

[0072] A "tissue-specific" promoter is a nucleotide sequence which, when operably linked with a polynucleotide which encodes or specifies a gene product, causes the gene product to be produced in a living human cell substantially only if the cell is a cell of the tissue type corresponding to the promoter.

[0073] A "transcribed polynucleotide" or "nucleotide transcript" is a polynucleotide (e.g., an mRNA, hnRNA, a cDNA, or an analog of such RNA or cDNA) which is complementary to or homologous with all or a portion of a mature mRNA made by transcription of a marker of the invention and normal post-transcriptional processing (e.g., splicing), if any, of the RNA transcript, and reverse transcription of the RNA transcript.

[0074] "Complementary" refers to the broad concept of sequence complementarity between regions of two nucleic acid strands or between two regions of the same nucleic acid strand. It is known that an adenine residue of a first nucleic acid region is capable of forming specific hydrogen bonds ("base pairing") with a residue of a second nucleic acid region which is antiparallel to the first region if the residue is thymine or uracil. Similarly, it is known that a cytosine residue of a first nucleic acid strand is capable of base pairing with a residue of a second nucleic acid strand which is antiparallel to the first strand if the residue is guanine. A first region of a nucleic acid is complementary to a second region of the same or a different nucleic acid if, when the two regions are arranged in an antiparallel fashion, at least one nucleotide residue of the first region is capable of base pairing with a residue of the second region. Preferably, the first region comprises a first portion and the second region comprises a second portion, whereby, when the first and second portions are arranged in an antiparallel fashion, at least about 50%, and preferably at least about 75%, at least about 90%, or at least about 95% of the nucleotide residues of the first portion are capable of base pairing with nucleotide residues in the second portion. More preferably, all nucleotide residues of the first portion are capable of base pairing with nucleotide residues in the second portion.

[0075] "Homologous" as used herein, refers to nucleotide sequence similarity between two regions of the same nucleic acid strand or between regions of two different nucleic acid strands. When a nucleotide residue position in both regions is occupied by the same nucleotide residue, then the regions are homologous at that position. A first region is homologous to a second region if at least one nucleotide residue position of each region is occupied by the same residue. Homology between two regions is expressed in terms of the proportion of nucleotide residue positions of the two regions that are occupied by the same nucleotide residue. By way of example, a region having the nucleotide sequence 5'-ATTGCC-3' and a region having the nucleotide sequence 5'-TATGGC-3' share 50% homology. Preferably, the first region comprises a first portion and the second region comprises a second portion, whereby, at least about 50%, and preferably at least about 75%, at least about 90%, or at least about 95% of the nucleotide residue positions of each of the portions are occupied by the same nucleotide residue. More preferably, all nucleotide residue positions of each of the portions are occupied by the same nucleotide residue.

[0076] A molecule is "fixed" or "affixed" to a substrate if it is covalently or non-covalently associated with the substrate such the substrate can be rinsed with a fluid (e.g., standard saline citrate, pH 7.4) without a substantial fraction of the molecule dissociating from the substrate.

[0077] As used herein, a "naturally-occurring" nucleic acid molecule refers to an RNA or DNA molecule having a nucleotide sequence that occurs in an organism found in nature.

[0078] A cancer is "inhibited" if at least one symptom of the cancer is alleviated, terminated, slowed, or prevented. As used herein, breast cancer is also "inhibited" if recurrence or metastasis of the cancer is reduced, slowed, delayed, or prevented.

[0079] A kit is any manufacture (e.g., a package or container) comprising at least one reagent, e.g., a probe, for specifically detecting the expression of a marker of the invention. The kit may be promoted, distributed, or sold as a unit for performing the methods of the present invention.

[0080] "Proteins of the invention" encompass marker proteins and their fragments; variant marker proteins and their fragments; peptides and polypeptides comprising an at least 15 amino acid segment of a marker or variant marker protein; and fusion proteins comprising a marker or variant marker protein, or an at least 15 amino acid segment of a marker or variant marker protein.

[0081] Unless otherwise specified herewithin, the terms "antibody" and "antibodies" broadly encompass naturally-occurring forms of antibodies (e.g., IgG, IgA, IgM, IgE) and recombinant antibodies such as single-chain antibodies, chimeric and humanized antibodies and multi-specific antibodies, as well as fragments and derivatives of all of the foregoing, which fragments and derivatives have at least an antigenic binding site. Antibody derivatives may comprise a protein or chemical moiety conjugated to an antibody.

[0082] The present invention is based, in part, on newly identified markers which are over-expressed in breast cancer cells as compared to their expression in normal (i.e., non-cancerous) breast cells. The enhanced expression of one or more of these markers in breast cells is herein correlated with the cancerous state of the tissue. The invention provides compositions, kits, and methods for assessing the cancerous state of breast cells (e.g., cells obtained from a human, cultured human cells, archived or preserved human cells and in vivo cells) as well as treating patients afflicted with breast cancer.

[0083] The compositions, kits, and methods of the invention have the following uses, among others:

[0084] assessing the status of breast cancer in a human patient;

[0085] assessing the stage of breast cancer in a human patient;

[0086] assessing the grade of breast cancer in a patient;

[0087] assessing the benign or malignant nature of breast cancer in a patient;

[0088] assessing the metastatic potential of breast cancer in a patient;

[0089] determining if breast cancer has metastasized to lymph nodes;

[0090] predicting the clinical outcome of a breast cancer patient;

[0091] assessing whether a patient is afflicted with breast cancer;

[0092] assessing the histological type of neoplasm associated with breast cancer in a patient;

[0093] making antibodies, antibody fragments or antibody derivatives that are useful for treating breast cancer and/or assessing whether a patient is afflicted with breast cancer;

[0094] assessing the presence of breast cancer cells;

[0095] assessing the efficacy of one or more test compounds for inhibiting breast cancer in a patient;

[0096] assessing the efficacy of a therapy for inhibiting breast cancer in a patient;

[0097] monitoring the progression of breast cancer in a patient;

[0098] selecting a composition or therapy for inhibiting breast cancer in a patient;

[0099] treating a patient afflicted with breast cancer;

[0100] inhibiting breast cancer in a patient;

[0101] assessing the breast carcinogenic potential of a test compound; and

[0102] preventing the onset of breast cancer in a patient at risk for developing breast cancer.

[0103] The invention thus includes a method of assessing breast cancer cells in a patient afflicted with breast cancer. This method comprises comparing the level of expression of a marker of the invention (listed in Table 1) in a patient sample and the normal level of expression of the marker in a control, e.g., a non-breast cancer sample or a non-cancer, normal sample. A significantly higher level of expression of the marker in the patient sample as compared to the normal level of expression is an indication that the patient is afflicted with a breast tumor.

[0104] Additionally provided is a method of assessing aggressiveness of breast cancer cells in a patient afflicted with breast cancer. The method comprises comparing the level of expression of a marker of the invention (listed in Table 2) in a patient sample and the normal level of expression of the marker in a control, e.g., a non-breast cancer sample or an indolent breast cancer sample. A significantly higher level of expression of the marker in the patient sample as compared to the normal level of expression is an indication that the patient is afflicted with an aggressive breast tumor.

[0105] Gene delivery vehicles, host cells and compositions (all described herein) containing nucleic acids comprising the entirety, or a segment of 15 or more nucleotides, of any of the sequences of the invention (e.g., SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 5, SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 19, SEQ ID NO: 21, SEQ ID NO: 23, SEQ ID NO: 25, SEQ ID NO: 27, SEQ ID NO: 29, SEQ ID NO: 31, SEQ ID NO: 33, SEQ ID NO: 35, SEQ ID NO: 37, SEQ ID NO: 39, SEQ ID NO: 41, SEQ ID NO: 43, SEQ ID NO: 45, SEQ ID NO: 47, SEQ ID NO: 49, SEQ ID NO: 51, SEQ ID NO: 53, SEQ ID NO: 55, SEQ ID NO: 57, SEQ ID NO: 59, SEQ ID NO: 61, SEQ ID NO: 63, and SEQ ID NO: 65) or the complement of such sequences, and polypeptides comprising the entirety, or a segment of 10 or more amino acids, of any of the sequences of SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 20, SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 26, SEQ ID NO: 28, SEQ ID NO: 30, SEQ ID NO: 32, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 38, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 50, SEQ ID NO: 52, SEQ ID NO: 54, SEQ ID NO: 56, SEQ ID NO: 58, SEQ ID NO: 60, SEQ ID NO: 62, SEQ ID NO: 64, SEQ ID NO: 66, SEQ ID NO: 68, SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 74, SEQ ID NO: 76, SEQ ID NO: 78, SEQ ID NO: 80, SEQ ID NO: 82, SEQ ID NO: 84, SEQ ID NO: 86, SEQ ID NO: 88, SEQ ID NO: 90, SEQ ID NO: 92, SEQ ID NO: 94, and SEQ ID NO: 96 are also provided by this invention.

[0106] As described herein, breast cancer in patients is associated with an increased level of expression of one or more markers of the invention. While, as discussed above, some of these changes in expression level result from occurrence of the breast cancer, others of these changes induce, maintain, and promote the cancerous state of breast cancer cells. Thus, breast cancer characterized by an increase in the level of expression of one or more markers of the invention can be inhibited by reducing and/or interfering with the expression of the markers and/or function of the proteins encoded by those markers.

[0107] Expression of a marker of the invention can be inhibited in a number of ways generally known in the art. For example, an RNA interference oligonucleotide or an antisense oligonucleotide can be provided to the breast cancer cells in order to inhibit transcription, translation, or both, of the marker(s). Alternately, a polynucleotide encoding an antibody, an antibody derivative, or an antibody fragment which specifically binds a marker protein, and operably linked with an appropriate promoter/regulator region, can be provided to the cell in order to generate intracellular antibodies which will inhibit the function or activity of the protein. The expression and/or function of a marker may also be inhibited by treating the breast cancer cell with a peptide or an antibody, antibody derivative or antibody fragment that specifically binds a marker protein. Using the methods described herein, a variety of molecules, particularly including molecules sufficiently small that they are able to cross the cell membrane, can be screened in order to identify molecules which inhibit expression of a marker or inhibit the function of a marker protein. The compound so identified can be provided to the patient in order to inhibit breast cancer cells of the patient.

[0108] Any marker or combination of markers of the invention, as well as any known markers in combination with the markers of the invention, may be used in the compositions, kits, and methods of the present invention. In general, it is preferable to use markers for which the difference between the level of expression of the marker in breast cancer cells and the level of expression of the same marker in normal breast cells is as great as possible. Although this difference can be as small as the limit of detection of the method for assessing expression of the marker, it is preferred that the difference be at least greater than the standard error of the assessment method, and preferably a difference of at least 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 25-, 100-, 500-, 1000-fold or greater than the level of expression of the same marker in normal breast tissue.

[0109] It is recognized that certain marker proteins are secreted from breast cells (i.e., one or both of normal and cancerous cells) to the extracellular space surrounding the cells. These markers are preferably used in certain embodiments of the compositions, kits, and methods of the invention, owing to the fact that the such marker proteins can be detected in a breast-associated body fluid sample, which may be more easily collected from a human patient than a tissue biopsy sample. In addition, preferred in vivo techniques for detection of a marker protein include introducing into a subject a labeled antibody directed against the protein. For example, the antibody can be labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques.

[0110] It is a simple matter for the skilled artisan to determine whether any particular marker protein is a secreted protein. In order to make this determination, the marker protein is expressed in, for example, a mammalian cell, preferably a human breast cell line, extracellular fluid is collected, and the presence or absence of the protein in the extracellular fluid is assessed (e.g., using a labeled antibody which binds specifically with the protein).

[0111] The following is one example of a method which can be used to detect secretion of a protein: About 8.times.10.sup.5 293T cells are incubated at 37.degree. C. in wells containing growth medium (Dulbecco's modified Eagle's medium {DMEM} supplemented with 10% fetal bovine serum) under a 5% (v/v) CO.sub.2, 95% air atmosphere to about 60-70% confluence. The cells are then transfected using a standard transfection mixture comprising 2 micrograms of DNA comprising an expression vector encoding the protein and 10 microliters of LipofectAMINE.TM. (GIBCO/BRL Catalog no. 18342-012) per well. The transfection mixture is maintained for about 5 hours, and then replaced with fresh growth medium and maintained in an air atmosphere. Each well is gently rinsed twice with DMEM which does not contain methionine or cysteine (DMEM-MC; ICN Catalog no. 16-424-54). About 1 milliliter of DMEM-MC and about 50 microcuries of Trans-.sup.35S.TM. reagent (ICN Catalog no. 51006) are added to each well. The wells are maintained under the 5% CO.sub.2 atmosphere described above and incubated at 37.degree. C. for a selected period. Following incubation, 150 microliters of conditioned medium is removed and centrifuged to remove floating cells and debris. The presence of the protein in the supernatant is an indication that the protein is secreted. Additional and alternative methods for detection of secreted proteins are known in the art and can be used in addition to, or alternative to this method.

[0112] It will be appreciated that patient samples containing breast cells may be used in the methods of the present invention. In these embodiments, the level of expression of the marker can be determined by assessing the amount (e.g., absolute amount or concentration) of the marker in a breast cell sample, e.g., breast biopsies obtained from a patient. The cell sample can, of course, be subjected to a variety of well-known post-collection preparative and storage techniques (e.g., nucleic acid and/or protein extraction, fixation, storage, freezing, ultrafiltration, concentration, evaporation, centrifugation, etc.) prior to assessing the amount of the marker in the sample. Likewise, breast biopsies may also be subjected to post-collection preparative and storage techniques, e.g., fixation.

[0113] The compositions, kits, and methods of the invention can be used to detect expression of marker proteins having at least one portion which is displayed on the surface of cells which express it. It is a simple matter for the skilled artisan to determine whether a marker protein, or a portion thereof, is exposed on the cell surface. For example, immunological methods may be used to detect such proteins on whole cells, or well known computer-based sequence analysis methods may be used to predict the presence of at least one extracellular domain (i.e., including both secreted proteins and proteins having at least one cell-surface domain). Expression of a marker protein having at least one portion which is displayed on the surface of a cell which expresses it may be detected without necessarily lysing the cell (e.g., using a labeled antibody which binds specifically with a cell-surface domain of the protein).

[0114] Expression of a marker of the invention may be assessed by any of a wide variety of well known methods for detecting expression of a transcribed nucleic acid or protein. Non-limiting examples of such methods include immunological methods for detection of secreted, cell-surface, cytoplasmic, or nuclear proteins, protein purification methods, protein function or activity assays, nucleic acid hybridization methods, nucleic acid reverse transcription methods, and nucleic acid amplification methods.

[0115] In a preferred embodiment, expression of a marker is assessed using an antibody (e.g., a radio-labeled, chromophore-labeled, fluorophore-labeled, or enzyme-labeled antibody), an antibody derivative (e.g., an antibody conjugated with a substrate or with the protein or ligand of a protein-ligand pair {e.g., biotin-streptavidin}), or an antibody fragment (e.g., a single-chain antibody, an isolated antibody hypervariable domain, etc.) which binds specifically with a marker protein or fragment thereof, including a marker protein which has undergone all or a portion of its normal post-translational modification.

[0116] In another preferred embodiment, expression of a marker is assessed by preparing mRNA/cDNA (i.e., a transcribed polynucleotide) from cells in a patient sample, and by hybridizing the mRNA/cDNA with a reference polynucleotide which is a complement of a marker nucleic acid, or a fragment thereof. cDNA can, optionally, be amplified using any of a variety of polymerase chain reaction methods prior to hybridization with the reference polynucleotide; preferably, it is not amplified. Expression of one or more markers can likewise be detected using quantitative PCR to assess the level of expression of the marker(s). Alternatively, any of the many known methods of detecting mutations or variants (e.g., single nucleotide polymorphisms, deletions, etc.) of a marker of the invention may be used to detect occurrence of a marker in a patient.

[0117] In a related embodiment, a mixture of transcribed polynucleotides obtained from the sample is contacted with a substrate having fixed thereto a polynucleotide complementary to or homologous with at least a portion (e.g., at least 7, 10, 15, 20, 25, 30, 40, 50, 100, 500, or more nucleotide residues) of a marker nucleic acid. If polynucleotides complementary to or homologous with are differentially detectable on the substrate (e.g., detectable using different chromophores or fluorophores, or fixed to different selected positions), then the levels of expression of a plurality of markers can be assessed simultaneously using a single substrate (e.g., a "gene chip" microarray of polynucleotides fixed at selected positions). When a method of assessing marker expression is used which involves hybridization of one nucleic acid with another, it is preferred that the hybridization be performed under stringent hybridization conditions.

[0118] Because the compositions, kits, and methods of the invention rely on detection of a difference in expression levels of one or more markers of the invention, it is preferable that the level of expression of the marker is significantly greater than the minimum detection limit of the method used to assess expression in at least one of normal breast cells and cancerous breast cells.

[0119] It is understood that by routine screening of additional patient samples using one or more of the markers of the invention, it will be realized that certain of the markers are over-expressed in cancers of various types, including specific breast cancers, as well as other cancers such as lung cancer, ovarian cancer, etc. For example, it will be confirmed that some of the markers of the invention are over-expressed in most (i.e., 50% or more) or substantially all (i.e., 80% or more) of breast cancer. The compositions, kits, and methods of the invention are thus useful for characterizing the benign or malignant nature of breast tumors in patients.

[0120] Furthermore, it will be confirmed that certain of the markers of the invention are associated with breast cancer of various stages (i.e., stage 0, I, II, II, and IV breast cancers, as well as subclassifications IIA, IIB, IIIA, and IIIB, using the FIGO Stage Grouping system for primary carcinoma of the breast; (see Breast, In: American Joint Committee on Cancer: AJCC Cancer Staging Manual. Lippincott-Raven Publishers, 5th ed., 1997, pp. 171-180), of various histologic subtypes (e.g., serous, mucinous, endometroid, and clear cell subtypes, as well as subclassifications and alternate classifications adenocarcinoma, papillary adenocarcinoma, papillary cystadenocarcinoma, surface papillary carcinoma, malignant adenofibroma, cystadenofibroma, adenocarcinoma, cystadenocarcinoma, adenoacanthoma, endometrioid stromal sarcoma, mesodermal (Mullerian) mixed tumor, mesonephroid tumor, malignant carcinoma, Brenner tumor, mixed epithelial tumor, and undifferentiated carcinoma, using the WHO/FIGO system for classification of malignant breast tumors; Scully, Atlas of Tumor Pathology, 3d series, Washington D.C.), and various grades (i.e., grade I {well differentiated}, grade II {moderately well differentiated}, and grade III {poorly differentiated from surrounding normal tissue})). In addition, as a greater number of patient samples are assessed for expression of the markers of the invention and the outcomes of the individual patients from whom the samples were obtained are correlated, it will also be confirmed that altered expression of certain of the markers of the invention are strongly correlated with malignant cancers and that altered expression of other markers of the invention are strongly correlated with benign tumors. The compositions, kits, and methods of the invention are thus useful for characterizing one or more of the stage, grade, histological type, and benign/malignant nature of breast cancer in patients.

[0121] When the compositions, kits, and methods of the invention are used for characterizing the one or more of the stage, grade, histological type, and benign or malignant nature of breast tumors in a patient, it is preferred that the marker or panel of markers of the invention is selected such that a positive result is obtained in at least about 20%, and preferably at least about 40%, 60%, or 80%, and more preferably in substantially all patients afflicted with a breast tumor of the corresponding stage, grade, histological type, or benign or malignant nature. Preferably, the marker or panel of markers of the invention is selected such that a positive predictive value (PPV) of greater than about 10% is obtained for the general population (more preferably coupled with an assay specificity greater than 80%).

[0122] When a plurality of markers of the invention are used in the compositions, kits, and methods of the invention, the level of expression of each marker in a patient sample can be compared with the normal level of expression of each of the plurality of markers in non-cancerous samples of the same type, either in a single reaction mixture (i.e., using reagents, such as different fluorescent probes, for each marker) or in individual reaction mixtures corresponding to one or more of the markers. In one embodiment, a significantly increased level of expression of more than one of the plurality of markers in the sample, relative to the corresponding normal levels, is an indication that the patient is afflicted with breast cancer. When a plurality of markers is used, it is preferred that 2, 3, 4, 5, 8, 10, 12, or 15, or more individual markers be used. Still further markers can be used to include a marker set wherein at least 20, 25, 30, 40, 50, or more individual markers are used.

[0123] In order to maximize the sensitivity of the compositions, kits, and methods of the invention (i.e., by interference attributable to cells of non-breast origin in a patient sample), it is preferable that the marker of the invention used therein be a marker which has a restricted tissue distribution, e.g., normally not expressed in a non-breast tissue.

[0124] Only a small number of markers are known to be associated with breast cancers (e.g., BRCA1 and BRCA2). These markers are not, of course, included among the markers of the invention, although they may be used together with one or more markers of the invention in a panel of markers, for example. It is well known that certain types of genes, such as oncogenes, tumor suppressor genes, growth factor-like genes, protease-like genes, and protein kinase-like genes are often involved with development of cancers of various types. Thus, among the markers of the invention, use of those which correspond to proteins which resemble known proteins encoded by known oncogenes and tumor suppressor genes, and those which correspond to proteins which resemble growth factors, proteases, and protein kinases are preferred.

[0125] It is recognized that the compositions, kits, and methods of the invention will be of particular utility to patients having an enhanced risk of developing breast cancer and their medical advisors. Patients recognized as having an enhanced risk of developing breast cancer include, for example, patients having a familial history of breast cancer, patients identified as having a mutant oncogene (i.e., at least one allele), and patients of advancing age (i.e., women older than about 50 or 60 years).

[0126] The level of expression of a marker in normal (i.e., non-cancerous) breast tissue can be assessed in a variety of ways. In one embodiment, this normal level of expression is determined by assessing the level of expression of the marker in a portion of breast cells which appears to be non-cancerous and by comparing this normal level of expression with the level of expression in a portion of the breast cells which is suspected of being cancerous. Alternately, and particularly as further information becomes available as a result of routine performance of the methods described herein, population-average values for normal expression of the markers of the invention may be used. In other embodiments, the `normal` level of expression of a marker may be determined by assessing expression of the marker in a patient sample obtained from a non-cancer-afflicted patient, from a patient sample obtained from a patient before the suspected onset of breast cancer in the patient, from archived patient samples, and the like.

[0127] The invention includes compositions, kits, and methods for assessing the presence of breast cancer cells in a sample (e.g., an archived tissue sample or a sample obtained from a patient). These compositions, kits, and methods are substantially the same as those described above, except that, where necessary, the compositions, kits, and methods are adapted for use with samples other than patient samples. For example, when the sample to be used is a parafinized, archived human tissue sample, it can be necessary to adjust the ratio of compounds in the compositions of the invention, in the kits of the invention, or the methods used to assess levels of marker expression in the sample. Such methods are well known in the art and within the skill of the ordinary artisan.

[0128] The invention includes a kit for assessing the presence of breast cancer cells (e.g., in a sample such as a patient sample). The kit comprises a plurality of reagents, each of which is capable of binding specifically with a marker nucleic acid or protein. Suitable reagents for binding with a marker protein include antibodies, antibody derivatives, antibody fragments, and the like. Suitable reagents for binding with a marker nucleic acid (e.g., a genomic DNA, an mRNA, a spliced mRNA, a cDNA, or the like) include complementary nucleic acids. For example, the nucleic acid reagents may include oligonucleotides (labeled or non-labeled) fixed to a substrate, labeled oligonucleotides not bound with a substrate, pairs of PCR primers, molecular beacon probes, and the like.

[0129] The kit of the invention may optionally comprise additional components useful for performing the methods of the invention. By way of example, the kit may comprise fluids (e.g., SSC buffer) suitable for annealing complementary nucleic acids or for binding an antibody with a protein with which it specifically binds, one or more sample compartments, an instructional material which describes performance of a method of the invention, a sample of normal breast cells, a sample of breast cancer cells, and the like.

[0130] The invention also includes a method of making an isolated hybridoma which produces an antibody useful for assessing whether a patient is afflicted with breast cancer. In this method, a protein or peptide comprising the entirety or a segment of a marker protein is synthesized or isolated (e.g., by purification from a cell in which it is expressed or by transcription and translation of a nucleic acid encoding the protein or peptide in vivo or in vitro using known methods). A vertebrate, preferably a mammal such as a mouse, rat, rabbit, or sheep, is immunized using the protein or peptide. The vertebrate may optionally (and preferably) be immunized at least one additional time with the protein or peptide, so that the vertebrate exhibits a robust immune response to the protein or peptide. Splenocytes are isolated from the immunized vertebrate and fused with an immortalized cell line to form hybridomas, using any of a variety of methods well known in the art. Hybridomas formed in this manner are then screened using standard methods to identify one or more hybridomas which produce an antibody which specifically binds with the marker protein or a fragment thereof. The invention also includes hybridomas made by this method and antibodies made using such hybridomas.

[0131] The invention also includes a method of assessing the efficacy of a test compound for inhibiting breast cancer cells. As described above, differences in the level of expression of the markers of the invention correlate with the cancerous state of breast cells. Although it is recognized that changes in the levels of expression of certain of the markers of the invention likely result from the cancerous state of breast cells, it is likewise recognized that changes in the levels of expression of other of the markers of the invention induce, maintain, and promote the cancerous state of those cells. Thus, compounds which inhibit a breast cancer in a patient will cause the level of expression of one or more of the markers of the invention to change to a level nearer the normal level of expression for that marker (i.e., the level of expression for the marker in non-cancerous breast cells).

[0132] This method thus comprises comparing expression of a marker in a first breast cell sample and maintained in the presence of the test compound and expression of the marker in a second breast cell sample and maintained in the absence of the test compound. A significantly reduced expression of a marker of the invention in the presence of the test compound is an indication that the test compound inhibits breast cancer. The breast cell samples may, for example, be aliquots of a single sample of normal breast cells obtained from a patient, pooled samples of normal breast cells obtained from a patient, cells of a normal breast cell line, aliquots of a single sample of breast cancer cells obtained from a patient, pooled samples of breast cancer cells obtained from a patient, cells of a breast cancer cell line, or the like. In one embodiment, the samples are breast cancer cells obtained from a patient and one or more of a plurality of compounds known to be effective for inhibiting various breast cancers are tested in order to identify the compound which is likely to best inhibit the breast cancer in the patient.

[0133] This method may likewise be used to assess the efficacy of a therapy for inhibiting breast cancer in a patient. In this method, the level of expression of one or more markers of the invention in a pair of samples (one subjected to the therapy, the other not subjected to the therapy) is assessed. As with the method of assessing the efficacy of test compounds, if the therapy induces a significantly lower level of expression of a marker of the invention, then the therapy is efficacious for inhibiting breast cancer. As above, if samples from a selected patient are used in this method, then alternative therapies can be assessed in vitro in order to select a therapy most likely to be efficacious for inhibiting breast cancer in the patient.

[0134] As described above, the cancerous state of human breast cells is correlated with changes in the levels of expression of the markers of the invention. The invention includes a method for assessing the human breast cell carcinogenic potential of a test compound. This method comprises maintaining separate aliquots of human breast cells in the presence and absence of the test compound. Expression of a marker of the invention in each of the aliquots is compared. A significantly higher level of expression of a marker of the invention in the aliquot maintained in the presence of the test compound (relative to the aliquot maintained in the absence of the test compound) is an indication that the test compound possesses human breast cell carcinogenic potential. The relative carcinogenic potentials of various test compounds can be assessed by comparing the degree of enhancement or inhibition of the level of expression of the relevant markers, by comparing the number of markers for which the level of expression is enhanced or inhibited, or by comparing both.

[0135] Various aspects of the invention are described in further detail in the following subsections.

Isolated Nucleic Acid Molecules

[0136] One aspect of the invention pertains to isolated nucleic acid molecules, including nucleic acids which encode a marker protein or a portion thereof. Isolated nucleic acids of the invention also include nucleic acid molecules sufficient for use as hybridization probes to identify marker nucleic acid molecules, and fragments of marker nucleic acid molecules, e.g., those suitable for use as PCR primers for the amplification or mutation of marker nucleic acid molecules. As used herein, the term "nucleic acid molecule" is intended to include DNA molecules (e.g., cDNA or genomic DNA) and RNA molecules (e.g., mRNA) and analogs of the DNA or RNA generated using nucleotide analogs. The nucleic acid molecule can be single-stranded or double-stranded, but preferably is double-stranded DNA.

[0137] An "isolated" nucleic acid molecule is one which is separated from other nucleic acid molecules which are present in the natural source of the nucleic acid molecule. Preferably, an "isolated" nucleic acid molecule is free of sequences (preferably protein-encoding sequences) which naturally flank the nucleic acid (i.e., sequences located at the 5' and 3' ends of the nucleic acid) in the genomic DNA of the organism from which the nucleic acid is derived. For example, in various embodiments, the isolated nucleic acid molecule can contain less than about 5 kB, 4 kB, 3 kB, 2 kB, 1 kB, 0.5 kB or 0.1 kB of nucleotide sequences which naturally flank the nucleic acid molecule in genomic DNA of the cell from which the nucleic acid is derived. Moreover, an "isolated" nucleic acid molecule, such as a cDNA molecule, can be substantially free of other cellular material, or culture medium when produced by recombinant techniques, or substantially free of chemical precursors or other chemicals when chemically synthesized.

[0138] A nucleic acid molecule of the present invention can be isolated using standard molecular biology techniques and the sequence information in the database records described herein. Using all or a portion of such nucleic acid sequences, nucleic acid molecules of the invention can be isolated using standard hybridization and cloning techniques (e.g., as described in Sambrook et al., ed., Molecular Cloning: A Laboratory Manual, 2nd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989).

[0139] A nucleic acid molecule of the invention can be amplified using cDNA, mRNA, or genomic DNA as a template and appropriate oligonucleotide primers according to standard PCR amplification techniques. The nucleic acid so amplified can be cloned into an appropriate vector and characterized by DNA sequence analysis. Furthermore, nucleotides corresponding to all or a portion of a nucleic acid molecule of the invention can be prepared by standard synthetic techniques, e.g., using an automated DNA synthesizer.

[0140] In another preferred embodiment, an isolated nucleic acid molecule of the invention comprises a nucleic acid molecule which has a nucleotide sequence complementary to the nucleotide sequence of a marker nucleic acid or to the nucleotide sequence of a nucleic acid encoding a marker protein. A nucleic acid molecule which is complementary to a given nucleotide sequence is one which is sufficiently complementary to the given nucleotide sequence that it can hybridize to the given nucleotide sequence thereby forming a stable duplex.

[0141] Moreover, a nucleic acid molecule of the invention can comprise only a portion of a nucleic acid sequence, wherein the full length nucleic acid sequence comprises a marker nucleic acid or which encodes a marker protein. Such nucleic acids can be used, for example, as a probe or primer. The probe/primer typically is used as one or more substantially purified oligonucleotides. The oligonucleotide typically comprises a region of nucleotide sequence that hybridizes under stringent conditions to at least about 7, preferably about 15, more preferably about 25, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350, or 400 or more consecutive nucleotides of a nucleic acid of the invention.

[0142] Probes based on the sequence of a nucleic acid molecule of the invention can be used to detect transcripts or genomic sequences corresponding to one or more markers of the invention. The probe comprises a label group attached thereto, e.g., a radioisotope, a fluorescent compound, an enzyme, or an enzyme co-factor. Such probes can be used as part of a diagnostic test kit for identifying cells or tissues which mis-express the protein, such as by measuring levels of a nucleic acid molecule encoding the protein in a sample of cells from a subject, e.g., detecting mRNA levels or determining whether a gene encoding the protein has been mutated or deleted.

[0143] The invention further encompasses nucleic acid molecules that differ, due to degeneracy of the genetic code, from the nucleotide sequence of nucleic acids encoding a marker protein (e.g., protein having the sequence of SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 20, SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 26, SEQ ID NO: 28, SEQ ID NO: 30, SEQ ID NO: 32, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 38, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 50, SEQ ID NO: 52, SEQ ID NO: 54, SEQ ID NO: 56, SEQ ID NO: 58, SEQ ID NO: 60, SEQ ID NO: 62, SEQ ID NO: 64, SEQ ID NO: 66, SEQ ID NO: 68, SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 74, SEQ ID NO: 76, SEQ ID NO: 78, SEQ ID NO: 80, SEQ ID NO: 82, SEQ ID NO: 84, SEQ ID NO: 86, SEQ ID NO: 88, SEQ ID NO: 90, SEQ ID NO: 92, SEQ ID NO: 94, and SEQ ID NO: 96), and thus encode the same protein.

[0144] It will be appreciated by those skilled in the art that DNA sequence polymorphisms that lead to changes in the amino acid sequence can exist within a population (e.g., the human population). Such genetic polymorphisms can exist among individuals within a population due to natural allelic variation. An allele is one of a group of genes which occur alternatively at a given genetic locus. In addition, it will be appreciated that DNA polymorphisms that affect RNA expression levels can also exist that may affect the overall expression level of that gene (e.g., by affecting regulation or degradation).

[0145] As used herein, the phrase "allelic variant" refers to a nucleotide sequence which occurs at a given locus or to a polypeptide encoded by the nucleotide sequence.

[0146] As used herein, the terms "gene" and "recombinant gene" refer to nucleic acid molecules comprising an open reading frame encoding a polypeptide corresponding to a marker of the invention. Such natural allelic variations can typically result in 1-5% variance in the nucleotide sequence of a given gene. Alternative alleles can be identified by sequencing the gene of interest in a number of different individuals. This can be readily carried out by using hybridization probes to identify the same genetic locus in a variety of individuals. Any and all such nucleotide variations and resulting amino acid polymorphisms or variations that are the result of natural allelic variation and that do not alter the functional activity are intended to be within the scope of the invention.

[0147] In another embodiment, an isolated nucleic acid molecule of the invention is at least 7, 15, 20, 25, 30, 40, 60, 80, 100, 150, 200, 250, 300, 350, 400, 450, 550, 650, 700, 800, 900, 1000, 1200, 1400, 1600, 1800, 2000, 2200, 2400, 2600, 2800, 3000, 3500, 4000, 4500, or more nucleotides in length and hybridizes under stringent conditions to a marker nucleic acid or to a nucleic acid encoding a marker protein. As used herein, the term "hybridizes under stringent conditions" is intended to describe conditions for hybridization and washing under which nucleotide sequences at least 60% (65%, 70%, preferably 75%) identical to each other typically remain hybridized to each other. Such stringent conditions are known to those skilled in the art and can be found in sections 6.3.1-6.3.6 of Current Protocols in Molecular Biology, John Wiley & Sons, N.Y. (1989). A preferred, non-limiting example of stringent hybridization conditions are hybridization in 6.times. sodium chloride/sodium citrate (SSC) at about 45.degree. C., followed by one or more washes in 0.2.times.SSC, 0.1% SDS at 50-65.degree. C.

[0148] In addition to naturally-occurring allelic variants of a nucleic acid molecule of the invention that can exist in the population, the skilled artisan will further appreciate that sequence changes can be introduced by mutation thereby leading to changes in the amino acid sequence of the encoded protein, without altering the biological activity of the protein encoded thereby. For example, one can make nucleotide substitutions leading to amino acid substitutions at "non-essential" amino acid residues. A "non-essential" amino acid residue is a residue that can be altered from the wild-type sequence without altering the biological activity, whereas an "essential" amino acid residue is required for biological activity. For example, amino acid residues that are not conserved or only semi-conserved among homologs of various species may be non-essential for activity and thus would be likely targets for alteration. Alternatively, amino acid residues that are conserved among the homologs of various species (e.g., murine and human) may be essential for activity and thus would not be likely targets for alteration.

[0149] Accordingly, another aspect of the invention pertains to nucleic acid molecules encoding a variant marker protein that contain changes in amino acid residues that are not essential for activity. Such variant marker proteins differ in amino acid sequence from the naturally-occurring marker proteins, yet retain biological activity. In one embodiment, such a variant marker protein has an amino acid sequence that is at least about 40% identical, 50%, 60%, 70%, 80%, 90%, 95%, or 98% identical to the amino acid sequence of a marker protein.

[0150] An isolated nucleic acid molecule encoding a variant marker protein can be created by introducing one or more nucleotide substitutions, additions or deletions into the nucleotide sequence of marker nucleic acids, such that one or more amino acid residue substitutions, additions, or deletions are introduced into the encoded protein. Mutations can be introduced by standard techniques, such as site-directed mutagenesis and PCR-mediated mutagenesis. Preferably, conservative amino acid substitutions are made at one or more predicted non-essential amino acid residues. A "conservative amino acid substitution" is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), non-polar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Alternatively, mutations can be introduced randomly along all or part of the coding sequence, such as by saturation mutagenesis, and the resultant mutants can be screened for biological activity to identify mutants that retain activity. Following mutagenesis, the encoded protein can be expressed recombinantly and the activity of the protein can be determined.

[0151] The present invention encompasses antisense nucleic acid molecules, i.e., molecules which are complementary to a sense nucleic acid of the invention, e.g., complementary to the coding strand of a double-stranded marker cDNA molecule or complementary to a marker mRNA sequence. Accordingly, an antisense nucleic acid of the invention can hydrogen bond to (i.e., anneal with) a sense nucleic acid of the invention. The antisense nucleic acid can be complementary to an entire coding strand, or to only a portion thereof, e.g., all or part of the protein coding region (or open reading frame). An antisense nucleic acid molecule can also be antisense to all or part of a non-coding region of the coding strand of a nucleotide sequence encoding a marker protein. The non-coding regions ("5' and 3' untranslated regions") are the 5' and 3' sequences which flank the coding region and are not translated into amino acids.

[0152] An antisense oligonucleotide can be, for example, about 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 or more nucleotides in length. An antisense nucleic acid of the invention can be constructed using chemical synthesis and enzymatic ligation reactions using procedures known in the art. For example, an antisense nucleic acid (e.g., an antisense oligonucleotide) can be chemically synthesized using naturally occurring nucleotides or variously modified nucleotides designed to increase the biological stability of the molecules or to increase the physical stability of the duplex formed between the antisense and sense nucleic acids, e.g., phosphorothioate derivatives and acridine substituted nucleotides can be used. Examples of modified nucleotides which can be used to generate the antisense nucleic acid include 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine, 5'-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N-6-isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v), 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w, and 2,6-diaminopurine. Alternatively, the antisense nucleic acid can be produced biologically using an expression vector into which a nucleic acid has been sub-cloned in an antisense orientation (i.e., RNA transcribed from the inserted nucleic acid will be of an antisense orientation to a target nucleic acid of interest, described further in the following subsection).

[0153] The antisense nucleic acid molecules of the invention are typically administered to a subject or generated in situ such that they hybridize with or bind to cellular mRNA and/or genomic DNA encoding a marker protein to thereby inhibit expression of the marker, e.g., by inhibiting transcription and/or translation. The hybridization can be by conventional nucleotide complementarity to form a stable duplex, or, for example, in the case of an antisense nucleic acid molecule which binds to DNA duplexes, through specific interactions in the major groove of the double helix. Examples of a route of administration of antisense nucleic acid molecules of the invention includes direct injection at a tissue site or infusion of the antisense nucleic acid into a breast-associated body fluid. Alternatively, antisense nucleic acid molecules can be modified to target selected cells and then administered systemically. For example, for systemic administration, antisense molecules can be modified such that they specifically bind to receptors or antigens expressed on a selected cell surface, e.g., by linking the antisense nucleic acid molecules to peptides or antibodies which bind to cell surface receptors or antigens. The antisense nucleic acid molecules can also be delivered to cells using the vectors described herein. To achieve sufficient intracellular concentrations of the antisense molecules, vector constructs in which the antisense nucleic acid molecule is placed under the control of a strong pol II or pol III promoter are preferred.

[0154] An antisense nucleic acid molecule of the invention can be an .alpha.-anomeric nucleic acid molecule. An .alpha.-anomeric nucleic acid molecule forms specific double-stranded hybrids with complementary RNA in which, contrary to the usual .alpha.-units, the strands run parallel to each other (Gaultier et al., 1987, Nucleic Acids Res. 15:6625-6641). The antisense nucleic acid molecule can also comprise a 2'-o-methylribonucleotide (Inoue et al., 1987, Nucleic Acids Res. 15:6131-6148) or a chimeric RNA-DNA analogue (Inoue et al., 1987, FEBS Lett. 215:327-330).

[0155] The invention also encompasses ribozymes. Ribozymes are catalytic RNA molecules with ribonuclease activity which are capable of cleaving a single-stranded nucleic acid, such as an mRNA, to which they have a complementary region. Thus, ribozymes (e.g., hammerhead ribozymes as described in Haselhoff and Gerlach, 1988, Nature 334:585-591) can be used to catalytically cleave mRNA transcripts to thereby inhibit translation of the protein encoded by the mRNA. A ribozyme having specificity for a nucleic acid molecule encoding a marker protein can be designed based upon the nucleotide sequence of a cDNA corresponding to the marker. For example, a derivative of a Tetrahymena L-19 IVS RNA can be constructed in which the nucleotide sequence of the active site is complementary to the nucleotide sequence to be cleaved (see Cech et al. U.S. Pat. No. 4,987,071; and Cech et al. U.S. Pat. No. 5,116,742). Alternatively, an mRNA encoding a polypeptide of the invention can be used to select a catalytic RNA having a specific ribonuclease activity from a pool of RNA molecules (see, e.g., Bartel and Szostak, 1993, Science 261:1411-1418).

[0156] The invention also encompasses nucleic acid molecules which form triple helical structures. For example, expression of a marker of the invention can be inhibited by targeting nucleotide sequences complementary to the regulatory region of the gene encoding the marker nucleic acid or protein (e.g., the promoter and/or enhancer) to form triple helical structures that prevent transcription of the gene in target cells. See generally Helene (1991) Anticancer Drug Des. 6(6):569-84; Helene (1992) Ann. N.Y. Acad. Sci. 660:27-36; and Maher (1992) Bioassays 14(12):807-15.

[0157] In various embodiments, the nucleic acid molecules of the invention can be modified at the base moiety, sugar moiety or phosphate backbone to improve, e.g., the stability, hybridization, or solubility of the molecule. For example, the deoxyribose phosphate backbone of the nucleic acids can be modified to generate peptide nucleic acids (see Hyrup et al., 1996, Bioorganic & Medicinal Chemistry 4(1): 5-23). As used herein, the terms "peptide nucleic acids" or "PNAs" refer to nucleic acid mimics, e.g., DNA mimics, in which the deoxyribose phosphate backbone is replaced by a pseudopeptide backbone and only the four natural nucleobases are retained. The neutral backbone of PNAs has been shown to allow for specific hybridization to DNA and RNA under conditions of low ionic strength. The synthesis of PNA oligomers can be performed using standard solid phase peptide synthesis protocols as described in Hyrup et al. (1996), supra; Perry-O'Keefe et al. (1996) Proc. Natl. Acad. Sci. USA 93:14670-675.

[0158] PNAs can be used in therapeutic and diagnostic applications. For example, PNAs can be used as antisense or antigene agents for sequence-specific modulation of gene expression by, e.g., inducing transcription or translation arrest or inhibiting replication. PNAs can also be used, e.g., in the analysis of single base pair mutations in a gene by, e.g., PNA directed PCR clamping; as artificial restriction enzymes when used in combination with other enzymes, e.g., S1 nucleases (Hyrup (1996), supra; or as probes or primers for DNA sequence and hybridization (Hyrup, 1996, supra; Perry-O'Keefe et al., 1996, Proc. Natl. Acad. Sci. USA 93:14670-675).

[0159] In another embodiment, PNAs can be modified, e.g., to enhance their stability or cellular uptake, by attaching lipophilic or other helper groups to PNA, by the formation of PNA-DNA chimeras, or by the use of liposomes or other techniques of drug delivery known in the art. For example, PNA-DNA chimeras can be generated which can combine the advantageous properties of PNA and DNA. Such chimeras allow DNA recognition enzymes, e.g., RNase H and DNA polymerases, to interact with the DNA portion while the PNA portion would provide high binding affinity and specificity. PNA-DNA chimeras can be linked using linkers of appropriate lengths selected in terms of base stacking, number of bonds between the nucleobases, and orientation (Hyrup, 1996, supra). The synthesis of PNA-DNA chimeras can be performed as described in Hyrup (1996), supra, and Finn et al. (1996) Nucleic Acids Res. 24(17):3357-63. For example, a DNA chain can be synthesized on a solid support using standard phosphoramidite coupling chemistry and modified nucleoside analogs. Compounds such as 5'-(4-methoxytrityl)amino-5'-deoxy-thymidine phosphoramidite can be used as a link between the PNA and the 5' end of DNA (Mag et al., 1989, Nucleic Acids Res. 17:5973-88). PNA monomers are then coupled in a step-wise manner to produce a chimeric molecule with a 5' PNA segment and a 3' DNA segment (Finn et al., 1996, Nucleic Acids Res. 24(17):3357-63). Alternatively, chimeric molecules can be synthesized with a 5' DNA segment and a 3' PNA segment (Peterser et al., 1975, Bioorganic Med. Chem. Lett. 5:1119-11124).

[0160] In other embodiments, the oligonucleotide can include other appended groups such as peptides (e.g., for targeting host cell receptors in vivo), or agents facilitating transport across the cell membrane (see, e.g., Letsinger et al., 1989, Proc. Natl. Acad. Sci. USA 86:6553-6556; Lemaitre et al., 1987, Proc. Natl. Acad. Sci. USA 84:648-652; PCT Publication No. WO 88/09810) or the blood-brain bather (see, e.g., PCT Publication No. WO 89/10134). In addition, oligonucleotides can be modified with hybridization-triggered cleavage agents (see, e.g., Krol et al., 1988, Bio/Techniques 6:958-976) or intercalating agents (see, e.g., Zon, 1988, Pharm. Res. 5:539-549). To this end, the oligonucleotide can be conjugated to another molecule, e.g., a peptide, hybridization triggered cross-linking agent, transport agent, hybridization-triggered cleavage agent, etc.

[0161] The invention also includes molecular beacon nucleic acids having at least one region which is complementary to a nucleic acid of the invention, such that the molecular beacon is useful for quantitating the presence of the nucleic acid of the invention in a sample. A "molecular beacon" nucleic acid is a nucleic acid comprising a pair of complementary regions and having a fluorophore and a fluorescent quencher associated therewith. The fluorophore and quencher are associated with different portions of the nucleic acid in such an orientation that when the complementary regions are annealed with one another, fluorescence of the fluorophore is quenched by the quencher. When the complementary regions of the nucleic acid are not annealed with one another, fluorescence of the fluorophore is quenched to a lesser degree. Molecular beacon nucleic acids are described, for example, in U.S. Pat. No. 5,876,930.

Isolated Proteins and Antibodies

[0162] One aspect of the invention pertains to isolated marker proteins and biologically active portions thereof, as well as polypeptide fragments suitable for use as immunogens to raise antibodies directed against a marker protein or a fragment thereof. In one embodiment, the native marker protein can be isolated from cells or tissue sources by an appropriate purification scheme using standard protein purification techniques. In another embodiment, a protein or peptide comprising the whole or a segment of the marker protein is produced by recombinant DNA techniques. Alternative to recombinant expression, such protein or peptide can be synthesized chemically using standard peptide synthesis techniques.

[0163] An "isolated" or "purified" protein or biologically active portion thereof is substantially free of cellular material or other contaminating proteins from the cell or tissue source from which the protein is derived, or substantially free of chemical precursors or other chemicals when chemically synthesized. The language "substantially free of cellular material" includes preparations of protein in which the protein is separated from cellular components of the cells from which it is isolated or recombinantly produced. Thus, protein that is substantially free of cellular material includes preparations of protein having less than about 30%, 20%, 10%, or 5% (by dry weight) of heterologous protein (also referred to herein as a "contaminating protein"). When the protein or biologically active portion thereof is recombinantly produced, it is also preferably substantially free of culture medium, i.e., culture medium represents less than about 20%, 10%, or 5% of the volume of the protein preparation. When the protein is produced by chemical synthesis, it is preferably substantially free of chemical precursors or other chemicals, i.e., it is separated from chemical precursors or other chemicals which are involved in the synthesis of the protein. Accordingly such preparations of the protein have less than about 30%, 20%, 10%, 5% (by dry weight) of chemical precursors or compounds other than the polypeptide of interest.

[0164] Biologically active portions of a marker protein include polypeptides comprising amino acid sequences sufficiently identical to or derived from the amino acid sequence of the marker protein, which include fewer amino acids than the full length protein, and exhibit at least one activity of the corresponding full-length protein. Typically, biologically active portions comprise a domain or motif with at least one activity of the corresponding full-length protein. A biologically active portion of a marker protein of the invention can be a polypeptide which is, for example, 10, 25, 50, 100 or more amino acids in length. Moreover, other biologically active portions, in which other regions of the marker protein are deleted, can be prepared by recombinant techniques and evaluated for one or more of the functional activities of the native form of the marker protein.

[0165] Preferred marker proteins are encoded by nucleotide sequences encoding proteins comprising the sequence of any one of: SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 20, SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 26, SEQ ID NO: 28, SEQ ID NO: 30, SEQ ID NO: 32, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 38, SEQ ID NO: 40, SEQ ID NO: 42, SEQ ID NO: 44, SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 50, SEQ ID NO: 52, SEQ ID NO: 54, SEQ ID NO: 56, SEQ ID NO: 58, SEQ ID NO: 60, SEQ ID NO: 62, SEQ ID NO: 64, SEQ ID NO: 66, SEQ ID NO: 68, SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 74, SEQ ID NO: 76, SEQ ID NO: 78, SEQ ID NO: 80, SEQ ID NO: 82, SEQ ID NO: 84, SEQ ID NO: 86, SEQ ID NO: 88, SEQ ID NO: 90, SEQ ID NO: 92, SEQ ID NO: 94, and SEQ ID NO: 96. Other useful proteins are substantially identical (e.g., at least about 40%, preferably 50%, 60%, 70%, 80%, 90%, 95%, or 99%) to one of these sequences and retain the functional activity of the corresponding naturally-occurring marker protein yet differ in amino acid sequence due to natural allelic variation or mutagenesis.

[0166] To determine the percent identity of two amino acid sequences or of two nucleic acids, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in the sequence of a first amino acid or nucleic acid sequence for optimal alignment with a second amino or nucleic acid sequence). The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences (i.e., % identity=# of identical positions/total # of positions (e.g., overlapping positions).times.100). In one embodiment the two sequences are the same length.

[0167] The determination of percent identity between two sequences can be accomplished using a mathematical algorithm. A preferred, non-limiting example of a mathematical algorithm utilized for the comparison of two sequences is the algorithm of Karlin and Altschul (1990) Proc. Natl. Acad. Sci. USA 87:2264-2268, modified as in Karlin and Altschul (1993) Proc. Natl. Acad. Sci. USA 90:5873-5877. Such an algorithm is incorporated into the BLASTN and BLASTX programs of Altschul, et al. (1990) J. Mol. Biol. 215:403-410. BLAST nucleotide searches can be performed with the BLASTN program, score=100, wordlength=12 to obtain nucleotide sequences homologous to a nucleic acid molecules of the invention. BLAST protein searches can be performed with the BLASTP program, score=50, wordlength=3 to obtain amino acid sequences homologous to a protein molecules of the invention. To obtain gapped alignments for comparison purposes, a newer version of the BLAST algorithm called Gapped BLAST can be utilized as described in Altschul et al. (1997) Nucleic Acids Res. 25:3389-3402, which is able to perform gapped local alignments for the programs BLASTN, BLASTP and BLASTX. Alternatively, PSI-Blast can be used to perform an iterated search which detects distant relationships between molecules. When utilizing BLAST, Gapped BLAST, and PSI-Blast programs, the default parameters of the respective programs (e.g., BLASTX and BLASTN) can be used. See http://www.ncbi.nlm.nih.gov. Another preferred, non-limiting example of a mathematical algorithm utilized for the comparison of sequences is the algorithm of Myers and Miller, (1988) CABIOS 4:11-17. Such an algorithm is incorporated into the ALIGN program (version 2.0) which is part of the GCG sequence alignment software package. When utilizing the ALIGN program for comparing amino acid sequences, a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4 can be used. Yet another useful algorithm for identifying regions of local sequence similarity and alignment is the FASTA algorithm as described in Pearson and Lipman (1988) Proc. Natl. Acad. Sci. USA 85:2444-2448. When using the FASTA algorithm for comparing nucleotide or amino acid sequences, a PAM120 weight residue table can, for example, be used with a k-tuple value of 2.

[0168] The percent identity between two sequences can be determined using techniques similar to those described above, with or without allowing gaps. In calculating percent identity, only exact matches are counted.

[0169] The invention also provides chimeric or fusion proteins comprising a marker protein or a segment thereof. As used herein, a "chimeric protein" or "fusion protein" comprises all or part (preferably a biologically active part) of a marker protein operably linked to a heterologous polypeptide (i.e., a polypeptide other than the marker protein). Within the fusion protein, the term "operably linked" is intended to indicate that the marker protein or segment thereof and the heterologous polypeptide are fused in-frame to each other. The heterologous polypeptide can be fused to the amino-terminus or the carboxyl-terminus of the marker protein or segment.

[0170] One useful fusion protein is a GST fusion protein in which a marker protein or segment is fused to the carboxyl terminus of GST sequences. Such fusion proteins can facilitate the purification of a recombinant polypeptide of the invention.

[0171] In another embodiment, the fusion protein contains a heterologous signal sequence at its amino terminus. For example, the native signal sequence of a marker protein can be removed and replaced with a signal sequence from another protein. For example, the gp67 secretory sequence of the baculovirus envelope protein can be used as a heterologous signal sequence (Ausubel et al., ed., Current Protocols in Molecular Biology, John Wiley & Sons, NY, 1992). Other examples of eukaryotic heterologous signal sequences include the secretory sequences of melittin and human placental alkaline phosphatase (Stratagene; La Jolla, Calif.). In yet another example, useful prokaryotic heterologous signal sequences include the phoA secretory signal (Sambrook et al., supra) and the protein A secretory signal (Pharmacia Biotech; Piscataway, N.J.).

[0172] In yet another embodiment, the fusion protein is an immunoglobulin fusion protein in which all or part of a marker protein is fused to sequences derived from a member of the immunoglobulin protein family. The immunoglobulin fusion proteins of the invention can be incorporated into pharmaceutical compositions and administered to a subject to inhibit an interaction between a ligand (soluble or membrane-bound) and a protein on the surface of a cell (receptor), to thereby suppress signal transduction in vivo. The immunoglobulin fusion protein can be used to affect the bioavailability of a cognate ligand of a marker protein Inhibition of ligand/receptor interaction can be useful therapeutically, both for treating proliferative and differentiative disorders and for modulating (e.g., promoting or inhibiting) cell survival. Moreover, the immunoglobulin fusion proteins of the invention can be used as immunogens to produce antibodies directed against a marker protein in a subject, to purify ligands and in screening assays to identify molecules which inhibit the interaction of the marker protein with ligands.

[0173] Chimeric and fusion proteins of the invention can be produced by standard recombinant DNA techniques. In another embodiment, the fusion gene can be synthesized by conventional techniques including automated DNA synthesizers. Alternatively, PCR amplification of gene fragments can be carried out using anchor primers which give rise to complementary overhangs between two consecutive gene fragments which can subsequently be annealed and re-amplified to generate a chimeric gene sequence (see, e.g., Ausubel et al., supra). Moreover, many expression vectors are commercially available that already encode a fusion moiety (e.g., a GST polypeptide). A nucleic acid encoding a polypeptide of the invention can be cloned into such an expression vector such that the fusion moiety is linked in-frame to the polypeptide of the invention.

[0174] A signal sequence can be used to facilitate secretion and isolation of marker proteins. Signal sequences are typically characterized by a core of hydrophobic amino acids which are generally cleaved from the mature protein during secretion in one or more cleavage events. Such signal peptides contain processing sites that allow cleavage of the signal sequence from the mature proteins as they pass through the secretory pathway. Thus, the invention pertains to marker proteins, fusion proteins or segments thereof having a signal sequence, as well as to such proteins from which the signal sequence has been proteolytically cleaved (i.e., the cleavage products). In one embodiment, a nucleic acid sequence encoding a signal sequence can be operably linked in an expression vector to a protein of interest, such as a marker protein or a segment thereof. The signal sequence directs secretion of the protein, such as from a eukaryotic host into which the expression vector is transformed, and the signal sequence is subsequently or concurrently cleaved. The protein can then be readily purified from the extracellular medium by art recognized methods. Alternatively, the signal sequence can be linked to the protein of interest using a sequence which facilitates purification, such as with a GST domain.

[0175] The present invention also pertains to variants of the marker proteins. Such variants have an altered amino acid sequence which can function as either agonists (mimetics) or as antagonists. Variants can be generated by mutagenesis, e.g., discrete point mutation or truncation. An agonist can retain substantially the same, or a subset, of the biological activities of the naturally occurring form of the protein. An antagonist of a protein can inhibit one or more of the activities of the naturally occurring form of the protein by, for example, competitively binding to a downstream or upstream member of a cellular signaling cascade which includes the protein of interest. Thus, specific biological effects can be elicited by treatment with a variant of limited function. Treatment of a subject with a variant having a subset of the biological activities of the naturally occurring form of the protein can have fewer side effects in a subject relative to treatment with the naturally occurring form of the protein.

[0176] Variants of a marker protein which function as either agonists (mimetics) or as antagonists can be identified by screening combinatorial libraries of mutants, e.g., truncation mutants, of the protein of the invention for agonist or antagonist activity. In one embodiment, a variegated library of variants is generated by combinatorial mutagenesis at the nucleic acid level and is encoded by a variegated gene library. A variegated library of variants can be produced by, for example, enzymatically ligating a mixture of synthetic oligonucleotides into gene sequences such that a degenerate set of potential protein sequences is expressible as individual polypeptides, or alternatively, as a set of larger fusion proteins (e.g., for phage display). There are a variety of methods which can be used to produce libraries of potential variants of the marker proteins from a degenerate oligonucleotide sequence. Methods for synthesizing degenerate oligonucleotides are known in the art (see, e.g., Narang, 1983, Tetrahedron 39:3; Itakura et al., 1984, Annu. Rev. Biochem. 53:323; Itakura et al., 1984, Science 198:1056; Ike et al., 1983 Nucleic Acid Res. 11:477).

[0177] In addition, libraries of segments of a marker protein can be used to generate a variegated population of polypeptides for screening and subsequent selection of variant marker proteins or segments thereof. For example, a library of coding sequence fragments can be generated by treating a double stranded PCR fragment of the coding sequence of interest with a nuclease under conditions wherein nicking occurs only about once per molecule, denaturing the double stranded DNA, renaturing the DNA to form double stranded DNA which can include sense/antisense pairs from different nicked products, removing single stranded portions from reformed duplexes by treatment with S1 nuclease, and ligating the resulting fragment library into an expression vector. By this method, an expression library can be derived which encodes amino terminal and internal fragments of various sizes of the protein of interest.

[0178] Several techniques are known in the art for screening gene products of combinatorial libraries made by point mutations or truncation, and for screening cDNA libraries for gene products having a selected property. The most widely used techniques, which are amenable to high through-put analysis, for screening large gene libraries typically include cloning the gene library into replicable expression vectors, transforming appropriate cells with the resulting library of vectors, and expressing the combinatorial genes under conditions in which detection of a desired activity facilitates isolation of the vector encoding the gene whose product was detected. Recursive ensemble mutagenesis (REM), a technique which enhances the frequency of functional mutants in the libraries, can be used in combination with the screening assays to identify variants of a protein of the invention (Arkin and Yourvan, 1992, Proc. Natl. Acad. Sci. USA 89:7811-7815; Delgrave et al., 1993, Protein Engineering 6(3):327-331).

[0179] Another aspect of the invention pertains to antibodies directed against a protein of the invention. In preferred embodiments, the antibodies specifically bind a marker protein or a fragment thereof. The terms "antibody" and "antibodies" as used interchangeably herein refer to immunoglobulin molecules as well as fragments and derivatives thereof that comprise an immunologically active portion of an immunoglobulin molecule, (i.e., such a portion contains an antigen binding site which specifically binds an antigen, such as a marker protein, e.g., an epitope of a marker protein). An antibody which specifically binds to a protein of the invention is an antibody which binds the protein, but does not substantially bind other molecules in a sample, e.g., a biological sample, which naturally contains the protein. Examples of an immunologically active portion of an immunoglobulin molecule include, but are not limited to, single-chain antibodies (scAb), F(ab) and F(ab').sub.2 fragments.

[0180] An isolated protein of the invention or a fragment thereof can be used as an immunogen to generate antibodies. The full-length protein can be used or, alternatively, the invention provides antigenic peptide fragments for use as immunogens. The antigenic peptide of a protein of the invention comprises at least 8 (preferably 10, 15, 20, or 30 or more) amino acid residues of the amino acid sequence of one of the proteins of the invention, and encompasses at least one epitope of the protein such that an antibody raised against the peptide forms a specific immune complex with the protein. Preferred epitopes encompassed by the antigenic peptide are regions that are located on the surface of the protein, e.g., hydrophilic regions. Hydrophobicity sequence analysis, hydrophilicity sequence analysis, or similar analyses can be used to identify hydrophilic regions. In preferred embodiments, an isolated marker protein or fragment thereof is used as an immunogen.

[0181] An immunogen typically is used to prepare antibodies by immunizing a suitable (i.e., immunocompetent) subject such as a rabbit, goat, mouse, or other mammal or vertebrate. An appropriate immunogenic preparation can contain, for example, recombinantly-expressed or chemically-synthesized protein or peptide. The preparation can further include an adjuvant, such as Freund's complete or incomplete adjuvant, or a similar immunostimulatory agent. Preferred immunogen compositions are those that contain no other human proteins such as, for example, immunogen compositions made using a non-human host cell for recombinant expression of a protein of the invention. In such a manner, the resulting antibody compositions have reduced or no binding of human proteins other than a protein of the invention.

[0182] The invention provides polyclonal and monoclonal antibodies. The term "monoclonal antibody" or "monoclonal antibody composition", as used herein, refers to a population of antibody molecules that contain only one species of an antigen binding site capable of immunoreacting with a particular epitope. Preferred polyclonal and monoclonal antibody compositions are ones that have been selected for antibodies directed against a protein of the invention. Particularly preferred polyclonal and monoclonal antibody preparations are ones that contain only antibodies directed against a marker protein or fragment thereof.

[0183] Polyclonal antibodies can be prepared by immunizing a suitable subject with a protein of the invention as an immunogen The antibody titer in the immunized subject can be monitored over time by standard techniques, such as with an enzyme linked immunosorbent assay (ELISA) using immobilized polypeptide. At an appropriate time after immunization, e.g., when the specific antibody titers are highest, antibody-producing cells can be obtained from the subject and used to prepare monoclonal antibodies (mAb) by standard techniques, such as the hybridoma technique originally described by Kohler and Milstein (1975) Nature 256:495-497, the human B cell hybridoma technique (see Kozbor et al., 1983, Immunol. Today 4:72), the EBV-hybridoma technique (see Cole et al., pp. 77-96 In Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc., 1985) or trioma techniques. The technology for producing hybridomas is well known (see generally Current Protocols in Immunology, Coligan et al. ed., John Wiley & Sons, New York, 1994). Hybridoma cells producing a monoclonal antibody of the invention are detected by screening the hybridoma culture supernatants for antibodies that bind the polypeptide of interest, e.g., using a standard ELISA assay.

[0184] Alternative to preparing monoclonal antibody-secreting hybridomas, a monoclonal antibody directed against a protein of the invention can be identified and isolated by screening a recombinant combinatorial immunoglobulin library (e.g., an antibody phage display library) with the polypeptide of interest. Kits for generating and screening phage display libraries are commercially available (e.g., the Pharmacia Recombinant Phage Antibody System, Catalog No. 27-9400-01; and the Stratagene SurfZAP Phage Display Kit, Catalog No. 240612). Additionally, examples of methods and reagents particularly amenable for use in generating and screening antibody display library can be found in, for example, U.S. Pat. No. 5,223,409; PCT Publication No. WO 92/18619; PCT Publication No. WO 91/17271; PCT Publication No. WO 92/20791; PCT Publication No. WO 92/15679; PCT Publication No. WO 93/01288; PCT Publication No. WO 92/01047; PCT Publication No. WO 92/09690; PCT Publication No. WO 90/02809; Fuchs et al. (1991) Bio/Technology 9:1370-1372; Hay et al. (1992) Hum. Antibod. Hybridomas 3:81-85; Huse et al. (1989) Science 246:1275-1281; Griffiths et al. (1993) EMBO J. 12:725-734.

[0185] The invention also provides recombinant antibodies that specifically bind a protein of the invention. In preferred embodiments, the recombinant antibodies specifically binds a marker protein or fragment thereof. Recombinant antibodies include, but are not limited to, chimeric and humanized monoclonal antibodies, comprising both human and non-human portions, single-chain antibodies and multi-specific antibodies. A chimeric antibody is a molecule in which different portions are derived from different animal species, such as those having a variable region derived from a murine mAb and a human immunoglobulin constant region. (See, e.g., Cabilly et al., U.S. Pat. No. 4,816,567; and Boss et al., U.S. Pat. No. 4,816,397, which are incorporated herein by reference in their entirety.) Single-chain antibodies have an antigen binding site and consist of a single polypeptides. They can be produced by techniques known in the art, for example using methods described in Ladner et. al U.S. Pat. No. 4,946,778 (which is incorporated herein by reference in its entirety); Bird et al., (1988) Science 242:423-426; Whitlow et al., (1991) Methods in Enzymology 2:1-9; Whitlow et al., (1991) Methods in Enzymology 2:97-105; and Huston et al., (1991) Methods in Enzymology Molecular Design and Modeling: Concepts and Applications 203:46-88. Multi-specific antibodies are antibody molecules having at least two antigen-binding sites that specifically bind different antigens. Such molecules can be produced by techniques known in the art, for example using methods described in Segal, U.S. Pat. No. 4,676,980 (the disclosure of which is incorporated herein by reference in its entirety); Holliger et al., (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Whitlow et al., (1994) Protein Eng. 7:1017-1026 and U.S. Pat. No. 6,121,424.

[0186] Humanized antibodies are antibody molecules from non-human species having one or more complementarity determining regions (CDRs) from the non-human species and a framework region from a human immunoglobulin molecule. (See, e.g., Queen, U.S. Pat. No. 5,585,089, which is incorporated herein by reference in its entirety.) Humanized monoclonal antibodies can be produced by recombinant DNA techniques known in the art, for example using methods described in PCT Publication No. WO 87/02671; European Patent Application 184,187; European Patent Application 171,496; European Patent Application 173,494; PCT Publication No. WO 86/01533; U.S. Pat. No. 4,816,567; European Patent Application 125,023; Better et al. (1988) Science 240:1041-1043; Liu et al. (1987) Proc. Natl. Acad. Sci. USA 84:3439-3443; Liu et al. (1987) J. Immunol. 139:3521-3526; Sun et al. (1987) Proc. Natl. Acad. Sci. USA 84:214-218; Nishimura et al. (1987) Cancer Res. 47:999-1005; Wood et al. (1985) Nature 314:446-449; and Shaw et al. (1988) J. Natl. Cancer Inst. 80:1553-1559); Morrison (1985) Science 229:1202-1207; Oi et al. (1986) Bio/Techniques 4:214; U.S. Pat. No. 5,225,539; Jones et al. (1986) Nature 321:552-525; Verhoeyan et al. (1988) Science 239:1534; and Beidler et al. (1988) J. Immunol. 141:4053-4060.

[0187] More particularly, humanized antibodies can be produced, for example, using transgenic mice which are incapable of expressing endogenous immunoglobulin heavy and light chains genes, but which can express human heavy and light chain genes. The transgenic mice are immunized in the normal fashion with a selected antigen, e.g., all or a portion of a polypeptide corresponding to a marker of the invention. Monoclonal antibodies directed against the antigen can be obtained using conventional hybridoma technology. The human immunoglobulin transgenes harbored by the transgenic mice rearrange during B cell differentiation, and subsequently undergo class switching and somatic mutation. Thus, using such a technique, it is possible to produce therapeutically useful IgG, IgA and IgE antibodies. For an overview of this technology for producing human antibodies, see Lonberg and Huszar (1995) Int. Rev. Immunol. 13:65-93). For a detailed discussion of this technology for producing human antibodies and human monoclonal antibodies and protocols for producing such antibodies, see, e.g., U.S. Pat. No. 5,625,126; U.S. Pat. No. 5,633,425; U.S. Pat. No. 5,569,825; U.S. Pat. No. 5,661,016; and U.S. Pat. No. 5,545,806. In addition, companies such as Abgenix, Inc. (Freemont, Calif.), can be engaged to provide human antibodies directed against a selected antigen using technology similar to that described above.

[0188] Completely human antibodies which recognize a selected epitope can be generated using a technique referred to as "guided selection." In this approach a selected non-human monoclonal antibody, e.g., a murine antibody, is used to guide the selection of a completely human antibody recognizing the same epitope (Jespers et al., 1994, Bio/technology 12:899-903).

[0189] The antibodies of the invention can be isolated after production (e.g., from the blood or serum of the subject) or synthesis and further purified by well-known techniques. For example, IgG antibodies can be purified using protein A chromatography. Antibodies specific for a protein of the invention can be selected or (e.g., partially purified) or purified by, e.g., affinity chromatography. For example, a recombinantly expressed and purified (or partially purified) protein of the invention is produced as described herein, and covalently or non-covalently coupled to a solid support such as, for example, a chromatography column. The column can then be used to affinity purify antibodies specific for the proteins of the invention from a sample containing antibodies directed against a large number of different epitopes, thereby generating a substantially purified antibody composition, i.e., one that is substantially free of contaminating antibodies. By a substantially purified antibody composition is meant, in this context, that the antibody sample contains at most only 30% (by dry weight) of contaminating antibodies directed against epitopes other than those of the desired protein of the invention, and preferably at most 20%, yet more preferably at most 10%, and most preferably at most 5% (by dry weight) of the sample is contaminating antibodies. A purified antibody composition means that at least 99% of the antibodies in the composition are directed against the desired protein of the invention.

[0190] In a preferred embodiment, the substantially purified antibodies of the invention may specifically bind to a signal peptide, a secreted sequence, an extracellular domain, a transmembrane or a cytoplasmic domain or cytoplasmic membrane of a protein of the invention. In a particularly preferred embodiment, the substantially purified antibodies of the invention specifically bind to a secreted sequence or an extracellular domain of the amino acid sequences of a protein of the invention. In a more preferred embodiment, the substantially purified antibodies of the invention specifically bind to a secreted sequence or an extracellular domain of the amino acid sequences of a marker protein.

[0191] An antibody directed against a protein of the invention can be used to isolate the protein by standard techniques, such as affinity chromatography or immunoprecipitation. Moreover, such an antibody can be used to detect the marker protein or fragment thereof (e.g., in a cellular lysate or cell supernatant) in order to evaluate the level and pattern of expression of the marker. The antibodies can also be used diagnostically to monitor protein levels in tissues or body fluids (e.g., in a breast-associated body fluid) as part of a clinical testing procedure, e.g., to, for example, determine the efficacy of a given treatment regimen. Detection can be facilitated by the use of an antibody derivative, which comprises an antibody of the invention coupled to a detectable substance. Examples of detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, and radioactive materials. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, .beta.-galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin, and aequorin, and examples of suitable radioactive material include .sup.125I, .sup.131I, .sup.35S or .sup.3H.

[0192] Antibodies of the invention may also be used as therapeutic agents in treating cancers. In a preferred embodiment, completely human antibodies of the invention are used for therapeutic treatment of human cancer patients, particularly those having a breast cancer. In another preferred embodiment, antibodies that bind specifically to a marker protein or fragment thereof are used for therapeutic treatment. Further, such therapeutic antibody may be an antibody derivative or immunotoxin comprising an antibody conjugated to a therapeutic moiety such as a cytotoxin, a therapeutic agent or a radioactive metal ion. A cytotoxin or cytotoxic agent includes any agent that is detrimental to cells. Examples include taxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin and analogs or homologs thereof. Therapeutic agents include, but are not limited to, antimetabolites (e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine), alkylating agents (e.g., mechlorethamine, thioepa chlorambucil, melphalan, carmustine (BSNU) and lomustine (CCNU), cyclothosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, and cis-dichlorodiamine platinum (II) (DDP) cisplatin), anthracyclines (e.g., daunorubicin (formerly daunomycin) and doxorubicin), antibiotics (e.g., dactinomycin (formerly actinomycin), bleomycin, mithramycin, and anthramycin (AMC)), and anti-mitotic agents (e.g., vincristine and vinblastine).

[0193] The conjugated antibodies of the invention can be used for modifying a given biological response, for the drug moiety is not to be construed as limited to classical chemical therapeutic agents. For example, the drug moiety may be a protein or polypeptide possessing a desired biological activity. Such proteins may include, for example, a toxin such as ribosome-inhibiting protein (see Better et al., U.S. Pat. No. 6,146,631, the disclosure of which is incorporated herein in its entirety), abrin, ricin A, pseudomonas exotoxin, or diphtheria toxin; a protein such as tumor necrosis factor, .alpha.-interferon, .beta.-interferon, nerve growth factor, platelet derived growth factor, tissue plasminogen activator; or, biological response modifiers such as, for example, lymphokines, interleukin-1 ("IL-1"), interleukin-2 ("IL-2"), interleukin-6 ("IL-6"), granulocyte macrophase colony stimulating factor ("GM-CSF"), granulocyte colony stimulating factor ("G-CSF"), or other growth factors.

[0194] Techniques for conjugating such therapeutic moiety to antibodies are well known, see, e.g., Amon et al., "Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Therapy", in Monoclonal Antibodies And Cancer Therapy, Reisfeld et al. (eds.), pp. 243-56 (Alan R. Liss, Inc. 1985); Hellstrom et al., "Antibodies For Drug Delivery", in Controlled Drug Delivery (2nd Ed.), Robinson et al. (eds.), pp. 623-53 (Marcel Dekker, Inc. 1987); Thorpe, "Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review", in Monoclonal Antibodies '84: Biological And Clinical Applications, Pinchera et al. (eds.), pp. 475-506 (1985); "Analysis, Results, And Future Prospective Of The Therapeutic Use Of Radiolabeled Antibody In Cancer Therapy", in Monoclonal Antibodies For Cancer Detection And Therapy, Baldwin et al. (eds.), pp. 303-16 (Academic Press 1985), and Thorpe et al., "The Preparation And Cytotoxic Properties Of Antibody-Toxin Conjugates", Immunol. Rev., 62:119-58 (1982).

[0195] Accordingly, in one aspect, the invention provides substantially purified antibodies, antibody fragments and derivatives, all of which specifically bind to a protein of the invention and preferably, a marker protein. In various embodiments, the substantially purified antibodies of the invention, or fragments or derivatives thereof, can be human, non-human, chimeric and/or humanized antibodies. In another aspect, the invention provides non-human antibodies, antibody fragments and derivatives, all of which specifically bind to a protein of the invention and preferably, a marker protein. Such non-human antibodies can be goat, mouse, sheep, horse, chicken, rabbit, or rat antibodies. Alternatively, the non-human antibodies of the invention can be chimeric and/or humanized antibodies. In addition, the non-human antibodies of the invention can be polyclonal antibodies or monoclonal antibodies. In still a further aspect, the invention provides monoclonal antibodies, antibody fragments and derivatives, all of which specifically bind to a protein of the invention and preferably, a marker protein. The monoclonal antibodies can be human, humanized, chimeric and/or non-human antibodies.

[0196] The invention also provides a kit containing an antibody of the invention conjugated to a detectable substance, and instructions for use. Still another aspect of the invention is a pharmaceutical composition comprising an antibody of the invention and a pharmaceutically acceptable carrier. In one embodiment, the pharmaceutical composition comprises an antibody of the invention, a therapeutic moiety, and a pharmaceutically acceptable carrier.

Recombinant Expression Vectors and Host Cells

[0197] Another aspect of the invention pertains to vectors, preferably expression vectors, containing a nucleic acid encoding a marker protein (or a portion of such a protein). As used herein, the term "vector" refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a "plasmid", which refers to a circular double stranded DNA loop into which additional DNA segments can be ligated. Another type of vector is a viral vector, wherein additional DNA segments can be ligated into the viral genome. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) are integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome. Moreover, certain vectors, namely expression vectors, are capable of directing the expression of genes to which they are operably linked. In general, expression vectors of utility in recombinant DNA techniques are often in the form of plasmids (vectors). However, the invention is intended to include such other forms of expression vectors, such as viral vectors (e.g., replication defective retroviruses, adenoviruses and adeno-associated viruses), which serve equivalent functions.

[0198] The recombinant expression vectors of the invention comprise a nucleic acid of the invention in a form suitable for expression of the nucleic acid in a host cell. This means that the recombinant expression vectors include one or more regulatory sequences, selected on the basis of the host cells to be used for expression, which is operably linked to the nucleic acid sequence to be expressed. Within a recombinant expression vector, "operably linked" is intended to mean that the nucleotide sequence of interest is linked to the regulatory sequence(s) in a manner which allows for expression of the nucleotide sequence (e.g., in an in vitro transcription/translation system or in a host cell when the vector is introduced into the host cell). The term "regulatory sequence" is intended to include promoters, enhancers and other expression control elements (e.g., polyadenylation signals). Such regulatory sequences are described, for example, in Goeddel, Methods in Enzymology: Gene Expression Technology vol. 185, Academic Press, San Diego, Calif. (1991). Regulatory sequences include those which direct constitutive expression of a nucleotide sequence in many types of host cell and those which direct expression of the nucleotide sequence only in certain host cells (e.g., tissue-specific regulatory sequences). It will be appreciated by those skilled in the art that the design of the expression vector can depend on such factors as the choice of the host cell to be transformed, the level of expression of protein desired, and the like. The expression vectors of the invention can be introduced into host cells to thereby produce proteins or peptides, including fusion proteins or peptides, encoded by nucleic acids as described herein.

[0199] The recombinant expression vectors of the invention can be designed for expression of a marker protein or a segment thereof in prokaryotic (e.g., E. coli) or eukaryotic cells (e.g., insect cells {using baculovirus expression vectors}, yeast cells or mammalian cells). Suitable host cells are discussed further in Goeddel, supra. Alternatively, the recombinant expression vector can be transcribed and translated in vitro, for example using T7 promoter regulatory sequences and T7 polymerase.

[0200] Expression of proteins in prokaryotes is most often carried out in E. coli with vectors containing constitutive or inducible promoters directing the expression of either fusion or non-fusion proteins. Fusion vectors add a number of amino acids to a protein encoded therein, usually to the amino terminus of the recombinant protein. Such fusion vectors typically serve three purposes: 1) to increase expression of recombinant protein; 2) to increase the solubility of the recombinant protein; and 3) to aid in the purification of the recombinant protein by acting as a ligand in affinity purification. Often, in fusion expression vectors, a proteolytic cleavage site is introduced at the junction of the fusion moiety and the recombinant protein to enable separation of the recombinant protein from the fusion moiety subsequent to purification of the fusion protein. Such enzymes, and their cognate recognition sequences, include Factor Xa, thrombin and enterokinase. Typical fusion expression vectors include pGEX (Pharmacia Biotech Inc; Smith and Johnson, 1988, Gene 67:31-40), pMAL (New England Biolabs, Beverly, Mass.) and pRIT5 (Pharmacia, Piscataway, N.J.) which fuse glutathione S-transferase (GST), maltose E binding protein, or protein A, respectively, to the target recombinant protein.

[0201] Examples of suitable inducible non-fusion E. coli expression vectors include pTrc (Amann et al., 1988, Gene 69:301-315) and pET 11d (Studier et al., p. 60-89, In Gene Expression Technology Methods in Enzymology vol. 185, Academic Press, San Diego, Calif., 1991). Target gene expression from the pTrc vector relies on host RNA polymerase transcription from a hybrid trp-lac fusion promoter. Target gene expression from the pET 11d vector relies on transcription from a T7 gn10-lac fusion promoter mediated by a co-expressed viral RNA polymerase (T7 gn1). This viral polymerase is supplied by host strains BL21(DE3) or HMS174(DE3) from a resident prophage harboring a T7 gn1 gene under the transcriptional control of the lacUV 5 promoter.

[0202] One strategy to maximize recombinant protein expression in E. coli is to express the protein in a host bacteria with an impaired capacity to proteolytically cleave the recombinant protein (Gottesman, p. 119-128, In Gene Expression Technology: Methods in Enzymology vol. 185, Academic Press, San Diego, Calif., 1990. Another strategy is to alter the nucleic acid sequence of the nucleic acid to be inserted into an expression vector so that the individual codons for each amino acid are those preferentially utilized in E. coli (Wada et al., 1992, Nucleic Acids Res. 20:2111-2118). Such alteration of nucleic acid sequences of the invention can be carried out by standard DNA synthesis techniques.

[0203] In another embodiment, the expression vector is a yeast expression vector. Examples of vectors for expression in yeast S. cerevisiae include pYepSec1 (Baldari et al., 1987, EMBO J. 6:229-234), pMFa (Kurjan and Herskowitz, 1982, Cell 30:933-943), pJRY88 (Schultz et al., 1987, Gene 54:113-123), pYES2 (Invitrogen Corporation, San Diego, Calif.), and pPicZ (Invitrogen Corp, San Diego, Calif.).

[0204] Alternatively, the expression vector is a baculovirus expression vector. Baculovirus vectors available for expression of proteins in cultured insect cells (e.g., Sf 9 cells) include the pAc series (Smith et al., 1983, Mol. Cell. Biol. 3:2156-2165) and the pVL series (Lucklow and Summers, 1989, Virology 170:31-39).

[0205] In yet another embodiment, a nucleic acid of the invention is expressed in mammalian cells using a mammalian expression vector. Examples of mammalian expression vectors include pCDM8 (Seed, 1987, Nature 329:840) and pMT2PC (Kaufman et al., 1987, EMBO J. 6:187-195). When used in mammalian cells, the expression vector's control functions are often provided by viral regulatory elements. For example, commonly used promoters are derived from polyoma, Adenovirus 2, cytomegalovirus and Simian Virus 40. For other suitable expression systems for both prokaryotic and eukaryotic cells see chapters 16 and 17 of Sambrook et al., supra.

[0206] In another embodiment, the recombinant mammalian expression vector is capable of directing expression of the nucleic acid preferentially in a particular cell type (e.g., tissue-specific regulatory elements are used to express the nucleic acid). Tissue-specific regulatory elements are known in the art. Non-limiting examples of suitable tissue-specific promoters include the albumin promoter (liver-specific; Pinkert et al., 1987, Genes Dev. 1:268-277), lymphoid-specific promoters (Calame and Eaton, 1988, Adv. Immunol. 43:235-275), in particular promoters of T cell receptors (Winoto and Baltimore, 1989, EMBO J. 8:729-733) and immunoglobulins (Banerji et al., 1983, Cell 33:729-740; Queen and Baltimore, 1983, Cell 33:741-748), neuron-specific promoters (e.g., the neurofilament promoter; Byrne and Ruddle, 1989, Proc. Natl. Acad. Sci. USA 86:5473-5477), pancreas-specific promoters (Edlund et al., 1985, Science 230:912-916), and mammary gland-specific promoters (e.g., milk whey promoter; U.S. Pat. No. 4,873,316 and European Application Publication No. 264,166). Developmentally-regulated promoters are also encompassed, for example the murine hox promoters (Kessel and Gruss, 1990, Science 249:374-379) and the .alpha.-fetoprotein promoter (Camper and Tilghman, 1989, Genes Dev. 3:537-546).

[0207] The invention further provides a recombinant expression vector comprising a DNA molecule of the invention cloned into the expression vector in an antisense orientation. That is, the DNA molecule is operably linked to a regulatory sequence in a manner which allows for expression (by transcription of the DNA molecule) of an RNA molecule which is antisense to the mRNA encoding a polypeptide of the invention. Regulatory sequences operably linked to a nucleic acid cloned in the antisense orientation can be chosen which direct the continuous expression of the antisense RNA molecule in a variety of cell types, for instance viral promoters and/or enhancers, or regulatory sequences can be chosen which direct constitutive, tissue-specific or cell type specific expression of antisense RNA. The antisense expression vector can be in the form of a recombinant plasmid, phagemid, or attenuated virus in which antisense nucleic acids are produced under the control of a high efficiency regulatory region, the activity of which can be determined by the cell type into which the vector is introduced. For a discussion of the regulation of gene expression using antisense genes see Weintraub et al., 1986, Trends in Genetics, Vol. 1(1).

[0208] Another aspect of the invention pertains to host cells into which a recombinant expression vector of the invention has been introduced. The terms "host cell" and "recombinant host cell" are used interchangeably herein. It is understood that such terms refer not only to the particular subject cell but to the progeny or potential progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term as used herein.

[0209] A host cell can be any prokaryotic (e.g., E. coli) or eukaryotic cell (e.g., insect cells, yeast or mammalian cells).

[0210] Vector DNA can be introduced into prokaryotic or eukaryotic cells via conventional transformation or transfection techniques. As used herein, the terms "transformation" and "transfection" are intended to refer to a variety of art-recognized techniques for introducing foreign nucleic acid into a host cell, including calcium phosphate or calcium chloride co-precipitation, DEAE-dextran-mediated transfection, lipofection, or electroporation. Suitable methods for transforming or transfecting host cells can be found in Sambrook, et al. (supra), and other laboratory manuals.

[0211] For stable transfection of mammalian cells, it is known that, depending upon the expression vector and transfection technique used, only a small fraction of cells may integrate the foreign DNA into their genome. In order to identify and select these integrants, a gene that encodes a selectable marker (e.g., for resistance to antibiotics) is generally introduced into the host cells along with the gene of interest. Preferred selectable markers include those which confer resistance to drugs, such as G418, hygromycin and methotrexate. Cells stably transfected with the introduced nucleic acid can be identified by drug selection (e.g., cells that have incorporated the selectable marker will survive, while the other cells die).

[0212] A host cell of the invention, such as a prokaryotic or eukaryotic host cell in culture, can be used to produce a marker protein or a segment thereof. Accordingly, the invention further provides methods for producing a marker protein or a segment thereof using the host cells of the invention. In one embodiment, the method comprises culturing the host cell of the invention (into which a recombinant expression vector encoding a marker protein or a segment thereof has been introduced) in a suitable medium such that the is produced. In another embodiment, the method further comprises isolating the a marker protein or a segment thereof from the medium or the host cell.

[0213] The host cells of the invention can also be used to produce nonhuman transgenic animals. For example, in one embodiment, a host cell of the invention is a fertilized oocyte or an embryonic stem cell into which a sequences encoding a marker protein or a segment thereof have been introduced. Such host cells can then be used to create non-human transgenic animals in which exogenous sequences encoding a marker protein of the invention have been introduced into their genome or homologous recombinant animals in which endogenous gene(s) encoding a marker protein have been altered. Such animals are useful for studying the function and/or activity of the marker protein and for identifying and/or evaluating modulators of marker protein. As used herein, a "transgenic animal" is a non-human animal, preferably a mammal, more preferably a rodent such as a rat or mouse, in which one or more of the cells of the animal includes a transgene. Other examples of transgenic animals include non-human primates, sheep, dogs, cows, goats, chickens, amphibians, etc. A transgene is exogenous DNA which is integrated into the genome of a cell from which a transgenic animal develops and which remains in the genome of the mature animal, thereby directing the expression of an encoded gene product in one or more cell types or tissues of the transgenic animal. As used herein, an "homologous recombinant animal" is a non-human animal, preferably a mammal, more preferably a mouse, in which an endogenous gene has been altered by homologous recombination between the endogenous gene and an exogenous DNA molecule introduced into a cell of the animal, e.g., an embryonic cell of the animal, prior to development of the animal.

[0214] A transgenic animal of the invention can be created by introducing a nucleic acid encoding a marker protein into the male pronuclei of a fertilized oocyte, e.g., by microinjection, retroviral infection, and allowing the oocyte to develop in a pseudopregnant female foster animal. Intronic sequences and polyadenylation signals can also be included in the transgene to increase the efficiency of expression of the transgene. A tissue-specific regulatory sequence(s) can be operably linked to the transgene to direct expression of the polypeptide of the invention to particular cells. Methods for generating transgenic animals via embryo manipulation and microinjection, particularly animals such as mice, have become conventional in the art and are described, for example, in U.S. Pat. Nos. 4,736,866 and 4,870,009, U.S. Pat. No. 4,873,191 and in Hogan, Manipulating the Mouse Embryo, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1986. Similar methods are used for production of other transgenic animals. A transgenic founder animal can be identified based upon the presence of the transgene in its genome and/or expression of mRNA encoding the transgene in tissues or cells of the animals. A transgenic founder animal can then be used to breed additional animals carrying the transgene. Moreover, transgenic animals carrying the transgene can further be bred to other transgenic animals carrying other transgenes.

[0215] To create an homologous recombinant animal, a vector is prepared which contains at least a portion of a gene encoding a marker protein into which a deletion, addition or substitution has been introduced to thereby alter, e.g., functionally disrupt, the gene. In a preferred embodiment, the vector is designed such that, upon homologous recombination, the endogenous gene is functionally disrupted (i.e., no longer encodes a functional protein; also referred to as a "knock out" vector). Alternatively, the vector can be designed such that, upon homologous recombination, the endogenous gene is mutated or otherwise altered but still encodes functional protein (e.g., the upstream regulatory region can be altered to thereby alter the expression of the endogenous protein). In the homologous recombination vector, the altered portion of the gene is flanked at its 5' and 3' ends by additional nucleic acid of the gene to allow for homologous recombination to occur between the exogenous gene carried by the vector and an endogenous gene in an embryonic stem cell. The additional flanking nucleic acid sequences are of sufficient length for successful homologous recombination with the endogenous gene. Typically, several kilobases of flanking DNA (both at the 5' and 3' ends) are included in the vector (see, e.g., Thomas and Capecchi, 1987, Cell 51:503 for a description of homologous recombination vectors). The vector is introduced into an embryonic stem cell line (e.g., by electroporation) and cells in which the introduced gene has homologously recombined with the endogenous gene are selected (see, e.g., Li et al., 1992, Cell 69:915). The selected cells are then injected into a blastocyst of an animal (e.g., a mouse) to form aggregation chimeras (see, e.g., Bradley, Teratocarcinomas and Embryonic Stem Cells: A Practical Approach, Robertson, Ed., IRL, Oxford, 1987, pp. 113-152). A chimeric embryo can then be implanted into a suitable pseudopregnant female foster animal and the embryo brought to term. Progeny harboring the homologously recombined DNA in their germ cells can be used to breed animals in which all cells of the animal contain the homologously recombined DNA by germline transmission of the transgene. Methods for constructing homologous recombination vectors and homologous recombinant animals are described further in Bradley (1991) Current Opinion in Bio/Technology 2:823-829 and in PCT Publication NOS. WO 90/11354, WO 91/01140, WO 92/0968, and WO 93/04169.

[0216] In another embodiment, transgenic non-human animals can be produced which contain selected systems which allow for regulated expression of the transgene. One example of such a system is the cre/loxP recombinase system of bacteriophage P1. For a description of the cre/loxP recombinase system, see, e.g., Lakso et al. (1992) Proc. Natl. Acad. Sci. USA 89:6232-6236. Another example of a recombinase system is the FLP recombinase system of Saccharomyces cerevisiae (O'Gorman et al., 1991, Science 251:1351-1355). If a cre/loxP recombinase system is used to regulate expression of the transgene, animals containing transgenes encoding both the Cre recombinase and a selected protein are required. Such animals can be provided through the construction of "double" transgenic animals, e.g., by mating two transgenic animals, one containing a transgene encoding a selected protein and the other containing a transgene encoding a recombinase.

[0217] Clones of the non-human transgenic animals described herein can also be produced according to the methods described in Wilmut et al. (1997) Nature 385:810-813 and PCT Publication NOS. WO 97/07668 and WO 97/07669.

Pharmaceutical Compositions

[0218] The nucleic acid molecules, polypeptides, and antibodies (also referred to herein as "active compounds") of the invention can be incorporated into pharmaceutical compositions suitable for administration. Such compositions typically comprise the nucleic acid molecule, protein, or antibody and a pharmaceutically acceptable carrier. As used herein the language "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.

[0219] The invention includes methods for preparing pharmaceutical compositions for modulating the expression or activity of a marker nucleic acid or protein. Such methods comprise formulating a pharmaceutically acceptable carrier with an agent which modulates expression or activity of a marker nucleic acid or protein. Such compositions can further include additional active agents. Thus, the invention further includes methods for preparing a pharmaceutical composition by formulating a pharmaceutically acceptable carrier with an agent which modulates expression or activity of a marker nucleic acid or protein and one or more additional active compounds.

[0220] The invention also provides methods (also referred to herein as "screening assays") for identifying modulators, i.e., candidate or test compounds or agents (e.g., peptides, peptidomimetics, peptoids, small molecules or other drugs) which (a) bind to the marker, or (b) have a modulatory (e.g., stimulatory or inhibitory) effect on the activity of the marker or, more specifically, (c) have a modulatory effect on the interactions of the marker with one or more of its natural substrates (e.g., peptide, protein, hormone, co-factor, or nucleic acid), or (d) have a modulatory effect on the expression of the marker. Such assays typically comprise a reaction between the marker and one or more assay components. The other components may be either the test compound itself, or a combination of test compound and a natural binding partner of the marker.

[0221] The test compounds of the present invention may be obtained from any available source, including systematic libraries of natural and/or synthetic compounds. Test compounds may also be obtained by any of the numerous approaches in combinatorial library methods known in the art, including: biological libraries; peptoid libraries (libraries of molecules having the functionalities of peptides, but with a novel, non-peptide backbone which are resistant to enzymatic degradation but which nevertheless remain bioactive; see, e.g., Zuckermann et al., 1994, J. Med. Chem. 37:2678-85); spatially addressable parallel solid phase or solution phase libraries; synthetic library methods requiring deconvolution; the `one-bead one-compound` library method; and synthetic library methods using affinity chromatography selection. The biological library and peptoid library approaches are limited to peptide libraries, while the other four approaches are applicable to peptide, non-peptide oligomer or small molecule libraries of compounds (Lam, 1997, Anticancer Drug Des. 12:145).

[0222] Examples of methods for the synthesis of molecular libraries can be found in the art, for example in: DeWitt et al. (1993) Proc. Natl. Acad. Sci. U.S.A. 90:6909; Erb et al. (1994) Proc. Natl. Acad. Sci. USA 91:11422; Zuckermann et al. (1994). J. Med. Chem. 37:2678; Cho et al. (1993) Science 261:1303; Carrell et al. (1994) Angew. Chem. Int. Ed. Engl. 33:2059; Carell et al. (1994) Angew. Chem. Int. Ed. Engl. 33:2061; and in Gallop et al. (1994) J. Med. Chem. 37:1233.

[0223] Libraries of compounds may be presented in solution (e.g., Houghten, 1992, Biotechniques 13:412-421), or on beads (Lam, 1991, Nature 354:82-84), chips (Fodor, 1993, Nature 364:555-556), bacteria and/or spores, (Ladner, U.S. Pat. No. 5,223,409), plasmids (Cull et al., 1992, Proc Natl Acad Sci USA 89:1865-1869) or on phage (Scott and Smith, 1990, Science 249:386-390; Devlin, 1990, Science 249:404-406; Cwirla et al., 1990, Proc. Natl. Acad. Sci. 87:6378-6382; Felici, 1991, J. Mol. Biol. 222:301-310; Ladner, supra.).

[0224] In one embodiment, the invention provides assays for screening candidate or test compounds which are substrates of a protein encoded by or corresponding to a marker or biologically active portion thereof. In another embodiment, the invention provides assays for screening candidate or test compounds which bind to a protein encoded by or corresponding to a marker or biologically active portion thereof. Determining the ability of the test compound to directly bind to a protein can be accomplished, for example, by coupling the compound with a radioisotope or enzymatic label such that binding of the compound to the marker can be determined by detecting the labeled marker compound in a complex. For example, compounds (e.g., marker substrates) can be labeled with .sup.125I, .sup.35S, .sup.14C, or .sup.3H, either directly or indirectly, and the radioisotope detected by direct counting of radioemission or by scintillation counting. Alternatively, assay components can be enzymatically labeled with, for example, horseradish peroxidase, alkaline phosphatase, or luciferase, and the enzymatic label detected by determination of conversion of an appropriate substrate to product.

[0225] In another embodiment, the invention provides assays for screening candidate or test compounds which modulate the expression of a marker or the activity of a protein encoded by or corresponding to a marker, or a biologically active portion thereof. In all likelihood, the protein encoded by or corresponding to the marker can, in vivo, interact with one or more molecules, such as but not limited to, peptides, proteins, hormones, cofactors and nucleic acids. For the purposes of this discussion, such cellular and extracellular molecules are referred to herein as "binding partners" or marker "substrate".

[0226] One necessary embodiment of the invention in order to facilitate such screening is the use of a protein encoded by or corresponding to marker to identify the protein's natural in vivo binding partners. There are many ways to accomplish this which are known to one skilled in the art. One example is the use of the marker protein as "bait protein" in a two-hybrid assay or three-hybrid assay (see, e.g., U.S. Pat. No. 5,283,317; Zervos et al., 1993, Cell 72:223-232; Madura et al., 1993, J. Biol. Chem. 268:12046-12054; Bartel et al, 1993, Biotechniques 14:920-924; Iwabuchi et al., 1993 Oncogene 8:1693-1696; Brent WO94/10300) in order to identify other proteins which bind to or interact with the marker (binding partners) and, therefore, are possibly involved in the natural function of the marker. Such marker binding partners are also likely to be involved in the propagation of signals by the marker protein or downstream elements of a marker protein-mediated signaling pathway. Alternatively, such marker protein binding partners may also be found to be inhibitors of the marker protein.

[0227] The two-hybrid system is based on the modular nature of most transcription factors, which consist of separable DNA-binding and activation domains. Briefly, the assay utilizes two different DNA constructs. In one construct, the gene that encodes a marker protein fused to a gene encoding the DNA binding domain of a known transcription factor (e.g., GAL-4). In the other construct, a DNA sequence, from a library of DNA sequences, that encodes an unidentified protein ("prey" or "sample") is fused to a gene that codes for the activation domain of the known transcription factor. If the "bait" and the "prey" proteins are able to interact, in vivo, forming a marker-dependent complex, the DNA-binding and activation domains of the transcription factor are brought into close proximity. This proximity allows transcription of a reporter gene (e.g., LacZ) which is operably linked to a transcriptional regulatory site responsive to the transcription factor. Expression of the reporter gene can be readily detected and cell colonies containing the functional transcription factor can be isolated and used to obtain the cloned gene which encodes the protein which interacts with the marker protein.

[0228] In a further embodiment, assays may be devised through the use of the invention for the purpose of identifying compounds which modulate (e.g., affect either positively or negatively) interactions between a marker protein and its substrates and/or binding partners. Such compounds can include, but are not limited to, molecules such as antibodies, peptides, hormones, oligonucleotides, nucleic acids, and analogs thereof. Such compounds may also be obtained from any available source, including systematic libraries of natural and/or synthetic compounds. The preferred assay components for use in this embodiment is a breast cancer marker protein identified herein, the known binding partner and/or substrate of same, and the test compound. Test compounds can be supplied from any source.

[0229] The basic principle of the assay systems used to identify compounds that interfere with the interaction between the marker protein and its binding partner involves preparing a reaction mixture containing the marker protein and its binding partner under conditions and for a time sufficient to allow the two products to interact and bind, thus forming a complex. In order to test an agent for inhibitory activity, the reaction mixture is prepared in the presence and absence of the test compound. The test compound can be initially included in the reaction mixture, or can be added at a time subsequent to the addition of the marker protein and its binding partner. Control reaction mixtures are incubated without the test compound or with a placebo. The formation of any complexes between the marker protein and its binding partner is then detected. The formation of a complex in the control reaction, but less or no such formation in the reaction mixture containing the test compound, indicates that the compound interferes with the interaction of the marker protein and its binding partner. Conversely, the formation of more complex in the presence of compound than in the control reaction indicates that the compound may enhance interaction of the marker protein and its binding partner.

[0230] The assay for compounds that interfere with the interaction of the marker protein with its binding partner may be conducted in a heterogeneous or homogeneous format. Heterogeneous assays involve anchoring either the marker protein or its binding partner onto a solid phase and detecting complexes anchored to the solid phase at the end of the reaction. In homogeneous assays, the entire reaction is carried out in a liquid phase. In either approach, the order of addition of reactants can be varied to obtain different information about the compounds being tested. For example, test compounds that interfere with the interaction between the marker proteins and the binding partners (e.g., by competition) can be identified by conducting the reaction in the presence of the test substance, i.e., by adding the test substance to the reaction mixture prior to or simultaneously with the marker and its interactive binding partner. Alternatively, test compounds that disrupt preformed complexes, e.g., compounds with higher binding constants that displace one of the components from the complex, can be tested by adding the test compound to the reaction mixture after complexes have been formed. The various formats are briefly described below.

[0231] In a heterogeneous assay system, either the marker protein or its binding partner is anchored onto a solid surface or matrix, while the other corresponding non-anchored component may be labeled, either directly or indirectly. In practice, microtitre plates are often utilized for this approach. The anchored species can be immobilized by a number of methods, either non-covalent or covalent, that are typically well known to one who practices the art. Non-covalent attachment can often be accomplished simply by coating the solid surface with a solution of the marker protein or its binding partner and drying. Alternatively, an immobilized antibody specific for the assay component to be anchored can be used for this purpose. Such surfaces can often be prepared in advance and stored.

[0232] In related embodiments, a fusion protein can be provided which adds a domain that allows one or both of the assay components to be anchored to a matrix. For example, glutathione-S-transferase/marker fusion proteins or glutathione-S-transferase/binding partner can be adsorbed onto glutathione sepharose beads (Sigma Chemical, St. Louis, Mo.) or glutathione derivatized microtiter plates, which are then combined with the test compound or the test compound and either the non-adsorbed marker or its binding partner, and the mixture incubated under conditions conducive to complex formation (e.g., physiological conditions). Following incubation, the beads or microtiter plate wells are washed to remove any unbound assay components, the immobilized complex assessed either directly or indirectly, for example, as described above. Alternatively, the complexes can be dissociated from the matrix, and the level of marker binding or activity determined using standard techniques.

[0233] Other techniques for immobilizing proteins on matrices can also be used in the screening assays of the invention. For example, either a marker protein or a marker protein binding partner can be immobilized utilizing conjugation of biotin and streptavidin. Biotinylated marker protein or target molecules can be prepared from biotin-NHS (N-hydroxy-succinimide) using techniques known in the art (e.g., biotinylation kit, Pierce Chemicals, Rockford, Ill.), and immobilized in the wells of streptavidin-coated 96 well plates (Pierce Chemical). In certain embodiments, the protein-immobilized surfaces can be prepared in advance and stored.

[0234] In order to conduct the assay, the corresponding partner of the immobilized assay component is exposed to the coated surface with or without the test compound. After the reaction is complete, unreacted assay components are removed (e.g., by washing) and any complexes formed will remain immobilized on the solid surface. The detection of complexes anchored on the solid surface can be accomplished in a number of ways. Where the non-immobilized component is pre-labeled, the detection of label immobilized on the surface indicates that complexes were formed. Where the non-immobilized component is not pre-labeled, an indirect label can be used to detect complexes anchored on the surface; e.g., using a labeled antibody specific for the initially non-immobilized species (the antibody, in turn, can be directly labeled or indirectly labeled with, e.g., a labeled anti-Ig antibody). Depending upon the order of addition of reaction components, test compounds which modulate (inhibit or enhance) complex formation or which disrupt preformed complexes can be detected.

[0235] In an alternate embodiment of the invention, a homogeneous assay may be used. This is typically a reaction, analogous to those mentioned above, which is conducted in a liquid phase in the presence or absence of the test compound. The formed complexes are then separated from unreacted components, and the amount of complex formed is determined. As mentioned for heterogeneous assay systems, the order of addition of reactants to the liquid phase can yield information about which test compounds modulate (inhibit or enhance) complex formation and which disrupt preformed complexes.

[0236] In such a homogeneous assay, the reaction products may be separated from unreacted assay components by any of a number of standard techniques, including but not limited to: differential centrifugation, chromatography, electrophoresis and immunoprecipitation. In differential centrifugation, complexes of molecules may be separated from uncomplexed molecules through a series of centrifugal steps, due to the different sedimentation equilibria of complexes based on their different sizes and densities (see, for example, Rivas, G., and Minton, A. P., Trends Biochem Sci 1993 August; 18(8):284-7). Standard chromatographic techniques may also be utilized to separate complexed molecules from uncomplexed ones. For example, gel filtration chromatography separates molecules based on size, and through the utilization of an appropriate gel filtration resin in a column format, for example, the relatively larger complex may be separated from the relatively smaller uncomplexed components. Similarly, the relatively different charge properties of the complex as compared to the uncomplexed molecules may be exploited to differentially separate the complex from the remaining individual reactants, for example through the use of ion-exchange chromatography resins. Such resins and chromatographic techniques are well known to one skilled in the art (see, e.g., Heegaard, 1998, J Mol. Recognit. 11:141-148; Hage and Tweed, 1997, J. Chromatogr. B. Biomed. Sci. Appl., 699:499-525). Gel electrophoresis may also be employed to separate complexed molecules from unbound species (see, e.g., Ausubel et al (eds.), In: Current Protocols in Molecular Biology, J. Wiley & Sons, New York. 1999). In this technique, protein or nucleic acid complexes are separated based on size or charge, for example. In order to maintain the binding interaction during the electrophoretic process, nondenaturing gels in the absence of reducing agent are typically preferred, but conditions appropriate to the particular interactants will be well known to one skilled in the art. Immunoprecipitation is another common technique utilized for the isolation of a protein-protein complex from solution (see, e.g., Ausubel et al (eds.), In: Current Protocols in Molecular Biology, J. Wiley & Sons, New York. 1999). In this technique, all proteins binding to an antibody specific to one of the binding molecules are precipitated from solution by conjugating the antibody to a polymer bead that may be readily collected by centrifugation. The bound assay components are released from the beads (through a specific proteolysis event or other technique well known in the art which will not disturb the protein-protein interaction in the complex), and a second immunoprecipitation step is performed, this time utilizing antibodies specific for the correspondingly different interacting assay component. In this manner, only formed complexes should remain attached to the beads. Variations in complex formation in both the presence and the absence of a test compound can be compared, thus offering information about the ability of the compound to modulate interactions between the marker protein and its binding partner.

[0237] Also within the scope of the present invention are methods for direct detection of interactions between the marker protein and its natural binding partner and/or a test compound in a homogeneous or heterogeneous assay system without further sample manipulation. For example, the technique of fluorescence energy transfer may be utilized (see, e.g., Lakowicz et al., U.S. Pat. No. 5,631,169; Stavrianopoulos et al., U.S. Pat. No. 4,868,103). Generally, this technique involves the addition of a fluorophore label on a first `donor` molecule (e.g., marker or test compound) such that its emitted fluorescent energy will be absorbed by a fluorescent label on a second, `acceptor` molecule (e.g., marker or test compound), which in turn is able to fluoresce due to the absorbed energy. Alternately, the `donor` protein molecule may simply utilize the natural fluorescent energy of tryptophan residues. Labels are chosen that emit different wavelengths of light, such that the `acceptor` molecule label may be differentiated from that of the `donor`. Since the efficiency of energy transfer between the labels is related to the distance separating the molecules, spatial relationships between the molecules can be assessed. In a situation in which binding occurs between the molecules, the fluorescent emission of the `acceptor` molecule label in the assay should be maximal. An FET binding event can be conveniently measured through standard fluorometric detection means well known in the art (e.g., using a fluorimeter). A test substance which either enhances or hinders participation of one of the species in the preformed complex will result in the generation of a signal variant to that of background. In this way, test substances that modulate interactions between a marker and its binding partner can be identified in controlled assays.

[0238] In another embodiment, modulators of marker expression are identified in a method wherein a cell is contacted with a candidate compound and the expression of marker mRNA or protein in the cell, is determined. The level of expression of marker mRNA or protein in the presence of the candidate compound is compared to the level of expression of marker mRNA or protein in the absence of the candidate compound. The candidate compound can then be identified as a modulator of marker expression based on this comparison. For example, when expression of marker mRNA or protein is greater (statistically significantly greater) in the presence of the candidate compound than in its absence, the candidate compound is identified as a stimulator of marker mRNA or protein expression. Conversely, when expression of marker mRNA or protein is less (statistically significantly less) in the presence of the candidate compound than in its absence, the candidate compound is identified as an inhibitor of marker mRNA or protein expression. The level of marker mRNA or protein expression in the cells can be determined by methods described herein for detecting marker mRNA or protein.

[0239] In another aspect, the invention pertains to a combination of two or more of the assays described herein. For example, a modulating agent can be identified using a cell-based or a cell free assay, and the ability of the agent to modulate the activity of a marker protein can be further confirmed in vivo, e.g., in a whole animal model for cellular transformation and/or tumorigenesis.

[0240] This invention further pertains to novel agents identified by the above-described screening assays. Accordingly, it is within the scope of this invention to further use an agent identified as described herein in an appropriate animal model. For example, an agent identified as described herein (e.g., an marker modulating agent, an antisense marker nucleic acid molecule, an marker-specific antibody, or an marker-binding partner) can be used in an animal model to determine the efficacy, toxicity, or side effects of treatment with such an agent. Alternatively, an agent identified as described herein can be used in an animal model to determine the mechanism of action of such an agent. Furthermore, this invention pertains to uses of novel agents identified by the above-described screening assays for treatments as described herein.

[0241] It is understood that appropriate doses of small molecule agents and protein or polypeptide agents depends upon a number of factors within the knowledge of the ordinarily skilled physician, veterinarian, or researcher. The dose(s) of these agents will vary, for example, depending upon the identity, size, and condition of the subject or sample being treated, further depending upon the route by which the composition is to be administered, if applicable, and the effect which the practitioner desires the agent to have upon the nucleic acid or polypeptide of the invention. Exemplary doses of a small molecule include milligram or microgram amounts per kilogram of subject or sample weight (e.g., about 1 microgram per kilogram to about 500 milligrams per kilogram, about 100 micrograms per kilogram to about 5 milligrams per kilogram, or about 1 microgram per kilogram to about 50 micrograms per kilogram). Exemplary doses of a protein or polypeptide include gram, milligram or microgram amounts per kilogram of subject or sample weight (e.g., about 1 microgram per kilogram to about 5 grams per kilogram, about 100 micrograms per kilogram to about 500 milligrams per kilogram, or about 1 milligram per kilogram to about 50 milligrams per kilogram). It is furthermore understood that appropriate doses of one of these agents depend upon the potency of the agent with respect to the expression or activity to be modulated. Such appropriate doses can be determined using the assays described herein. When one or more of these agents is to be administered to an animal (e.g., a human) in order to modulate expression or activity of a polypeptide or nucleic acid of the invention, a physician, veterinarian, or researcher can, for example, prescribe a relatively low dose at first, subsequently increasing the dose until an appropriate response is obtained. In addition, it is understood that the specific dose level for any particular animal subject will depend upon a variety of factors including the activity of the specific agent employed, the age, body weight, general health, gender, and diet of the subject, the time of administration, the route of administration, the rate of excretion, any drug combination, and the degree of expression or activity to be modulated.

[0242] A pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediamine-tetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampules, disposable syringes or multiple dose vials made of glass or plastic.

[0243] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL (BASF; Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

[0244] Sterile injectable solutions can be prepared by incorporating the active compound (e.g., a polypeptide or antibody) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium, and then incorporating the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0245] Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed.

[0246] Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches, and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0247] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from a pressurized container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

[0248] Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.

[0249] The compounds can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.

[0250] In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes having monoclonal antibodies incorporated therein or thereon) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

[0251] It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.

[0252] For antibodies, the preferred dosage is 0.1 mg/kg to 100 mg/kg of body weight (generally 10 mg/kg to 20 mg/kg). If the antibody is to act in the brain, a dosage of 50 mg/kg to 100 mg/kg is usually appropriate. Generally, partially human antibodies and fully human antibodies have a longer half-life within the human body than other antibodies. Accordingly, lower dosages and less frequent administration is often possible. Modifications such as lipidation can be used to stabilize antibodies and to enhance uptake and tissue penetration. A method for lipidation of antibodies is described by Cruikshank et al. (1997) J. Acquired Immune Deficiency Syndromes and Human Retrovirology 14:193.

[0253] The invention also provides vaccine compositions for the prevention and/or treatment of breast cancer. The invention provides breast cancer vaccine compositions in which a protein of a marker of Table 1, or a combination of proteins of the markers of Table 1, are introduced into a subject in order to stimulate an immune response against the breast cancer. The invention also provides breast cancer vaccine compositions in which a gene expression construct, which expresses a marker or fragment of a marker identified in Table 1, is introduced into the subject such that a protein or fragment of a protein encoded by a marker of Table 1 is produced by transfected cells in the subject at a higher than normal level and elicits an immune response.

[0254] In one embodiment, a breast cancer vaccine is provided and employed as an immunotherapeutic agent for the prevention of breast cancer. In another embodiment, a breast cancer vaccine is provided and employed as an immunotherapeutic agent for the treatment of breast cancer.

[0255] By way of example, a breast cancer vaccine comprised of the proteins of the markers of Table 1, may be employed for the prevention and/or treatment of breast cancer in a subject by administering the vaccine by a variety of routes, e.g., intradermally, subcutaneously, or intramuscularly. In addition, the breast cancer vaccine can be administered together with adjuvants and/or immunomodulators to boost the activity of the vaccine and the subject's response. In one embodiment, devices and/or compositions containing the vaccine, suitable for sustained or intermittent release could be, implanted in the body or topically applied thereto for the relatively slow release of such materials into the body. The breast cancer vaccine can be introduced along with immunomodulatory compounds, which can alter the type of immune response produced in order to produce a response which will be more effective in eliminating the cancer.

[0256] In another embodiment, a breast cancer vaccine comprised of an expression construct of the markers of Table 1, may be introduced by injection into muscle or by coating onto microprojectiles and using a device designed for the purpose to fire the projectiles at high speed into the skin. The cells of the subject will then express the protein(s) or fragments of proteins of the markers of Table 1 and induce an immune response. In addition, the breast cancer vaccine may be introduced along with expression constructs for immunomodulatory molecules, such as cytokines, which may increase the immune response or modulate the type of immune response produced in order to produce a response which will be more effective in eliminating the cancer.

[0257] The marker nucleic acid molecules can be inserted into vectors and used as gene therapy vectors. Gene therapy vectors can be delivered to a subject by, for example, intravenous injection, local administration (U.S. Pat. No. 5,328,470), or by stereotactic injection (see, e.g., Chen et al., 1994, Proc. Natl. Acad. Sci. USA 91:3054-3057). The pharmaceutical preparation of the gene therapy vector can include the gene therapy vector in an acceptable diluent, or can comprise a slow release matrix in which the gene delivery vehicle is imbedded. Alternatively, where the complete gene delivery vector can be produced intact from recombinant cells, e.g., retroviral vectors, the pharmaceutical preparation can include one or more cells which produce the gene delivery system.

[0258] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

Predictive Medicine

[0259] The present invention pertains to the field of predictive medicine in which diagnostic assays, prognostic assays, pharmacogenomics, and monitoring clinical trails are used for prognostic (predictive) purposes to thereby treat an individual prophylactically. Accordingly, one aspect of the present invention relates to diagnostic assays for determining the level of expression of one or more marker proteins or nucleic acids, in order to determine whether an individual is at risk of developing breast cancer. Such assays can be used for prognostic or predictive purposes to thereby prophylactically treat an individual prior to the onset of the cancer.

[0260] Yet another aspect of the invention pertains to monitoring the influence of agents (e.g., drugs or other compounds administered either to inhibit breast cancer or to treat or prevent any other disorder {i.e., in order to understand any breast carcinogenic effects that such treatment may have}) on the expression or activity of a marker of the invention in clinical trials. These and other agents are described in further detail in the following sections.

Diagnostic Assays

[0261] An exemplary method for detecting the presence or absence of a marker protein or nucleic acid in a biological sample involves obtaining a biological sample (e.g., a breast associated body fluid) from a test subject and contacting the biological sample with a compound or an agent capable of detecting the polypeptide or nucleic acid (e.g., mRNA, genomic DNA, or cDNA). The detection methods of the invention can thus be used to detect mRNA, protein, cDNA, or genomic DNA, for example, in a biological sample in vitro as well as in vivo. For example, in vitro techniques for detection of mRNA include Northern hybridizations and in situ hybridizations. In vitro techniques for detection of a marker protein include enzyme linked immunosorbent assays (ELISAs), Western blots, immunoprecipitations and immunofluorescence. In vitro techniques for detection of genomic DNA include Southern hybridizations. Furthermore, in vivo techniques for detection of a marker protein include introducing into a subject a labeled antibody directed against the protein or fragment thereof. For example, the antibody can be labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques.

[0262] A general principle of such diagnostic and prognostic assays involves preparing a sample or reaction mixture that may contain a marker, and a probe, under appropriate conditions and for a time sufficient to allow the marker and probe to interact and bind, thus forming a complex that can be removed and/or detected in the reaction mixture. These assays can be conducted in a variety of ways.

[0263] For example, one method to conduct such an assay would involve anchoring the marker or probe onto a solid phase support, also referred to as a substrate, and detecting target marker/probe complexes anchored on the solid phase at the end of the reaction. In one embodiment of such a method, a sample from a subject, which is to be assayed for presence and/or concentration of marker, can be anchored onto a carrier or solid phase support. In another embodiment, the reverse situation is possible, in which the probe can be anchored to a solid phase and a sample from a subject can be allowed to react as an unanchored component of the assay.

[0264] There are many established methods for anchoring assay components to a solid phase. These include, without limitation, marker or probe molecules which are immobilized through conjugation of biotin and streptavidin. Such biotinylated assay components can be prepared from biotin-NHS (N-hydroxy-succinimide) using techniques known in the art (e.g., biotinylation kit, Pierce Chemicals, Rockford, Ill.), and immobilized in the wells of streptavidin-coated 96 well plates (Pierce Chemical). In certain embodiments, the surfaces with immobilized assay components can be prepared in advance and stored.

[0265] Other suitable carriers or solid phase supports for such assays include any material capable of binding the class of molecule to which the marker or probe belongs. Well-known supports or carriers include, but are not limited to, glass, polystyrene, nylon, polypropylene, nylon, polyethylene, dextran, amylases, natural and modified celluloses, polyacrylamides, gabbros, and magnetite.

[0266] In order to conduct assays with the above mentioned approaches, the non-immobilized component is added to the solid phase upon which the second component is anchored. After the reaction is complete, uncomplexed components may be removed (e.g., by washing) under conditions such that any complexes formed will remain immobilized upon the solid phase. The detection of marker/probe complexes anchored to the solid phase can be accomplished in a number of methods outlined herein.

[0267] In a preferred embodiment, the probe, when it is the unanchored assay component, can be labeled for the purpose of detection and readout of the assay, either directly or indirectly, with detectable labels discussed herein and which are well-known to one skilled in the art.

[0268] It is also possible to directly detect marker/probe complex formation without further manipulation or labeling of either component (marker or probe), for example by utilizing the technique of fluorescence energy transfer (see, for example, Lakowicz et al., U.S. Pat. No. 5,631,169; Stavrianopoulos, et al., U.S. Pat. No. 4,868,103). A fluorophore label on the first, `donor` molecule is selected such that, upon excitation with incident light of appropriate wavelength, its emitted fluorescent energy will be absorbed by a fluorescent label on a second `acceptor` molecule, which in turn is able to fluoresce due to the absorbed energy. Alternately, the `donor` protein molecule may simply utilize the natural fluorescent energy of tryptophan residues. Labels are chosen that emit different wavelengths of light, such that the `acceptor` molecule label may be differentiated from that of the `donor`. Since the efficiency of energy transfer between the labels is related to the distance separating the molecules, spatial relationships between the molecules can be assessed. In a situation in which binding occurs between the molecules, the fluorescent emission of the `acceptor` molecule label in the assay should be maximal. An FET binding event can be conveniently measured through standard fluorometric detection means well known in the art (e.g., using a fluorimeter).

[0269] In another embodiment, determination of the ability of a probe to recognize a marker can be accomplished without labeling either assay component (probe or marker) by utilizing a technology such as real-time Biomolecular Interaction Analysis (BIA) (see, e.g., Sjolander, S. and Urbaniczky, C., 1991, Anal. Chem. 63:2338-2345 and Szabo et al., 1995, Curr. Opin. Struct. Biol. 5:699-705). As used herein, "BIA" or "surface plasmon resonance" is a technology for studying biospecific interactions in real time, without labeling any of the interactants (e.g., BIAcore). Changes in the mass at the binding surface (indicative of a binding event) result in alterations of the refractive index of light near the surface (the optical phenomenon of surface plasmon resonance (SPR)), resulting in a detectable signal which can be used as an indication of real-time reactions between biological molecules.

[0270] Alternatively, in another embodiment, analogous diagnostic and prognostic assays can be conducted with marker and probe as solutes in a liquid phase. In such an assay, the complexed marker and probe are separated from uncomplexed components by any of a number of standard techniques, including but not limited to: differential centrifugation, chromatography, electrophoresis and immunoprecipitation. In differential centrifugation, marker/probe complexes may be separated from uncomplexed assay components through a series of centrifugal steps, due to the different sedimentation equilibria of complexes based on their different sizes and densities (see, for example, Rivas, G., and Minton, A. P., 1993, Trends Biochem Sci. 18(8):284-7). Standard chromatographic techniques may also be utilized to separate complexed molecules from uncomplexed ones. For example, gel filtration chromatography separates molecules based on size, and through the utilization of an appropriate gel filtration resin in a column format, for example, the relatively larger complex may be separated from the relatively smaller uncomplexed components. Similarly, the relatively different charge properties of the marker/probe complex as compared to the uncomplexed components may be exploited to differentiate the complex from uncomplexed components, for example through the utilization of ion-exchange chromatography resins. Such resins and chromatographic techniques are well known to one skilled in the art (see, e.g., Heegaard, N. H., 1998, J. Mol. Recognit. Winter 11(1-6):141-8; Hage, D. S., and Tweed, S. A. J Chromatogr B Biomed Sci Appl 1997 Oct. 10; 699(1-2):499-525). Gel electrophoresis may also be employed to separate complexed assay components from unbound components (see, e.g., Ausubel et al., ed., Current Protocols in Molecular Biology, John Wiley & Sons, New York, 1987-1999). In this technique, protein or nucleic acid complexes are separated based on size or charge, for example. In order to maintain the binding interaction during the electrophoretic process, non-denaturing gel matrix materials and conditions in the absence of reducing agent are typically preferred. Appropriate conditions to the particular assay and components thereof will be well known to one skilled in the art.

[0271] In a particular embodiment, the level of marker mRNA can be determined both by in situ and by in vitro formats in a biological sample using methods known in the art. The term "biological sample" is intended to include tissues, cells, biological fluids and isolates thereof, isolated from a subject, as well as tissues, cells and fluids present within a subject. Many expression detection methods use isolated RNA. For in vitro methods, any RNA isolation technique that does not select against the isolation of mRNA can be utilized for the purification of RNA from breast cells (see, e.g., Ausubel et al., ed., Current Protocols in Molecular Biology, John Wiley & Sons, New York 1987-1999). Additionally, large numbers of tissue samples can readily be processed using techniques well known to those of skill in the art, such as, for example, the single-step RNA isolation process of Chomczynski (1989, U.S. Pat. No. 4,843,155).

[0272] The isolated mRNA can be used in hybridization or amplification assays that include, but are not limited to, Southern or Northern analyses, polymerase chain reaction analyses and probe arrays. One preferred diagnostic method for the detection of mRNA levels involves contacting the isolated mRNA with a nucleic acid molecule (probe) that can hybridize to the mRNA encoded by the gene being detected. The nucleic acid probe can be, for example, a full-length cDNA, or a portion thereof, such as an oligonucleotide of at least 7, 15, 30, 50, 100, 250 or 500 nucleotides in length and sufficient to specifically hybridize under stringent conditions to a mRNA or genomic DNA encoding a marker of the present invention. Other suitable probes for use in the diagnostic assays of the invention are described herein. Hybridization of an mRNA with the probe indicates that the marker in question is being expressed.

[0273] In one format, the mRNA is immobilized on a solid surface and contacted with a probe, for example by running the isolated mRNA on an agarose gel and transferring the mRNA from the gel to a membrane, such as nitrocellulose. In an alternative format, the probe(s) are immobilized on a solid surface and the mRNA is contacted with the probe(s), for example, in an Affymetrix gene chip array. A skilled artisan can readily adapt known mRNA detection methods for use in detecting the level of mRNA encoded by the markers of the present invention.

[0274] An alternative method for determining the level of mRNA marker in a sample involves the process of nucleic acid amplification, e.g., by rtPCR (the experimental embodiment set forth in Mullis, 1987, U.S. Pat. No. 4,683,202), ligase chain reaction (Barany, 1991, Proc. Natl. Acad. Sci. USA, 88:189-193), self sustained sequence replication (Guatelli et al., 1990, Proc. Natl. Acad. Sci. USA 87:1874-1878), transcriptional amplification system (Kwoh et al., 1989, Proc. Natl. Acad. Sci. USA 86:1173-1177), Q-Beta Replicase (Lizardi et al., 1988, Bio/Technology 6:1197), rolling circle replication (Lizardi et al., U.S. Pat. No. 5,854,033) or any other nucleic acid amplification method, followed by the detection of the amplified molecules using techniques well known to those of skill in the art. These detection schemes are especially useful for the detection of nucleic acid molecules if such molecules are present in very low numbers. As used herein, amplification primers are defined as being a pair of nucleic acid molecules that can anneal to 5' or 3' regions of a gene (plus and minus strands, respectively, or vice-versa) and contain a short region in between. In general, amplification primers are from about 10 to 30 nucleotides in length and flank a region from about 50 to 200 nucleotides in length. Under appropriate conditions and with appropriate reagents, such primers permit the amplification of a nucleic acid molecule comprising the nucleotide sequence flanked by the primers.

[0275] For in situ methods, mRNA does not need to be isolated from the breast cells prior to detection. In such methods, a cell or tissue sample is prepared/processed using known histological methods. The sample is then immobilized on a support, typically a glass slide, and then contacted with a probe that can hybridize to mRNA that encodes the marker.

[0276] As an alternative to making determinations based on the absolute expression level of the marker, determinations may be based on the normalized expression level of the marker. Expression levels are normalized by correcting the absolute expression level of a marker by comparing its expression to the expression of a gene that is not a marker, e.g., a housekeeping gene that is constitutively expressed. Suitable genes for normalization include housekeeping genes such as the actin gene, or epithelial cell-specific genes. This normalization allows the comparison of the expression level in one sample, e.g., a patient sample, to another sample, e.g., a non-breast cancer sample, or between samples from different sources.

[0277] Alternatively, the expression level can be provided as a relative expression level. To determine a relative expression level of a marker, the level of expression of the marker is determined for 10 or more samples of normal versus cancer cell isolates, preferably 50 or more samples, prior to the determination of the expression level for the sample in question. The mean expression level of each of the genes assayed in the larger number of samples is determined and this is used as a baseline expression level for the marker. The expression level of the marker determined for the test sample (absolute level of expression) is then divided by the mean expression value obtained for that marker. This provides a relative expression level.

[0278] Preferably, the samples used in the baseline determination will be from breast cancer or from non-breast cancer cells of breast tissue. The choice of the cell source is dependent on the use of the relative expression level. Using expression found in normal tissues as a mean expression score aids in validating whether the marker assayed is breast specific (versus normal cells). In addition, as more data is accumulated, the mean expression value can be revised, providing improved relative expression values based on accumulated data. Expression data from breast cells provides a means for grading the severity of the breast cancer state.

[0279] In another embodiment of the present invention, a marker protein is detected. A preferred agent for detecting marker protein of the invention is an antibody capable of binding to such a protein or a fragment thereof, preferably an antibody with a detectable label. Antibodies can be polyclonal, or more preferably, monoclonal. An intact antibody, or a fragment or derivative thereof (e.g., Fab or F(ab').sub.2) can be used. The term "labeled", with regard to the probe or antibody, is intended to encompass direct labeling of the probe or antibody by coupling (i.e., physically linking) a detectable substance to the probe or antibody, as well as indirect labeling of the probe or antibody by reactivity with another reagent that is directly labeled. Examples of indirect labeling include detection of a primary antibody using a fluorescently labeled secondary antibody and end-labeling of a DNA probe with biotin such that it can be detected with fluorescently labeled streptavidin.

[0280] Proteins from breast cells can be isolated using techniques that are well known to those of skill in the art. The protein isolation methods employed can, for example, be such as those described in Harlow and Lane (Harlow and Lane, 1988, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.).

[0281] A variety of formats can be employed to determine whether a sample contains a protein that binds to a given antibody. Examples of such formats include, but are not limited to, enzyme immunoassay (EIA), radioimmunoassay (RIA), Western blot analysis and enzyme linked immunoabsorbant assay (ELISA). A skilled artisan can readily adapt known protein/antibody detection methods for use in determining whether breast cells express a marker of the present invention.

[0282] In one format, antibodies, or antibody fragments or derivatives, can be used in methods such as Western blots or immunofluorescence techniques to detect the expressed proteins. In such uses, it is generally preferable to immobilize either the antibody or proteins on a solid support. Suitable solid phase supports or carriers include any support capable of binding an antigen or an antibody. Well-known supports or carriers include glass, polystyrene, polypropylene, polyethylene, dextran, nylon, amylases, natural and modified celluloses, polyacrylamides, gabbros, and magnetite.

[0283] One skilled in the art will know many other suitable carriers for binding antibody or antigen, and will be able to adapt such support for use with the present invention. For example, protein isolated from breast cells can be run on a polyacrylamide gel electrophoresis and immobilized onto a solid phase support such as nitrocellulose. The support can then be washed with suitable buffers followed by treatment with the detectably labeled antibody. The solid phase support can then be washed with the buffer a second time to remove unbound antibody. The amount of bound label on the solid support can then be detected by conventional means.

[0284] The invention also encompasses kits for detecting the presence of a marker protein or nucleic acid in a biological sample (e.g., a breast-associated body fluid such as a nipple aspirate). Such kits can be used to determine if a subject is suffering from or is at increased risk of developing breast cancer. For example, the kit can comprise a labeled compound or agent capable of detecting a marker protein or nucleic acid in a biological sample and means for determining the amount of the protein or mRNA in the sample (e.g., an antibody which binds the protein or a fragment thereof, or an oligonucleotide probe which binds to DNA or mRNA encoding the protein). Kits can also include instructions for interpreting the results obtained using the kit.

[0285] For antibody-based kits, the kit can comprise, for example: (1) a first antibody (e.g., attached to a solid support) which binds to a marker protein; and, optionally, (2) a second, different antibody which binds to either the protein or the first antibody and is conjugated to a detectable label.

[0286] For oligonucleotide-based kits, the kit can comprise, for example: (1) an oligonucleotide, e.g., a detectably labeled oligonucleotide, which hybridizes to a nucleic acid sequence encoding a marker protein or (2) a pair of primers useful for amplifying a marker nucleic acid molecule. The kit can also comprise, e.g., a buffering agent, a preservative, or a protein stabilizing agent. The kit can further comprise components necessary for detecting the detectable label (e.g., an enzyme or a substrate). The kit can also contain a control sample or a series of control samples which can be assayed and compared to the test sample. Each component of the kit can be enclosed within an individual container and all of the various containers can be within a single package, along with instructions for interpreting the results of the assays performed using the kit.

Pharmacogenomics

[0287] The markers of the invention are also useful as pharmacogenomic markers. As used herein, a "pharmacogenomic marker" is an objective biochemical marker whose expression level correlates with a specific clinical drug response or susceptibility in a patient (see, e.g., McLeod et al. (1999) Eur. J. Cancer 35(12): 1650-1652). The presence or quantity of the pharmacogenomic marker expression is related to the predicted responsive of the patient and more particularly the patient's tumor to therapy with a specific drug or class of drugs. By assessing the presence or quantity of the expression of one or more pharmacogenomic markers in a patient, a drug therapy which is most appropriate for the patient, or which is predicted to have a greater degree of success, may be selected. For example, based on the presence or quantity of RNA or protein encoded by specific tumor markers in a patient, a drug or course of treatment may be selected that is optimized for the treatment of the specific tumor likely to be present in the patient. The use of pharmacogenomic markers therefore permits selecting or designing the most appropriate treatment for each cancer patient without trying different drugs or regimes.

[0288] Another aspect of pharmacogenomics deals with genetic conditions that alters the way the body acts on drugs. These pharmacogenetic conditions can occur either as rare defects or as polymorphisms. For example, glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common inherited enzymopathy in which the main clinical complication is hemolysis after ingestion of oxidant drugs (anti-malarials, sulfonamides, analgesics, nitrofurans) and consumption of fava beans.

[0289] As an illustrative embodiment, the activity of drug metabolizing enzymes is a major determinant of both the intensity and duration of drug action. The discovery of genetic polymorphisms of drug metabolizing enzymes (e.g., N-acetyltransferase 2 (NAT 2) and cytochrome P450 enzymes CYP2D6 and CYP2C19) has provided an explanation as to why some patients do not obtain the expected drug effects or show exaggerated drug response and serious toxicity after taking the standard and safe dose of a drug. These polymorphisms are expressed in two phenotypes in the population, the extensive metabolizer (EM) and poor metabolizer (PM). The prevalence of PM is different among different populations. For example, the gene coding for CYP2D6 is highly polymorphic and several mutations have been identified in PM, which all lead to the absence of functional CYP2D6. Poor metabolizers of CYP2D6 and CYP2C19 quite frequently experience exaggerated drug response and side effects when they receive standard doses. If a metabolite is the active therapeutic moiety, a PM will show no therapeutic response, as demonstrated for the analgesic effect of codeine mediated by its CYP2D6-formed metabolite morphine. The other extreme are the so called ultra-rapid metabolizers who do not respond to standard doses. Recently, the molecular basis of ultra-rapid metabolism has been identified to be due to CYP2D6 gene amplification.

[0290] Thus, the level of expression of a marker of the invention in an individual can be determined to thereby select appropriate agent(s) for therapeutic or prophylactic treatment of the individual. In addition, pharmacogenetic studies can be used to apply genotyping of polymorphic alleles encoding drug-metabolizing enzymes to the identification of an individual's drug responsiveness phenotype. This knowledge, when applied to dosing or drug selection, can avoid adverse reactions or therapeutic failure and thus enhance therapeutic or prophylactic efficiency when treating a subject with a modulator of expression of a marker of the invention.

Monitoring Clinical Trials

[0291] Monitoring the influence of agents (e.g., drug compounds) on the level of expression of a marker of the invention can be applied not only in basic drug screening, but also in clinical trials. For example, the effectiveness of an agent to affect marker expression can be monitored in clinical trials of subjects receiving treatment for breast cancer. In a preferred embodiment, the present invention provides a method for monitoring the effectiveness of treatment of a subject with an agent (e.g., an agonist, antagonist, peptidomimetic, protein, peptide, nucleic acid, small molecule, or other drug candidate) comprising the steps of (i) obtaining a pre-administration sample from a subject prior to administration of the agent; (ii) detecting the level of expression of one or more selected markers of the invention in the pre-administration sample; (iii) obtaining one or more post-administration samples from the subject; (iv) detecting the level of expression of the marker(s) in the post-administration samples; (v) comparing the level of expression of the marker(s) in the pre-administration sample with the level of expression of the marker(s) in the post-administration sample or samples; and (vi) altering the administration of the agent to the subject accordingly. For example, increased expression of marker gene(s) during the course of treatment may indicate ineffective dosage and the desirability of increasing the dosage. Conversely, decreased expression of the marker gene(s) may indicate efficacious treatment and no need to change dosage.

Electronic Apparatus Readable Media and Arrays

[0292] Electronic apparatus readable media comprising a marker of the present invention is also provided. As used herein, "electronic apparatus readable media" refers to any suitable medium for storing, holding or containing data or information that can be read and accessed directly by an electronic apparatus. Such media can include, but are not limited to: magnetic storage media, such as floppy discs, hard disc storage medium, and magnetic tape; optical storage media such as compact disc; electronic storage media such as RAM, ROM, EPROM, EEPROM and the like; general hard disks and hybrids of these categories such as magnetic/optical storage media. The medium is adapted or configured for having recorded thereon a marker of the present invention.

[0293] As used herein, the term "electronic apparatus" is intended to include any suitable computing or processing apparatus or other device configured or adapted for storing data or information. Examples of electronic apparatus suitable for use with the present invention include stand-alone computing apparatus; networks, including a local area network (LAN), a wide area network (WAN) Internet, Intranet, and Extranet; electronic appliances such as a personal digital assistants (PDAs), cellular phone, pager and the like; and local and distributed processing systems.

[0294] As used herein, "recorded" refers to a process for storing or encoding information on the electronic apparatus readable medium. Those skilled in the art can readily adopt any of the presently known methods for recording information on known media to generate manufactures comprising the markers of the present invention.

[0295] A variety of software programs and formats can be used to store the marker information of the present invention on the electronic apparatus readable medium. For example, the marker nucleic acid sequence can be represented in a word processing text file, formatted in commercially-available software such as WordPerfect and MicroSoft Word, or represented in the form of an ASCII file, stored in a database application, such as DB2, Sybase, Oracle, or the like, as well as in other forms. Any number of data processor structuring formats (e.g., text file or database) may be employed in order to obtain or create a medium having recorded thereon the markers of the present invention.

[0296] By providing the markers of the invention in readable form, one can routinely access the marker sequence information for a variety of purposes. For example, one skilled in the art can use the nucleotide or amino acid sequences of the present invention in readable form to compare a target sequence or target structural motif with the sequence information stored within the data storage means. Search means are used to identify fragments or regions of the sequences of the invention which match a particular target sequence or target motif.

[0297] The present invention therefore provides a medium for holding instructions for performing a method for determining whether a subject has breast cancer or a pre-disposition to breast cancer, wherein the method comprises the steps of determining the presence or absence of a marker and based on the presence or absence of the marker, determining whether the subject has breast cancer or a pre-disposition to breast cancer and/or recommending a particular treatment for breast cancer or pre-breast cancer condition.

[0298] The present invention further provides in an electronic system and/or in a network, a method for determining whether a subject has breast cancer or a pre-disposition to breast cancer associated with a marker wherein the method comprises the steps of determining the presence or absence of the marker, and based on the presence or absence of the marker, determining whether the subject has breast cancer or a pre-disposition to breast cancer, and/or recommending a particular treatment for the breast cancer or pre-breast cancer condition. The method may further comprise the step of receiving phenotypic information associated with the subject and/or acquiring from a network phenotypic information associated with the subject.

[0299] The present invention also provides in a network, a method for determining whether a subject has breast cancer or a pre-disposition to breast cancer associated with a marker, said method comprising the steps of receiving information associated with the marker receiving phenotypic information associated with the subject, acquiring information from the network corresponding to the marker and/or breast cancer, and based on one or more of the phenotypic information, the marker, and the acquired information, determining whether the subject has a breast cancer or a pre-disposition to breast cancer. The method may further comprise the step of recommending a particular treatment for the breast cancer or pre-breast cancer condition.

[0300] The present invention also provides a business method for determining whether a subject has breast cancer, an aggressive breast tumor or a pre-disposition to breast cancer, said method comprising the steps of receiving information associated with the marker, receiving phenotypic information associated with the subject, acquiring information from the network corresponding to the marker and/or breast cancer, and based on one or more of the phenotypic information, the marker, and the acquired information, determining whether the subject has breast cancer or a pre-disposition to breast cancer. The method may further comprise the step of recommending a particular treatment for the breast cancer or pre-breast cancer condition.

[0301] The invention also includes an array comprising a marker of the present invention. The array can be used to assay expression of one or more genes in the array. In one embodiment, the array can be used to assay gene expression in a tissue to ascertain tissue specificity of genes in the array. In this manner, up to about 7600 genes can be simultaneously assayed for expression. This allows a profile to be developed showing a battery of genes specifically expressed in one or more tissues.

[0302] In addition to such qualitative determination, the invention allows the quantitation of gene expression. Thus, not only tissue specificity, but also the level of expression of a battery of genes in the tissue is ascertainable. Thus, genes can be grouped on the basis of their tissue expression per se and level of expression in that tissue. This is useful, for example, in ascertaining the relationship of gene expression between or among tissues. Thus, one tissue can be perturbed and the effect on gene expression in a second tissue can be determined. In this context, the effect of one cell type on another cell type in response to a biological stimulus can be determined. Such a determination is useful, for example, to know the effect of cell-cell interaction at the level of gene expression. If an agent is administered therapeutically to treat one cell type but has an undesirable effect on another cell type, the invention provides an assay to determine the molecular basis of the undesirable effect and thus provides the opportunity to co-administer a counteracting agent or otherwise treat the undesired effect. Similarly, even within a single cell type, undesirable biological effects can be determined at the molecular level. Thus, the effects of an agent on expression of other than the target gene can be ascertained and counteracted.

[0303] In another embodiment, the array can be used to monitor the time course of expression of one or more genes in the array. This can occur in various biological contexts, as disclosed herein, for example development of breast cancer, progression of breast cancer, and processes, such a cellular transformation associated with breast cancer.

[0304] The array is also useful for ascertaining the effect of the expression of a gene on the expression of other genes in the same cell or in different cells. This provides, for example, for a selection of alternate molecular targets for therapeutic intervention if the ultimate or downstream target cannot be regulated.

[0305] The array is also useful for ascertaining differential expression patterns of one or more genes in normal and abnormal cells. This provides a battery of genes that could serve as a molecular target for diagnosis or therapeutic intervention.

Surrogate Markers

[0306] The markers of the invention may serve as surrogate markers for one or more disorders or disease states or for conditions leading up to disease states, and in particular, breast cancer. As used herein, a "surrogate marker" is an objective biochemical marker which correlates with the absence or presence of a disease or disorder, or with the progression of a disease or disorder (e.g., with the presence or absence of a tumor). The presence or quantity of such markers is independent of the disease. Therefore, these markers may serve to indicate whether a particular course of treatment is effective in lessening a disease state or disorder. Surrogate markers are of particular use when the presence or extent of a disease state or disorder is difficult to assess through standard methodologies (e.g., early stage tumors), or when an assessment of disease progression is desired before a potentially dangerous clinical endpoint is reached (e.g., an assessment of cardiovascular disease may be made using cholesterol levels as a surrogate marker, and an analysis of HIV infection may be made using HIV RNA levels as a surrogate marker, well in advance of the undesirable clinical outcomes of myocardial infarction or fully-developed AIDS). Examples of the use of surrogate markers in the art include: Koomen et al. (2000) J. Mass. Spectrom. 35: 258-264; and James (1994) AIDS Treatment News Archive 209.

[0307] The markers of the invention are also useful as pharmacodynamic markers. As used herein, a "pharmacodynamic marker" is an objective biochemical marker which correlates specifically with drug effects. The presence or quantity of a pharmacodynamic marker is not related to the disease state or disorder for which the drug is being administered; therefore, the presence or quantity of the marker is indicative of the presence or activity of the drug in a subject. For example, a pharmacodynamic marker may be indicative of the concentration of the drug in a biological tissue, in that the marker is either expressed or transcribed or not expressed or transcribed in that tissue in relationship to the level of the drug. In this fashion, the distribution or uptake of the drug may be monitored by the pharmacodynamic marker. Similarly, the presence or quantity of the pharmacodynamic marker may be related to the presence or quantity of the metabolic product of a drug, such that the presence or quantity of the marker is indicative of the relative breakdown rate of the drug in vivo. Pharmacodynamic markers are of particular use in increasing the sensitivity of detection of drug effects, particularly when the drug is administered in low doses. Since even a small amount of a drug may be sufficient to activate multiple rounds of marker transcription or expression, the amplified marker may be in a quantity which is more readily detectable than the drug itself. Also, the marker may be more easily detected due to the nature of the marker itself; for example, using the methods described herein, antibodies may be employed in an immune-based detection system for a protein marker, or marker-specific radiolabeled probes may be used to detect a mRNA marker. Furthermore, the use of a pharmacodynamic marker may offer mechanism-based prediction of risk due to drug treatment beyond the range of possible direct observations. Examples of the use of pharmacodynamic markers in the art include: Matsuda et al. U.S. Pat. No. 6,033,862; Hattis et al. (1991) Env. Health Perspect. 90: 229-238; Schentag (1999) Am. J. Health-Syst. Pharm. 56 Suppl. 3: S21-S24; and Nicolau (1999) Am, J. Health-Syst. Pharm. 56 Suppl. 3: S16-S20.

EXAMPLE 1

Identification of Breast Cancer Markers by cDNA and Tissue Microarrays

I. Materials and Methods

Sample Collection and RNA Preparation

[0308] Breast tissues were collected and snap frozen in liquid nitrogen. The histology and cellular composition of tissues were confirmed before RNA extraction was performed. Total RNA was extracted from the frozen tissues using Trizol Reagent (Invitrogen, San Diego, Calif.) followed by a secondary clean up step with Qiagen's RNeasy kit to increase RNA probe labeling efficiency (Qiagen, Valencia Calif.). Only RNA with a 28S/18S ribosomal RNA ratio of at least 1.0, calculated from ethidium staining of the RNA after electrophoresis on agarose gels, was used in this study.

cDNA Microarray Hybridization

[0309] cDNA microarrays containing 30,732 Unigene clones from Research Genetics (Hunstville, Ala.) were generated on nylon filters. A total of 4-6 ug of total RNA was used as template to generate radioactively labeled cDNA by reverse transcription with .sup.33P-dCTP, oligo dT-30 primer and Superscript II Reverse Transcriptase (Life Technologies). .sup.33P-labeled first strand cDNA was preannealed with cot-1 DNA and poly-dA 40-60 (Pharmacia, Peapack, N.J.) to reduce non-specific hybridization. Each filter was hybridized at 65.degree. C. for 16 hours with approximately 6.times.10.sup.6 counts of labeled probe in a buffer containing 7% sodium dodecyl sulfate (SDS), 250 mM Na.sub.3PO.sub.4 (pH 7.2), 1 mM EDTA, 0.5% Casein-Hammerstein and 0.1 mg/ml of denatured salmon sperm DNA. After the filters were washed with 4% and 1% SDS wash buffer (20 mM Na.sub.3PO.sub.4 (pH 7.2), 1 mM EDTA and 4% or 1% SDS), they were exposed to Fuji Phosphoimager screens and scanned using a Fuji scanner BAS 2500. Spots were quantitated using an automated array analysis program, Grid Guru v1.0, developed at Millennium Pharmaceuticals, Inc.

Marker Scoring Algorithm and Data Analysis

[0310] To correct for differences in hybridization efficiency, the digitized data from each microarray filter was normalized by the median intensity of all spots on that filter. Both array-based and gene-based hierarchical clustering was performed and visualized using Stanford's Gene Cluster and Tree View software. Differentially expressed genes were ranked by calculating the Marker Score for each gene.

[0311] Samples were divided into control and tester groups for computation of Marker Score. The starting point for the Marker Score is average fold change (ratio) of the tester samples above the control samples. The score was designed to reflect both the degree of change (the expression ratio) and the number of tester samples showing differential expression, while not being dominated by a small fraction of tester samples with very high values. To reduce this "outlier" effect, genes were treated with expression ratios greater than 10 as not meaningfully different from those with ratios of 10. This desired performance from a Marker Score was accomplished by transforming the tester:control expression ratio using an asymptotic compression function before taking the average fold-change across tester samples. A Marker Score has a value of 1 when the testers do not appear to be expressed more highly than the controls and a value greater than 1 otherwise. A Marker Score cannot exceed a value of 10 for any gene.

[0312] The Marker Score Sg for gene g is therefore computed as the average of the ratios of weighted intensities of the individual testers and a control level as follows:

S.sub.g=(.SIGMA.S.sub.gs)/N.sub.tester

S.sub.gs=C(x.sub.gs/(k+x.sub.g.sup.Q)), where S.sub.gs represents the Marker Score for gene g and the sample s, C(r) is the compression function C(r)=A(1-e.sup.-r/A) for r.gtoreq.1, and C(r)=1 for r<1, A is an upper asymptote on the fold-change value (we used 10), x.sub.gs is the expression value of gene g on sample s, x.sub.g.sup.Q is the Qth percentile of the control samples' expression value; typically Q=50, k is a constant reflecting the additive noise in the data, i.e., the fixed component of the variance in repeated measurements. A value of 0.25 was derived for this parameter from calibration experiments using microarray technology. N.sub.tester is the number of tester samples

In Situ Hybridization of Tissue Microarrays

[0313] Formalin-fixed, paraffin embedded breast tissue microarrays were provided. Prehybridization treatment was performed with an automatic Tissue-Tek DRS 2000 Slide Stainer (Sakura, Torrance, Calif.) using a previously described protocol (Duncan, L. M., et al., 2001, J. Clin. Oncol. 19(2): 568-576). The breast tissues were deparaffinized, rehydrated and postfixed with 4% paraformaldehyde in PBS for 15 minutes. After washing with PBS, the tissue microarrays were digested with 2 ug/ml proteinase K at 37.degree. C. for 15 minutes and again incubated with 4% paraformaldehyde/PBS for 10 minutes. Tissue sections were subsequently incubated with 0.2N HCL for 10 minutes, 0.25% acetic anhydride/0.1 mol/L triethanolamine for 10 minutes, and dehydrated with graded ethanol. Antisense probes were labeled with .sup.35S-UTP in an in vitro transcription reaction (Riboprobe Combination System, Promega, Madison, Wis.) using 500 ng of linearized plasmid DNA derived from IMAGE clones. Hybridizations were performed at 50.degree. C. for 18 hours using probes labeled at 5.times.10.sup.7 cpm/ml in 10 mM Tris-HCl (pH 7.6) buffer containing 50% formamide, 10% dextran sulfate, 1.times.Denhardt's solution, 0.6 M NaCl, 10 mM DTT, 0.25% SDS and 200 ug/ml tRNA. After hybridization, slides were washed with 5.times. standard saline citrate (SSC) at 50.degree. C. for 10 minutes, 50% formamide/2.times.SSC at 50.degree. C. for 30 minutes, 10 mM Tris-HCl (pH 7.6)/500 mM NaCl/1 mM EDTA (TNE) at 37.degree. C. for 10 minutes, incubated in 10 ug/ml Rnase A in TNE at 37.degree. C. for 30 minutes, washed in TNE at 37.degree. C. for 10 minutes, incubated once in 2.times.SSC at 50.degree. C. for 20 minutes, twice in 0.2.times.SSC at 50.degree. C. for 20 minutes, and dehydrated with graded ethanol. Localization of mRNA transcripts was determined by dipping slides in Kodak NTB2 photoemulsion (Eastman Kodak, Rochester, N.Y.) and exposing for 14-21 days at 4.degree. C. The slides were counterstained using Myers hematoxylin and alcoholic eosin Y.

Gene Expression Analysis Using Quantitative PCR

[0314] Gene expression was measured by TAQMAN.RTM. quantitative PCR (Applied Biosystems) in cDNA prepared from normal and diseased (e.g., cancerous) human tissue samples. Briefly, total RNA was prepared from patient samples by a single step extraction method using TRIZOL Reagent according to the manufacturer's instructions (Invitrogen). Each RNA preparation was treated with DNase I (Ambion) at 37.degree. C. for 1 hour. DNAse I treatment was determined to be complete if the sample required at least 38 PCR amplification cycles to reach a threshold level of fluorescence using .beta.-2 microglobulin as an internal amplicon reference (or 35 PCR amplification cycles for 18 s ribosome gene). The integrity of the RNA samples following DNase I treatment was confirmed by agarose gel electrophoresis and ethidium bromide staining. After phenol extraction cDNA was prepared from the sample using the Taqman Reverse Transcription Reagents following the manufacturer's instructions (Applied Biosytems). A negative control of RNA without reverse transcriptase was mock reverse transcribed for each RNA sample.

[0315] Probes were designed by PrimerExpress software (Applied Biosystems) based on the sequence of the specific genes and their related transcripts. Each target gene probe was labeled using FAM (6-carboxyfluorescein), and the 18 s reference probe was labeled with a different fluorescent dye, VIC. The differential labeling of the target gene and internal reference gene thus enabled measurement in same well. Primer and probes were checked for their sensitivity and specificity for each transcript of the specific gene. Forward and reverse primers and the probes for both 18 s and target gene were added to the TAQMAN.RTM. Universal PCR Master Mix (Applied Biosystems). Although the final concentration of primer and probe could vary, each was internally consistent within a given experiment. A typical experiment contained 100 nM of forward and reverse primers plus 200 nM probe for 18 s and 900 nM forward and reverse primers plus 250 nM probe for the target gene. TAQMAN.RTM. matrix experiments were carried out on an ABI PRISM 7700 Sequence Detection System (Applied Biosystems). The thermal cycler conditions were as follows: hold for 2 min at 50.degree. C. and 10 min at 95.degree. C., followed by two-step PCR for 40 cycles of 95.degree. C. for 15 sec followed by 60.degree. C. for 1 min

[0316] The following method was used to quantitatively calculate gene expression in the various tissues relative to 18 s expression in the same tissue. The threshold cycle (Ct) value is defined as the cycle at which a statistically significant increase in fluorescence is detected. A lower Ct value is indicative of a higher mRNA concentration. The Ct value of the gene is normalized by subtracting the Ct value of the 18 s ribosome gene to obtain a .DELTA.Ct value using the following formula: .DELTA.Ct=Ct (target transcript)-Ct (18 s). Relative expression is then calculated using the arithmetic formula given by 2-.DELTA.Ct.

II. Results

Screening Marker Selection

[0317] All of the markers listed in Table 1 were identified by transcription profiling as defined in the materials and methods section above using mRNA from a breast screening panel consisting of patient samples of a "breast tumor pool" (3 breast tumor patient samples), a "breast normal pool" (3 normal breast epithelium patient samples), an "other normals pool" (one sample from normal heart, kidney, small intestine, spleen, white blood cells, lung, liver, brain, bone marrow and colon patient tissue samples) and an "others tumors pool" (4 cervical carcinoma, 5 colon tumor, 8 lung carcinoma patient samples of various types, 4 ovarian tumor samples, and 5 prostate tumor samples). Clones having expression of at least three-fold higher in at least 25% of breast tumors, compared to their expression breast normal, other normal or other tumors, were designated as breast tumor specific screening markers. These cDNA clones were selected to have their protein-encoding transcript sequences determined.

[0318] In order to determine the full-length protein-encoding transcripts for the selected cDNA clones, the sequence(s) of the selected clones were used to query the public and proprietary sequence databases in order to identify other EST sequences or clusters with significant overlap. Thus, contiguous EST sequences and/or clusters were assembled into protein-encoding transcripts. Alternative transcript analysis for all of the claimed markers was undertaken as follows.

[0319] Using existing mappings of known nucleotide sequences for any given marker gene to the human genome sequence and by additionally mapping novel nucleotide sequences for any given marker gene onto the human genome sequence (e.g., using resources like the "UCSC genome browser" or in-house resources of similar functionality in conjunction with algorithms like BLAT that allow a rapid and precise mapping of search sequences onto genomic sequence), the exon-intron structure of a marker gene was established, taking additionally into account EST sequences matching the same gene.

[0320] PCR primers were designed to amplify the coding sequence of a given marker gene from the tissue of interest and control samples. Any alternative 5' or 3' ends of a marker gene arising from this analysis with the potential to alter the coding sequence led to the design of an additional primer specific for this alternative end.

[0321] PCR products obtained with cDNA templates derived from breast tumor specimens were cloned into a plasmid vector and characterized by DNA sequence analysis. Typically, 96 clones were analyzed by restriction digestion and gel electrophoresis of the PCR products or by DNA sequence analysis.

[0322] Clones representative of alternative gene transcripts occurring at a frequency of 2% or greater were sequenced. The identification of protein sequence corresponding to these alternative transcripts was accomplished by the identification of the open reading frame (ORF) contained within a manually curated assembly (contig) based on all available sequences. The identified sequences are designated in Table 1 and the sequence listing.

[0323] Differential gene expression of genes with identified alternative transcripts was confirmed by TAQMAN.RTM. quantitative PCR (Applied Biosystems) in cDNA prepared from the patient tissue specimens. Gene specific TAQMAN.RTM. reagents which were sensitive for all transcripts identified for a given gene were prepared in certain instances (e.g., BCMP11, DNAJC1 and NPY1R). Additionally, splice-form specific TAQMAN.RTM. reagent sets were developed for each transcript of certain markers separately (e.g., M725, M726, M727, M111, M149, M730, M165A, M731, M732, M96A, M739, M740, M741, M716, M717). With one exception, gene-specific as well as transcript-specific expression profiles demonstrating differential tumor-normal expression, with similar amplification efficiencies were found. In one case (M731, a NPY1R transcript), expression was not demonstrated with TAQMAN.RTM. PCR, presumably due to low abundance of this transcript.

Staging Marker Selection

[0324] All of the markers listed in Table 2 were identified by transcription profiling as defined in the materials and methods section using mRNA from 23 IDC node negative breast tumors with good outcome, defined as greater than five years of disease-free survival, and 16 IDC node negative breast tumors with poor clinical outcome, defined as less than three years of disease free survival. Clones having expression of at least three-fold higher in at least 25% of poor clinical outcome tumors, compared to their expression in good clinical outcome tumors, were designated as poor clinical outcome tumor specific markers. These cDNA clones were selected to have their protein-encoding transcript sequences determined.

[0325] Determination of the full-length protein encoding transcripts for selected cDNA clones was carried out as described above for the screening markers. The identified sequences are designated in Table 2 and the sequence listing. The differential gene expression of the identified alternative transcripts was confirmed by TAQMAN.RTM. quantitative PCR (Applied Biosystems) in cDNA prepared from patient tissue specimens from invasive ductal carcinoma (IDC) tumors with good outcome and poor outcome. Splice-form specific TaqMan primers and probe reagent sets were developed for each transcript and similar amplification efficiencies were obtained with all reagent sets for each gene (see Table 3).

[0326] The identification of protein sequences corresponding to these alternative transcripts was accomplished by the identification of the open reading frame (ORF) contained within a manually curated assembly (contig) based on all available sequences. The identified protein sequences are designated in Table 2 and the sequence listing.

TABLE-US-00003 TABLE 3 Breast Cancer Staging Marker Differential Expression GOP POP Pos/ GOP Pos/ POP Marker Gene Name Total Freq Total Freq M672A ASS: argininosuccinate synthetase 0 of 25 0.0% 0 of 39 0.0% M675A CAB2: hypothetical protein MGC9753 2 of 28 7.1% 3 of 37 8.1% M367 CD24: CD24 antigen (small cell lung 6 of 32 18.8% 16 of 38 42.1% carcinoma cluster 4 antigen) M709 FACL2: fatty-acid-Coenzyme A ligase, 0 of 25 0.0% 0 of 39 0.0% M710 long-chain 2 M495 GSTP1: glutathione S-transferase pi 0 of 25 0.0% 0 of 39 0.0% M674 HN1: hematological and neurological 0 of 25 0.0% 0 of 39 0.0% expressed 1 M234A MGC14832: hypothetical protein 0 of 25 0.0% 0 of 39 0.0% MGC14832 M408 NDRG1: N-myc downstream regulated 5 of 35 14.3% 12 of 39 30.8% protein M711 ORMDL3: ORM1-like 3 (S. cerevisiae) 5 of 28 17.9% 13 of 35 37.1% M514 DARPP-32: dopamine and cAMP regulated 0 of 25 0.0% 0 of 39 0.0% M708 phosphoprotein, (PPP1R1B: protein phosphatase 1, regulatory (inhibitor) subunit 1B) M678A PSMB9: proteasome subunit, beta type, 9 0 of 25 0.0% 0 of 39 0.0% M421A SERHL: kraken-like 5 of 33 15.2% 9 of 37 24.3% M185A SLPI: secretory leukocyte protease inhibitor 3 of 25 12.0% 4 of 36 11.1% (antileukoproteinase)

EXAMPLE 2

Gene Expression Analysis by End-Point PCR

I. Materials and Methods

[0327] Briefly, total RNA from different samples was pooled to be used as template to generate first strand cDNA. Equal amounts of each sample were included in the pool. The breast screening panel consisted of patient samples of a "breast tumor pool" (3 breast tumor patient samples), a "breast normal pool" (3 normal breast epithelium patient samples), an "other normals pool" (one sample from normal heart, kidney, small intestine, spleen, white blood cells, lung, liver, brain, bone marrow and colon patient tissue samples) and an "others tumors pool" (4 cervical carcinoma, 5 colon tumor, 8 lung carcinoma patient samples of various types, 4 ovarian tumor samples, and 5 prostate tumor samples) (see, e.g., Table 2). The breast staging panel consisted of patient samples of a "tumor good outcome pool" (4 adenocarcinoma patient samples), a "tumor poor outcome pool" (5 adenocardinoma patient samples), a "breast normal pool" (4 normal breast epithelium patient samples), an "other normals pool" (one patient sample from normal heart, kidney, small intestine, spleen, white blood cells, lung, liver brain, bone marrow and colon) and an "others tumors pool" (cervical, colon, lung, ovarian and prostate tumors) (see, e.g., Table 3).

[0328] Total RNA was prepared from patient samples by a single step extraction method using TRIZOL Reagent according to the manufacturer's instructions (Invitrogen). Each RNA preparation was treated with DNase I (Ambion) at 37.degree. C. for 1 hour. RNA from each patient sample was pooled into one of the four patient pools, e.g., breast normal pool, breast tumor pool, other normals pool, others tumors pool. ThermoScript RT-PCR System (Invitrogen, San Diego, Calif.) was used to obtain cDNA from each of the five patient pools. Briefly, 1 .mu.g RNA was denatured at 65.degree. C. for 5 min with 1 .mu.l of 50 .mu.M oligo (dT)20 primer in a 10 .mu.l volume according to the manufacturer's instructions. The reaction was terminated by incubation at 85.degree. C. for 5 min. The final product was diluted with water to a final volume of 100 .mu.l.

[0329] Gene specific primers were designed just outside the Open Reading Frame (as shown in Table 2 categories "Endpoint PCR Primer 1" and "Endpoint PCR Primer 2"). The PCR conditions were optimized for the primers and the size of the product expected. 2 .mu.l of cDNA was used in a 20 .mu.l reaction with touchdown cycling conditions. Products were run on an ethidium bromide containing agarose gel, and resulting gel pictures were semi-quantitatively analyzed and scored. The gel pictures of the end-point PCR on the tissue panel were scored on a scale of 1-5. Each picture was scored independently by three people based on visual band intensity and results compiled, scores were compared to confirm all three agreed on the relative intensities of the bands and modifications were made where needed. The median of the three scores was then recorded as the final score.

II. Results

TABLE-US-00004 [0330] TABLE 4 Breast Screening Endpoint PCR Data Endpoint Endpoint Gene PCR PCR Normal Tumor Breast Breast Marker Name Primer 1 Primer 2 Pool Pool Normal Tumor M196A BCMP11 1-20 243-262 3 3 3 5 M725 BCMP11 2-21 523-543 0 0 0 2 M726 BCMP11 1-20 107-126 3 3 3 5 M727 BCMP11 1-20 244-263 3 3 3 5 M156 CXCL9 12-38 479-498 0 3 0 4 M419 CXCL10 29-51 366-385 1 1 2 4 M728 DNAJC1 388-410 1155-1179 0 0 0 2 M729 DNAJC1 388-410 1137-1161 0 0 0 2 M111 DNAJC1 252-274 1775-1799 1 1 2 3 M428A FLJ22774 528-553 3028-3050 0 2 M149A LIV-1 266-283 2612-2638 0 3 2 5 M730 LIV-1 309-324 1748-1719 2 3 M158A MMP11 433-450 1518-1536 0 0 0 3 M165A NPY1R 195-215 1440-1459 2 2 3 5 M731 NPY1R 164-184 1506-1525 2 2 3 5 M732 NPY1R 195-215 1154-1173 2 2 3 5 M235 NY-BR-1 3539-3560 4171-4195 1 0 3 4 M562 PIP 4-22 494-509 0 3 4 5 M96A SCUBE2 342-365 3272-3294 0 0 3 5 M739 SCUBE2 342-365 3032-3054 0 0 3 5 M740 SCUBE2 342-365 2894-2916 0 0 3 5 M741 SCUBE2 342-365 3359-3381 0 0 3 5 M242 TFF1 22-42 351-371 0 0 2 5

[0331] Markers were expressed at higher levels in the breast tumor samples than those obtained from the other tumor samples or the normal sample groups (Table 4). Particular strong expression was observed with M725, M728, M729, M158A, M242, M156, M419, and M149A in the breast tumor group when compared to those obtained from the breast normal, other normal, or the other tumor group.

TABLE-US-00005 TABLE 5 Breast Staging Endpoint PCR Data Endpoint Endpoint Gene PCR PCR Tum Out Tum Out Marker Symbol Primer 1 Primer 2 Good Poor M672A ASS 69-88 1323-1344 1 5 M675A CAB2 1-21 1153-1177 0 3 M367 CD24 6-29 361-384 3 4 M514 DARPP-32, 179-198 1201-1220 1 5 variant 1 M708 DARPP-32, 137-156 1541-1560 1 4 variant 2 M709 FACL2 1-24 2307-2332 0 3 M710 M495 GSTP1 3-22 676-697 1 3 M674 HN1 54-72 601-622 2 5 M234A MGC14832 2-19 374-396 2 5 M408 NDRG1 66-85 1374-1393 1 3 M711 ORMDL3 287-308 874-896 0 4 M678A PSMB9 1-18 739-761 1 3 M421A SERHL 51-69 1103-1122 3 5 M185A SLPI 13-33 519-538 N/A 4

[0332] The markers were expressed at higher levels in the breast tumor samples of the poor outcome group than those obtained from the good outcome group (Table 5). Particular strong expression was observed with M672A, M675A, M514, M708, M710, M674, M234A, M711, and M421A in the poor outcome group when compared to those obtained from the good outcome group.

EXAMPLE 3

Characterization of OSF-2 Splice Variants

I. Materials and Methods

[0333] cDNA Synthesis

[0334] Total RNA was isolated from 3 normal and 12 tumor breast tissue samples similar to procedures described above in Examples 1 and 2. Briefly, using the TRIZOL Reagent (Invitrogen, San Diego, Calif.) System according to manufacturer instructions, followed by RNAeasy (Qiagen, Valencia, Calif.) or DNase I (Ambion) treatment according to manufacturers instructions. 1 .mu.g from each sample was combined into normal and tumor pools. ThermoScript RT-PCR System (Invitrogen, San Diego, Calif.) was used to obtain cDNA as described in Example 2 above. The final product was diluted with water to a final volume of 400-800 .mu.l.

[0335] cDNA was amplified using OSF-2 gene specific primers from exon 16 and exon 23 to cover the region involved in splice variation. Primers for PCR amplification were designed using Primer Version 5.0 software (Whitehead Institute, Cambridge, Mass.). PCR conditions were optimized for the primers and product size expected. 0.5 .mu.l of diluted RT reaction was used in a 30 .mu.l reaction with PCR conditions, after an initial 95.degree. C. denaturing step of 2 minutes, consisting of 55 cycles of 95.degree. C. for 30 sec, annealing @ 60.degree. C. for 35 sec and elongation temp of 72.degree. C. for 30 sec and a final elongation step of 72.degree. C. for 7 min

Cloning Colony PCR and Sequencing

[0336] PCR products for both reactions derived from RT/PCR were gel-purified and cloned into pCR2.1 using TOPO TA cloning kit and transforming into E. coli One-Shot Chemically Competent cells (Invitrogen, San Diego, Calif.) according to manufacturer's instructions. Resulting colonies were selected and colony PCR was carried out in 30 .mu.L volume as described under above using colony cells originating from the normal and the tumor pools as template. Resulting PCR product was purified using QIAquick 96 multiwell kit (Qiagen Inc., Valencia Calif.), and submitted for sequencing. Sequencing was preformed using ABI 3700 Automated Sequencer with Big Dye Terminators version 1.1.

[0337] The program BLAST [Kent, 2002] was used to align all clone sequences to genomic sequence of the OSF-2 locus. Only sequences matching the entire variable region of OSF-2, i.e., spanning at least from exon 17 to exon 22 or from exon 21 to exon 16 ("qualifying sequences`), were considered. Sequences were then grouped according to their presence-absence pattern of the variable exons 17-21.

II. Results

[0338] OSF-2 expression is subject to alternative splicing events creating eight transcript variants, which are characterized by different combinations of exons 17 to 21 (of 23 total exons) (see Table 6). Variable exons 17-19 and 21 are positioned within the coding sequence and can be present or absent without changing the transcripts' reading frame, giving rise to different protein products in a modular fashion.

TABLE-US-00006 TABLE 6 Schematic Representation of OSF-2 Alternative Splice Variants Marker ID Exon Exon Exon Exon Exon Exon Exon M56A 16 17 18 19 20 21 22 M733 16 17 18 19 20 22 M734 16 18 19 20 21 22 M735 16 18 19 20 22 M491A 16 19 20 21 22 M736 16 19 20 22 M737 16 20 21 22 M738 16 20 22

[0339] The relative expression levels of the eight listed splice variants of OSF-2 are different between normal and tumor tissue. Table 7 depicts the relative frequencies of each transcript in normal, and breast tumor tissue as obtained by analyzing qualifying sequences of clones derived from normal breast tissue and breast tumor tissue.

TABLE-US-00007 TABLE 7 Relative frequencies of OSF-2 splice variant transcripts in tissue % of all % of all transcripts transcripts Marker ID Description of transcript in normal in tumor M56A (1) all exons, +21 10.09 3.50 M733 (2) all exons, no 21 4.28 2.33 M734 (3) no 17, +21 31.50 23.03 M735 (4) no 17, no 21 24.46 32.07 M491A (5) no (17, 18), +21 11.62 11.95 M736 (6) no (17, 18), no 21 12.54 19.83 M737 (7) no (17-19), +21 0.61 2.33 M738 (8) no (17-19), no 21 2.45 4.67 Other transcripts 2.45 0.29 ALL 100 100

[0340] There is an increased level exon 21 containing transcripts in normal breast tissue, and increased level of transcripts lacking exon 21 in breast tumor tissue, (e.g., a total of 59% of all transcripts in breast tumor tissue lacking exon 21, compared to only 45% of all transcripts lacking exon 21 in normal breast tissue in samples analyzed).

[0341] Expression levels were determined for transcripts either containing or lacking exon 21 for OSF-2. Two reagent sets were used: one specific for transcripts containing exon 21 and a second one specific for transcripts that do not. A significant tumor/normal increased expression was observed. For example, an average 2.5-fold over-expression in tumor samples, is observed with the reagent set specific for OSF-2 transcripts lacking exon 21. This increase is not observed in assessing the OSF-2 transcripts containing exon 21. These results reflect both the differences in relative transcript frequencies between normal and tumor tissue as described above and a general overexpression of OSF-2 in tumor tissue as originally observed with transcriptional profiling microarray experiments using probes unable to distinguish between the OSF-2 variants described.

[0342] The references cited herein, including journal articles, patents, published patent applications, and database records including GenBank, IMAGE consortium and Derwent cited throughout this application, are hereby incorporated by reference.

Other Embodiments

[0343] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims:

Sequence CWU 1

1

961623DNAhumanCDS(48)...(548) 1aagagcactg gccaagtcag cttcttctga gagagtctct agaagac atg atg cta 56 Met Met Leu 1cac tca gct ttg ggt ctc tgc ctc tta ctc gtc aca gtt tct tcc aac 104His Ser Ala Leu Gly Leu Cys Leu Leu Leu Val Thr Val Ser Ser Asn 5 10 15ctt gcc att gca ata aaa aag gaa aag agg cct cct cag aca ctc tca 152Leu Ala Ile Ala Ile Lys Lys Glu Lys Arg Pro Pro Gln Thr Leu Ser20 25 30 35aga gga tgg gga gat gac atc act tgg gta caa act tat gaa gaa ggt 200Arg Gly Trp Gly Asp Asp Ile Thr Trp Val Gln Thr Tyr Glu Glu Gly 40 45 50ctc ttt tat gct caa aaa agt aag aag cca tta atg gtt att cat cac 248Leu Phe Tyr Ala Gln Lys Ser Lys Lys Pro Leu Met Val Ile His His 55 60 65ctg gag gat tgt caa tac tct caa gca cta aag aaa gta ttt gcc caa 296Leu Glu Asp Cys Gln Tyr Ser Gln Ala Leu Lys Lys Val Phe Ala Gln 70 75 80aat gaa gaa ata caa gaa atg gct cag aat aag ttc atc atg cta aac 344Asn Glu Glu Ile Gln Glu Met Ala Gln Asn Lys Phe Ile Met Leu Asn 85 90 95ctt atg cat gaa acc act gat aag aat tta tca cct gat ggg caa tat 392Leu Met His Glu Thr Thr Asp Lys Asn Leu Ser Pro Asp Gly Gln Tyr100 105 110 115gtg cct aga atc atg ttt gta gac cct tct tta aca gtt aga gct gac 440Val Pro Arg Ile Met Phe Val Asp Pro Ser Leu Thr Val Arg Ala Asp 120 125 130ata gct gga aga tac tct aac aga ttg tac aca tat gag cct cgg gat 488Ile Ala Gly Arg Tyr Ser Asn Arg Leu Tyr Thr Tyr Glu Pro Arg Asp 135 140 145tta ccc cta ttg ata gaa aac atg aag aaa gca tta aga ctt att cag 536Leu Pro Leu Leu Ile Glu Asn Met Lys Lys Ala Leu Arg Leu Ile Gln 150 155 160tca gag cta taa gagatgatag aaaaaagcct tcacttcaaa gaagtcaaat 588Ser Glu Leu * 165ttcatgaaga aaacctctgg cacattgaca aatac 6232166PRThuman 2Met Met Leu His Ser Ala Leu Gly Leu Cys Leu Leu Leu Val Thr Val1 5 10 15Ser Ser Asn Leu Ala Ile Ala Ile Lys Lys Glu Lys Arg Pro Pro Gln 20 25 30Thr Leu Ser Arg Gly Trp Gly Asp Asp Ile Thr Trp Val Gln Thr Tyr 35 40 45Glu Glu Gly Leu Phe Tyr Ala Gln Lys Ser Lys Lys Pro Leu Met Val 50 55 60Ile His His Leu Glu Asp Cys Gln Tyr Ser Gln Ala Leu Lys Lys Val65 70 75 80Phe Ala Gln Asn Glu Glu Ile Gln Glu Met Ala Gln Asn Lys Phe Ile 85 90 95Met Leu Asn Leu Met His Glu Thr Thr Asp Lys Asn Leu Ser Pro Asp 100 105 110Gly Gln Tyr Val Pro Arg Ile Met Phe Val Asp Pro Ser Leu Thr Val 115 120 125Arg Ala Asp Ile Ala Gly Arg Tyr Ser Asn Arg Leu Tyr Thr Tyr Glu 130 135 140Pro Arg Asp Leu Pro Leu Leu Ile Glu Asn Met Lys Lys Ala Leu Arg145 150 155 160Leu Ile Gln Ser Glu Leu 1653543DNAhumanCDS(49)...(501) 3caagagcact ggccaagtca gcttcttctg agagagtctc tagaagac atg atg cta 57 Met Met Leu 1cac tca gct ttg ggt ctc tgc ctc tta ctc gtc aca gtt tct tcc aac 105His Ser Ala Leu Gly Leu Cys Leu Leu Leu Val Thr Val Ser Ser Asn 5 10 15ctt gcc att gca ata aaa aag gaa aag agg cct cct cag aca ctc tca 153Leu Ala Ile Ala Ile Lys Lys Glu Lys Arg Pro Pro Gln Thr Leu Ser20 25 30 35aga gga tgg gga gat gac atc act tgg gta caa act tat gaa gaa ggt 201Arg Gly Trp Gly Asp Asp Ile Thr Trp Val Gln Thr Tyr Glu Glu Gly 40 45 50ctc ttt tat gct caa aaa agt aag aag cca tta atg gtt att cat cac 249Leu Phe Tyr Ala Gln Lys Ser Lys Lys Pro Leu Met Val Ile His His 55 60 65ctg gag gat tgt caa tac tct caa gca cta aag aaa gta ttt gcc caa 297Leu Glu Asp Cys Gln Tyr Ser Gln Ala Leu Lys Lys Val Phe Ala Gln 70 75 80aat gaa gaa ata caa gaa atg gct cag aat aag ttc atc atg cta aac 345Asn Glu Glu Ile Gln Glu Met Ala Gln Asn Lys Phe Ile Met Leu Asn 85 90 95ctt atg cat gaa acc act gat aag aat tta tca cct gat ggg caa tat 393Leu Met His Glu Thr Thr Asp Lys Asn Leu Ser Pro Asp Gly Gln Tyr100 105 110 115gtg cct aga atc atg ttt gta gac cct tct tta aca gtt aga gct gac 441Val Pro Arg Ile Met Phe Val Asp Pro Ser Leu Thr Val Arg Ala Asp 120 125 130ata gct gga aga tac tct aac aga ttg tac aca tat gag cct cgg gat 489Ile Ala Gly Arg Tyr Ser Asn Arg Leu Tyr Thr Tyr Glu Pro Arg Asp 135 140 145tta ccc cta taa gaaatttgga tacagagaca tgcatacaga aggaatgcca 541Leu Pro Leu * 150tg 5434150PRThuman 4Met Met Leu His Ser Ala Leu Gly Leu Cys Leu Leu Leu Val Thr Val1 5 10 15Ser Ser Asn Leu Ala Ile Ala Ile Lys Lys Glu Lys Arg Pro Pro Gln 20 25 30Thr Leu Ser Arg Gly Trp Gly Asp Asp Ile Thr Trp Val Gln Thr Tyr 35 40 45Glu Glu Gly Leu Phe Tyr Ala Gln Lys Ser Lys Lys Pro Leu Met Val 50 55 60Ile His His Leu Glu Asp Cys Gln Tyr Ser Gln Ala Leu Lys Lys Val65 70 75 80Phe Ala Gln Asn Glu Glu Ile Gln Glu Met Ala Gln Asn Lys Phe Ile 85 90 95Met Leu Asn Leu Met His Glu Thr Thr Asp Lys Asn Leu Ser Pro Asp 100 105 110Gly Gln Tyr Val Pro Arg Ile Met Phe Val Asp Pro Ser Leu Thr Val 115 120 125Arg Ala Asp Ile Ala Gly Arg Tyr Ser Asn Arg Leu Tyr Thr Tyr Glu 130 135 140Pro Arg Asp Leu Pro Leu145 1505577DNAhumanCDS(98)...(412) 5aagagcactg gccaagtcag gatggggaga tgacatcact tgggtacaaa cttatgaaga 60aggtctcttt tatgctcaaa aaagtaagaa gccatta atg gtt att cat cac ctg 115 Met Val Ile His His Leu 1 5gag gat tgt caa tac tct caa gca cta aag aaa gta ttt gcc caa aat 163Glu Asp Cys Gln Tyr Ser Gln Ala Leu Lys Lys Val Phe Ala Gln Asn 10 15 20gaa gaa ata caa gaa atg gct cag aat aag ttc atc atg cta aac ctt 211Glu Glu Ile Gln Glu Met Ala Gln Asn Lys Phe Ile Met Leu Asn Leu 25 30 35atg cat gaa acc act gat aag aat tta tca cct gat ggg caa tat gtg 259Met His Glu Thr Thr Asp Lys Asn Leu Ser Pro Asp Gly Gln Tyr Val 40 45 50cct aga atc atg ttt gta gac cct tct tta aca gtt aga gct gac ata 307Pro Arg Ile Met Phe Val Asp Pro Ser Leu Thr Val Arg Ala Asp Ile55 60 65 70gct gga aga tac tct aac aga ttg tac aca tat gag cct cgg gat tta 355Ala Gly Arg Tyr Ser Asn Arg Leu Tyr Thr Tyr Glu Pro Arg Asp Leu 75 80 85ccc cta ttg ata gaa aac atg aag aaa gca tta aga ctt att cag tca 403Pro Leu Leu Ile Glu Asn Met Lys Lys Ala Leu Arg Leu Ile Gln Ser 90 95 100gag cta taa gagatgatgg aaaaaagcct tcacttcaaa gaagtcaaat 452Glu Leu *ttcatgaaga aaacctctgg cacattgaca aatactaaat gtgcaagtat atagattttg 512taatattact atttagtttt tttaatgtgt ttgcaatagt cttattaaaa taaatgtttt 572ttaaa 5776104PRThuman 6Met Val Ile His His Leu Glu Asp Cys Gln Tyr Ser Gln Ala Leu Lys1 5 10 15Lys Val Phe Ala Gln Asn Glu Glu Ile Gln Glu Met Ala Gln Asn Lys 20 25 30Phe Ile Met Leu Asn Leu Met His Glu Thr Thr Asp Lys Asn Leu Ser 35 40 45Pro Asp Gly Gln Tyr Val Pro Arg Ile Met Phe Val Asp Pro Ser Leu 50 55 60Thr Val Arg Ala Asp Ile Ala Gly Arg Tyr Ser Asn Arg Leu Tyr Thr65 70 75 80Tyr Glu Pro Arg Asp Leu Pro Leu Leu Ile Glu Asn Met Lys Lys Ala 85 90 95Leu Arg Leu Ile Gln Ser Glu Leu 1007630DNAhumanCDS(49)...(465) 7aagagcactg gccaagtcag gcttcttctg agagagtctc tagaagac atg atg cta 57 Met Met Leu 1cac tca gct ttg ggt ctc tgc ctc tta ctc gtc aca gtt tct tcc aac 105His Ser Ala Leu Gly Leu Cys Leu Leu Leu Val Thr Val Ser Ser Asn 5 10 15ctt gcc att gca ata aaa aag gaa aag agg cct cct cag aca ctc tca 153Leu Ala Ile Ala Ile Lys Lys Glu Lys Arg Pro Pro Gln Thr Leu Ser20 25 30 35aga gga tgg gga gat gac atc act tgg gta caa act tat gaa gaa ggt 201Arg Gly Trp Gly Asp Asp Ile Thr Trp Val Gln Thr Tyr Glu Glu Gly 40 45 50ctc ttt tat gct caa aaa agt aag aag cca tta atg gtt att cat cac 249Leu Phe Tyr Ala Gln Lys Ser Lys Lys Pro Leu Met Val Ile His His 55 60 65ctg gag gat tgt caa tac tct caa gca cta aag aaa gta ttt gcc caa 297Leu Glu Asp Cys Gln Tyr Ser Gln Ala Leu Lys Lys Val Phe Ala Gln 70 75 80aat gaa gaa ata caa gaa atg gct cag aat aag ttc atc atg cta aac 345Asn Glu Glu Ile Gln Glu Met Ala Gln Asn Lys Phe Ile Met Leu Asn 85 90 95ctt atg cat gaa acc act gat aag aat tta tca cct gat ggg caa tat 393Leu Met His Glu Thr Thr Asp Lys Asn Leu Ser Pro Asp Gly Gln Tyr100 105 110 115gtg cct aga atc atg ttt gta gtg ata gaa aac atg aag aaa gca tta 441Val Pro Arg Ile Met Phe Val Val Ile Glu Asn Met Lys Lys Ala Leu 120 125 130aga ctt att cag tca gag cta taa gagatgatgg aaaaaagcct tcacttcaaa 495Arg Leu Ile Gln Ser Glu Leu * 135gaagtcaaat ttcatgaaga aaacctctgg cacattgaca aatactaaat gtgcaagtat 555atagattttg taatattact atttagtttt tttaatgtgt ttgcaatagt cttattaaaa 615taaatgtttt ttaaa 6308138PRThuman 8Met Met Leu His Ser Ala Leu Gly Leu Cys Leu Leu Leu Val Thr Val1 5 10 15Ser Ser Asn Leu Ala Ile Ala Ile Lys Lys Glu Lys Arg Pro Pro Gln 20 25 30Thr Leu Ser Arg Gly Trp Gly Asp Asp Ile Thr Trp Val Gln Thr Tyr 35 40 45Glu Glu Gly Leu Phe Tyr Ala Gln Lys Ser Lys Lys Pro Leu Met Val 50 55 60Ile His His Leu Glu Asp Cys Gln Tyr Ser Gln Ala Leu Lys Lys Val65 70 75 80Phe Ala Gln Asn Glu Glu Ile Gln Glu Met Ala Gln Asn Lys Phe Ile 85 90 95Met Leu Asn Leu Met His Glu Thr Thr Asp Lys Asn Leu Ser Pro Asp 100 105 110Gly Gln Tyr Val Pro Arg Ile Met Phe Val Val Ile Glu Asn Met Lys 115 120 125Lys Ala Leu Arg Leu Ile Gln Ser Glu Leu 130 13592545DNAhumanCDS(40)...(417) 9atccaataca ggagtgactt ggaactccat tctatcact atg aag aaa agt ggt 54 Met Lys Lys Ser Gly 1 5gtt ctt ttc ctc ttg ggc atc atc ttg ctg gtt ctg att gga gtg caa 102Val Leu Phe Leu Leu Gly Ile Ile Leu Leu Val Leu Ile Gly Val Gln 10 15 20gga acc cca gta gtg aga aag ggt cgc tgt tcc tgc atc agc acc aac 150Gly Thr Pro Val Val Arg Lys Gly Arg Cys Ser Cys Ile Ser Thr Asn 25 30 35caa ggg act atc cac cta caa tcc ttg aaa gac ctt aaa caa ttt gcc 198Gln Gly Thr Ile His Leu Gln Ser Leu Lys Asp Leu Lys Gln Phe Ala 40 45 50cca agc cct tcc tgc gag aaa att gaa atc att gct aca ctg aag aat 246Pro Ser Pro Ser Cys Glu Lys Ile Glu Ile Ile Ala Thr Leu Lys Asn 55 60 65gga gtt caa aca tgt cta aac cca gat tca gca gat gtg aag gaa ctg 294Gly Val Gln Thr Cys Leu Asn Pro Asp Ser Ala Asp Val Lys Glu Leu70 75 80 85att aaa aag tgg gag aaa cag gtc agc caa aag aaa aag caa aag aat 342Ile Lys Lys Trp Glu Lys Gln Val Ser Gln Lys Lys Lys Gln Lys Asn 90 95 100ggg aaa aaa cat caa aaa aag aaa gtt ctg aaa gtt cga aaa tct caa 390Gly Lys Lys His Gln Lys Lys Lys Val Leu Lys Val Arg Lys Ser Gln 105 110 115cgt tct cgt caa aag aag act aca taa gagaccactt caccaataag 437Arg Ser Arg Gln Lys Lys Thr Thr * 120 125tattctgtgt taaaaatgtt ctattttaat tataccgcta tcattccaaa ggaggatggc 497atataataca aaggcttatt aatttgacta gaaaatttaa aacattactc tgaaattgta 557actaaagtta gaaagttgat tttaagaatc caaacgttaa gaattgttaa aggctatgat 617tgtctttgtt cttctaccac ccaccagttg aatttcatca tgcttaaggc catgatttta 677gcaataccca tgtctacaca gatgttcacc caaccacatc ccactcacaa cagctgcctg 737gaagagcagc cctaggcttc cacgtactgc agcctccaga gagtatctga ggcacatgtc 797agcaagtcct aagcctgtta gcatgctggt gagccaagca gtttgaaatt gagctggacc 857tcaccaagct gctgtggcca tcaacctctg tatttgaatc agcctacagg cctcacacac 917aatgtgtctg agagattcat gctgattgtt attgggtatc accactggag atcaccagtg 977tgtggctttc agagcctcct ttctggcttt ggaagccatg tgattccatc ttgcccgctc 1037aggctgacca ctttatttct ttttgttccc ctttgcttca ttcaagtcag ctcttctcca 1097tcctaccaca atgcagtgcc tttcttctct ccagtgcacc tgtcatatgc tctgatttat 1157ctgagtcaac tcctttctca tcttgtcccc aacaccccac agaagtgctt tcttctccca 1217attcatcctc actcagtcca gcttagttca agtcctgcct cttaaataaa cctttttgga 1277cacacaaatt atcttaaaac tcctgtttca cttggttcag taccacatgg gtgaacactc 1337aatggttaac taattcttgg gtgtttatcc tatctctcca accagattgt cagctccttg 1397agggcaagag ccacagtata tttccctgtt tcttccacag tgcctaataa tactgtggaa 1457ctaggtttta ataatttttt aattgatgtt gttatgggca ggatggcaac cagaccattg 1517tctcagagca ggtgctggct ctttcctggc tactccatgt tggctagcct ctggtaacct 1577cttacttatt atcttcagga cactcactac agggaccagg gatgatgcaa catccttgtc 1637tttttatgac aggatgtttg ctcagcttct ccaacaataa gaagcacgtg gtaaaacact 1697tgcggatatt ctggactgtt tttaaaaaat atacagttta ccgaaaatca tataatctta 1757caatgaaaag gactttatag atcagccagt gaccaacctt ttcccaacca tacaaaaatt 1817ccttttcccg aaggaaaagg gctttctcaa taagcctcag ctttctaaga tctaacaaga 1877tagccaccga gatccttatc gaaactcatt ttaggcaaat atgagtttta ttgtccgttt 1937acttgtttca gagtttgtat tgtgattatc aattaccaca ccatctccca tgaagaaagg 1997gaacggtgaa gtactaagcg ctagaggaag cagccaagtc ggttagtgga agcatgattg 2057gtgcccagtt agcctctgca ggatgtggaa acctccttcc aggggaggtt cagtgaattg 2117tgtaggagag gttgtctgtg gccagaattt aaacctatac tcactttccc aaattgaatc 2177actgctcaca ctgctgatga tttagagtgc tgtccggtgg agatcccacc cgaacgtctt 2237atctaatcat gaaactccct agttccttca tgtaacttcc ctgaaaaatc taagtgtttc 2297ataaatttga gagtctgtga cccacttacc ttgcatctca caggtagaca gtatataact 2357aacaaccaaa gactacatat tgtcactgac acacacgtta taatcattta tcatatatat 2417acatacatgc atacactctc aaagcaaata atttttcact tcaaaacagt attgacttgt 2477ataccttgta atttgaaata ttttctttgt taaaatagaa tggtatcaat aaatagacca 2537ttaatcag 254510125PRThuman 10Met Lys Lys Ser Gly Val Leu Phe Leu Leu Gly Ile Ile Leu Leu Val1 5 10 15Leu Ile Gly Val Gln Gly Thr Pro Val Val Arg Lys Gly Arg Cys Ser 20 25 30Cys Ile Ser Thr Asn Gln Gly Thr Ile His Leu Gln Ser Leu Lys Asp 35 40 45Leu Lys Gln Phe Ala Pro Ser Pro Ser Cys Glu Lys Ile Glu Ile Ile 50 55 60Ala Thr Leu Lys Asn Gly Val Gln Thr Cys Leu Asn Pro Asp Ser Ala65 70 75 80Asp Val Lys Glu Leu Ile Lys Lys Trp Glu Lys Gln Val Ser Gln Lys 85 90 95Lys Lys Gln Lys Asn Gly Lys Lys His Gln Lys Lys Lys Val Leu Lys 100 105 110Val Arg Lys Ser Gln Arg Ser Arg Gln Lys Lys Thr Thr 115 120 125111172DNAhumanCDS(67)...(363) 11gagacattcc tcaattgctt agacatattc tgagcctaca gcagaggaac ctccagtctc 60agcacc atg aat caa act gcg att ctg att tgc tgc ctt atc ttt ctg 108 Met Asn Gln Thr Ala Ile Leu Ile Cys Cys Leu Ile Phe Leu 1 5 10act cta agt ggc att caa gga gta cct ctc tct aga acc gta cgc tgt 156Thr Leu Ser Gly Ile Gln Gly Val Pro Leu Ser Arg Thr Val Arg Cys15 20 25 30acc tgc atc agc att agt aat caa cct gtt aat cca agg tct tta gaa 204Thr Cys Ile Ser Ile Ser Asn Gln Pro Val Asn Pro Arg Ser Leu Glu 35

40 45aaa ctt gaa att att cct gca agc caa ttt tgt cca cgt gtt gag atc 252Lys Leu Glu Ile Ile Pro Ala Ser Gln Phe Cys Pro Arg Val Glu Ile 50 55 60att gct aca atg aaa aag aag ggt gag aag aga tgt ctg aat cca gaa 300Ile Ala Thr Met Lys Lys Lys Gly Glu Lys Arg Cys Leu Asn Pro Glu 65 70 75tcg aag gcc atc aag aat tta ctg aaa gca gtt agc aag gaa atg tct 348Ser Lys Ala Ile Lys Asn Leu Leu Lys Ala Val Ser Lys Glu Met Ser 80 85 90aaa aga tct cct taa aaccagaggg gagcaaaatc gatgcagtgc ttccaaggat 403Lys Arg Ser Pro *95ggaccacaca gaggctgcct ctcccatcac ttccctacat ggagtatatg tcaagccata 463attgttctta gtttgcagtt acactaaaag gtgaccaatg atggtcacca aatcagctgc 523tactactcct gtaggaaggt taatgttcat catcctaagc tattcagtaa taactctacc 583ctggcactat aatgtaagct ctactgaggt gctatgttct tagtggatgt tctgaccctg 643cttcaaatat ttccctcacc tttcccatct tccaagggta ctaaggaatc tttctgcttt 703ggggtttatc agaattctca gaatctcaaa taactaaaag gtatgcaatc aaatctgctt 763tttaaagaat gctctttact tcatggactt ccactgccat cctcccaagg ggcccaaatt 823ctttcagtgg ctacctacat acaattccaa acacatacag gaaggtagaa atatctgaaa 883atgtatgtgt aagtattctt atttaatgaa agactgtaca aagtataagt cttagatgta 943tatatttcct atattgtttt cagtgtacat ggaataacat gtaattaagt actatgtatc 1003aatgagtaac aggaaaattt taaaaataca gatagatata tgctctgcat gttacataag 1063ataaatgtgc tgaatggttt tcaaataaaa atgaggtact ctcctggaaa tattaagaaa 1123gactatctaa atgttgaaag atcaaaaggt taataaagta attataact 11721298PRThuman 12Met Asn Gln Thr Ala Ile Leu Ile Cys Cys Leu Ile Phe Leu Thr Leu1 5 10 15Ser Gly Ile Gln Gly Val Pro Leu Ser Arg Thr Val Arg Cys Thr Cys 20 25 30Ile Ser Ile Ser Asn Gln Pro Val Asn Pro Arg Ser Leu Glu Lys Leu 35 40 45Glu Ile Ile Pro Ala Ser Gln Phe Cys Pro Arg Val Glu Ile Ile Ala 50 55 60Thr Met Lys Lys Lys Gly Glu Lys Arg Cys Leu Asn Pro Glu Ser Lys65 70 75 80Ala Ile Lys Asn Leu Leu Lys Ala Val Ser Lys Glu Met Ser Lys Arg 85 90 95Ser Pro131261DNAhumanCDS(244)...(1152) 13ggcgagggtc ttcggaacgt agcgctggct gcggccccgc ccgcctaccc acccgcccgt 60ccggcagccg gctcccgccg cctccgcgct ctgtctgggg ccagccacct ggcgggccgc 120tccggtgcgc ctgcccgcgc ttttcactga caggcgctgt tccccacagc cagcgccgcc 180cgccacgtcc cagctctcgg ccaacggagc tgcgcggcgg gtgacctttc cgagcccagc 240gcg atg acg gct cct tgc tcc cag ccg gcg cag ctt cct gga cgc cgc 288 Met Thr Ala Pro Cys Ser Gln Pro Ala Gln Leu Pro Gly Arg Arg 1 5 10 15cag ctc ggg ctg gtg ccg ttc ccg ccg ccg ccg ccg cgg acg ccg ctg 336Gln Leu Gly Leu Val Pro Phe Pro Pro Pro Pro Pro Arg Thr Pro Leu 20 25 30ctg tgg ctg ctg ctg ctg ctg ctg gcc gcc gtg gcg ccg gcg cgc ggc 384Leu Trp Leu Leu Leu Leu Leu Leu Ala Ala Val Ala Pro Ala Arg Gly 35 40 45tgg gag agc gga gac ctg gag ttg ttt gac tta gtg gag gag gtg cag 432Trp Glu Ser Gly Asp Leu Glu Leu Phe Asp Leu Val Glu Glu Val Gln 50 55 60ctc aac ttc tac cag ttc ctc ggg gtg cag cag gca cct gaa tgg aca 480Leu Asn Phe Tyr Gln Phe Leu Gly Val Gln Gln Ala Pro Glu Trp Thr 65 70 75gaa gag gac ctc agc caa ctg aca aga agt atg gtt aag ttc cca gga 528Glu Glu Asp Leu Ser Gln Leu Thr Arg Ser Met Val Lys Phe Pro Gly80 85 90 95ggg act cca ggt cga tgg gaa aag att gcc cac gaa ttg ggt cga tct 576Gly Thr Pro Gly Arg Trp Glu Lys Ile Ala His Glu Leu Gly Arg Ser 100 105 110gtg aca gat gtg aca acc aaa gcc aag caa ctg aag gat tca gtg acc 624Val Thr Asp Val Thr Thr Lys Ala Lys Gln Leu Lys Asp Ser Val Thr 115 120 125tgc tcc cca gga atg gtt aga ctc tcc gaa ctc aaa tcg aca gtt cag 672Cys Ser Pro Gly Met Val Arg Leu Ser Glu Leu Lys Ser Thr Val Gln 130 135 140aat tcc agg ccc atc aaa acg gcc acc acc ttg ccc gat gac atg atc 720Asn Ser Arg Pro Ile Lys Thr Ala Thr Thr Leu Pro Asp Asp Met Ile 145 150 155acc cag cga gag gac gca gag ggg gtg gca gcg gag gag gag cag gag 768Thr Gln Arg Glu Asp Ala Glu Gly Val Ala Ala Glu Glu Glu Gln Glu160 165 170 175gga gac tcc ggt gag cag gag acc ggg gcc act gat gcc cgg cct cgg 816Gly Asp Ser Gly Glu Gln Glu Thr Gly Ala Thr Asp Ala Arg Pro Arg 180 185 190agg cgg aag cca gcc agg ctg ctg gag gct aca gcg aag ccg gag cca 864Arg Arg Lys Pro Ala Arg Leu Leu Glu Ala Thr Ala Lys Pro Glu Pro 195 200 205gag gag aag tcc aga gcc aag cgg cag aag gac ttt gac ata gca gaa 912Glu Glu Lys Ser Arg Ala Lys Arg Gln Lys Asp Phe Asp Ile Ala Glu 210 215 220caa aac gag tcc agc gac gag gag agc ctg aga aaa gag aga gct cgg 960Gln Asn Glu Ser Ser Asp Glu Glu Ser Leu Arg Lys Glu Arg Ala Arg 225 230 235tct gca gag gag ccg tgg act caa aat caa cag aaa ctt ctg gaa ctg 1008Ser Ala Glu Glu Pro Trp Thr Gln Asn Gln Gln Lys Leu Leu Glu Leu240 245 250 255gcg ttg cag cag tac cca agg gga tcc tct gac cgc tgg gac aaa ata 1056Ala Leu Gln Gln Tyr Pro Arg Gly Ser Ser Asp Arg Trp Asp Lys Ile 260 265 270gcc aga tgt gtc ccg tcc aag agc aag gaa gac tgt atc gct agg tac 1104Ala Arg Cys Val Pro Ser Lys Ser Lys Glu Asp Cys Ile Ala Arg Tyr 275 280 285aag ttg ctg gtt gaa ctg gtc caa aag aaa aaa caa gct aaa agc tga 1152Lys Leu Leu Val Glu Leu Val Gln Lys Lys Lys Gln Ala Lys Ser * 290 295 300atattctggg agatgatgtt caccttcatt ttccaaaatg aatatcttaa aaatcttatg 1212cagaaatttg cattttgtac ctcaatattt ctacgtcatg tgccttagt 126114302PRThuman 14Met Thr Ala Pro Cys Ser Gln Pro Ala Gln Leu Pro Gly Arg Arg Gln1 5 10 15Leu Gly Leu Val Pro Phe Pro Pro Pro Pro Pro Arg Thr Pro Leu Leu 20 25 30Trp Leu Leu Leu Leu Leu Leu Ala Ala Val Ala Pro Ala Arg Gly Trp 35 40 45Glu Ser Gly Asp Leu Glu Leu Phe Asp Leu Val Glu Glu Val Gln Leu 50 55 60Asn Phe Tyr Gln Phe Leu Gly Val Gln Gln Ala Pro Glu Trp Thr Glu65 70 75 80Glu Asp Leu Ser Gln Leu Thr Arg Ser Met Val Lys Phe Pro Gly Gly 85 90 95Thr Pro Gly Arg Trp Glu Lys Ile Ala His Glu Leu Gly Arg Ser Val 100 105 110Thr Asp Val Thr Thr Lys Ala Lys Gln Leu Lys Asp Ser Val Thr Cys 115 120 125Ser Pro Gly Met Val Arg Leu Ser Glu Leu Lys Ser Thr Val Gln Asn 130 135 140Ser Arg Pro Ile Lys Thr Ala Thr Thr Leu Pro Asp Asp Met Ile Thr145 150 155 160Gln Arg Glu Asp Ala Glu Gly Val Ala Ala Glu Glu Glu Gln Glu Gly 165 170 175Asp Ser Gly Glu Gln Glu Thr Gly Ala Thr Asp Ala Arg Pro Arg Arg 180 185 190Arg Lys Pro Ala Arg Leu Leu Glu Ala Thr Ala Lys Pro Glu Pro Glu 195 200 205Glu Lys Ser Arg Ala Lys Arg Gln Lys Asp Phe Asp Ile Ala Glu Gln 210 215 220Asn Glu Ser Ser Asp Glu Glu Ser Leu Arg Lys Glu Arg Ala Arg Ser225 230 235 240Ala Glu Glu Pro Trp Thr Gln Asn Gln Gln Lys Leu Leu Glu Leu Ala 245 250 255Leu Gln Gln Tyr Pro Arg Gly Ser Ser Asp Arg Trp Asp Lys Ile Ala 260 265 270Arg Cys Val Pro Ser Lys Ser Lys Glu Asp Cys Ile Ala Arg Tyr Lys 275 280 285Leu Leu Val Glu Leu Val Gln Lys Lys Lys Gln Ala Lys Ser 290 295 300151243DNAhumanCDS(244)...(1134) 15ggcgagggtc ttcggaacgt agcgctggct gcggccccgc ccgcctaccc acccgcccgt 60ccggcagccg gctcccgccg cctccgcgct ctgtctgggg ccagccacct ggcgggccgc 120tccggtgcgc ctgcccgcgc ttttcactga caggcgctgt tccccacagc cagcgccgcc 180cgccacgtcc cagctctcgg ccaacggagc tgcgcggcgg gtgacctttc cgagcccagc 240gcg atg acg gct cct tgc tcc cag ccg gcg cag ctt cct gga cgc cgc 288 Met Thr Ala Pro Cys Ser Gln Pro Ala Gln Leu Pro Gly Arg Arg 1 5 10 15cag ctc ggg ctg gtg ccg ttc ccg ccg ccg ccg ccg cgg acg ccg ctg 336Gln Leu Gly Leu Val Pro Phe Pro Pro Pro Pro Pro Arg Thr Pro Leu 20 25 30ctg tgg ctg ctg ctg ctg ctg ctg gcc gcc gtg gcg ccg gcg cgc ggc 384Leu Trp Leu Leu Leu Leu Leu Leu Ala Ala Val Ala Pro Ala Arg Gly 35 40 45tgg gag agc gga gac ctg gag ttg ttt gac tta gtg gag gag gtg cag 432Trp Glu Ser Gly Asp Leu Glu Leu Phe Asp Leu Val Glu Glu Val Gln 50 55 60ctc aac ttc tac cag ttc ctc ggg gtg cag cag gat gca tca tct gca 480Leu Asn Phe Tyr Gln Phe Leu Gly Val Gln Gln Asp Ala Ser Ser Ala 65 70 75gac atc aga aaa gca tat cgt aag ctt tca cta act tta cat cca gac 528Asp Ile Arg Lys Ala Tyr Arg Lys Leu Ser Leu Thr Leu His Pro Asp80 85 90 95aag aat aaa gat gaa aat gca gaa act cag ttt aga caa gtg aca acc 576Lys Asn Lys Asp Glu Asn Ala Glu Thr Gln Phe Arg Gln Val Thr Thr 100 105 110aaa gcc aag caa ctg aag gat tca gtg acc tgc tcc cca gga atg gtt 624Lys Ala Lys Gln Leu Lys Asp Ser Val Thr Cys Ser Pro Gly Met Val 115 120 125aga ctc tcc gaa ctc aaa tcg aca gtt cag aat tcc agg ccc atc aaa 672Arg Leu Ser Glu Leu Lys Ser Thr Val Gln Asn Ser Arg Pro Ile Lys 130 135 140acg gcc acc acc ttg ccc gat gac atg atc acc cag cga gag gac gca 720Thr Ala Thr Thr Leu Pro Asp Asp Met Ile Thr Gln Arg Glu Asp Ala 145 150 155gag ggg gtg gca gcg gag gag gag cag gag gga gac tcc ggt gag cag 768Glu Gly Val Ala Ala Glu Glu Glu Gln Glu Gly Asp Ser Gly Glu Gln160 165 170 175gag acc ggg gcc act gat gcc cgg cct cgg agg cgg aag cca gcc agg 816Glu Thr Gly Ala Thr Asp Ala Arg Pro Arg Arg Arg Lys Pro Ala Arg 180 185 190ctg ctg gag gct aca gcg aag ccg gag cca gag gag aag tcc aga gcc 864Leu Leu Glu Ala Thr Ala Lys Pro Glu Pro Glu Glu Lys Ser Arg Ala 195 200 205aag cgg cag aag gac ttt gac ata gca gaa caa aac gag tcc agc gac 912Lys Arg Gln Lys Asp Phe Asp Ile Ala Glu Gln Asn Glu Ser Ser Asp 210 215 220gag gag agc ctg aga aaa gag aga gct cgg tct gca gag gag ccg tgg 960Glu Glu Ser Leu Arg Lys Glu Arg Ala Arg Ser Ala Glu Glu Pro Trp 225 230 235act caa aat caa cag aaa ctt ctg gaa ctg gcg ttg cag cag tac cca 1008Thr Gln Asn Gln Gln Lys Leu Leu Glu Leu Ala Leu Gln Gln Tyr Pro240 245 250 255agg gga tcc tct gac cgc tgg gac aaa ata gcc aga tgt gtc ccg tcc 1056Arg Gly Ser Ser Asp Arg Trp Asp Lys Ile Ala Arg Cys Val Pro Ser 260 265 270aag agc aag gaa gac tgt atc gct agg tac aag ttg ctg gtt gaa ctg 1104Lys Ser Lys Glu Asp Cys Ile Ala Arg Tyr Lys Leu Leu Val Glu Leu 275 280 285gtc caa aag aaa aaa caa gct aaa agc tga atattctggg agatgatgtt 1154Val Gln Lys Lys Lys Gln Ala Lys Ser * 290 295caccttcatt ttccaaaatg aatatcttaa aaatcttatg cagaaatttg cattttgtac 1214ctcaatattt ctacgtcatg tgccttagt 124316296PRThuman 16Met Thr Ala Pro Cys Ser Gln Pro Ala Gln Leu Pro Gly Arg Arg Gln1 5 10 15Leu Gly Leu Val Pro Phe Pro Pro Pro Pro Pro Arg Thr Pro Leu Leu 20 25 30Trp Leu Leu Leu Leu Leu Leu Ala Ala Val Ala Pro Ala Arg Gly Trp 35 40 45Glu Ser Gly Asp Leu Glu Leu Phe Asp Leu Val Glu Glu Val Gln Leu 50 55 60Asn Phe Tyr Gln Phe Leu Gly Val Gln Gln Asp Ala Ser Ser Ala Asp65 70 75 80Ile Arg Lys Ala Tyr Arg Lys Leu Ser Leu Thr Leu His Pro Asp Lys 85 90 95Asn Lys Asp Glu Asn Ala Glu Thr Gln Phe Arg Gln Val Thr Thr Lys 100 105 110Ala Lys Gln Leu Lys Asp Ser Val Thr Cys Ser Pro Gly Met Val Arg 115 120 125Leu Ser Glu Leu Lys Ser Thr Val Gln Asn Ser Arg Pro Ile Lys Thr 130 135 140Ala Thr Thr Leu Pro Asp Asp Met Ile Thr Gln Arg Glu Asp Ala Glu145 150 155 160Gly Val Ala Ala Glu Glu Glu Gln Glu Gly Asp Ser Gly Glu Gln Glu 165 170 175Thr Gly Ala Thr Asp Ala Arg Pro Arg Arg Arg Lys Pro Ala Arg Leu 180 185 190Leu Glu Ala Thr Ala Lys Pro Glu Pro Glu Glu Lys Ser Arg Ala Lys 195 200 205Arg Gln Lys Asp Phe Asp Ile Ala Glu Gln Asn Glu Ser Ser Asp Glu 210 215 220Glu Ser Leu Arg Lys Glu Arg Ala Arg Ser Ala Glu Glu Pro Trp Thr225 230 235 240Gln Asn Gln Gln Lys Leu Leu Glu Leu Ala Leu Gln Gln Tyr Pro Arg 245 250 255Gly Ser Ser Asp Arg Trp Asp Lys Ile Ala Arg Cys Val Pro Ser Lys 260 265 270Ser Lys Glu Asp Cys Ile Ala Arg Tyr Lys Leu Leu Val Glu Leu Val 275 280 285Gln Lys Lys Lys Gln Ala Lys Ser 290 295171881DNAhumanCDS(108)...(1772) 17gcgcttttca ctgacaggcg ctgttcccca cagccagcgc cgcccgccac gtcccagctc 60tcggccaacg gagctgcgcg gcgggtgacc tttccgagcc cagcgcg atg acg gct 116 Met Thr Ala 1cct tgc tcc cag ccg gcg cag ctt cct gga cgc cgc cag ctc ggg ctg 164Pro Cys Ser Gln Pro Ala Gln Leu Pro Gly Arg Arg Gln Leu Gly Leu 5 10 15gtg ccg ttc ccg ccg ccg ccg ccg cgg acg ccg ctg ctg tgg ctg ctg 212Val Pro Phe Pro Pro Pro Pro Pro Arg Thr Pro Leu Leu Trp Leu Leu20 25 30 35ctg ctg ctg ctg gcc gcc gtg gcg ccg gcg cgc ggc tgg gag agc gga 260Leu Leu Leu Leu Ala Ala Val Ala Pro Ala Arg Gly Trp Glu Ser Gly 40 45 50gac ctg gag ttg ttt gac tta gtg gag gag gtg cag ctc aac ttc tac 308Asp Leu Glu Leu Phe Asp Leu Val Glu Glu Val Gln Leu Asn Phe Tyr 55 60 65cag ttc ctc ggg gtg cag cag gat gca tca tct gca gac atc aga aaa 356Gln Phe Leu Gly Val Gln Gln Asp Ala Ser Ser Ala Asp Ile Arg Lys 70 75 80gca tat cgt aag ctt tca cta act tta cat cca gac aag aat aaa gat 404Ala Tyr Arg Lys Leu Ser Leu Thr Leu His Pro Asp Lys Asn Lys Asp 85 90 95gaa aat gca gaa act cag ttt aga caa ttg gtg gcc att tat gaa gtt 452Glu Asn Ala Glu Thr Gln Phe Arg Gln Leu Val Ala Ile Tyr Glu Val100 105 110 115tta aag gat gat gaa cga agg cag agg tat gat gat att ctg atc aat 500Leu Lys Asp Asp Glu Arg Arg Gln Arg Tyr Asp Asp Ile Leu Ile Asn 120 125 130gga ctt cca gat tgg cga cag cct gta ttc tac tac agg cgg gtg aga 548Gly Leu Pro Asp Trp Arg Gln Pro Val Phe Tyr Tyr Arg Arg Val Arg 135 140 145aaa atg agc aat gct gag ctg gca tta ctc ttg ttc att att ctc aca 596Lys Met Ser Asn Ala Glu Leu Ala Leu Leu Leu Phe Ile Ile Leu Thr 150 155 160gtg ggt cat tat gct gtg gtt tgg tca atc tac ctg gaa aaa caa ctg 644Val Gly His Tyr Ala Val Val Trp Ser Ile Tyr Leu Glu Lys Gln Leu 165 170 175gat gaa cta cta agt aga aaa aag aga gaa aag aaa aaa aag act ggc 692Asp Glu Leu Leu Ser Arg Lys Lys Arg Glu Lys Lys Lys Lys Thr Gly180 185 190 195agc aag agt gtg gat gta tca aaa ctc ggt gct tca gaa aaa aat gaa 740Ser Lys Ser Val Asp Val Ser Lys Leu Gly Ala Ser Glu Lys Asn Glu 200 205 210aga ttg ctg atg aaa cca cag tgg cat gat ttg ctt cca tgc aaa ctg 788Arg Leu Leu Met Lys Pro Gln Trp His Asp Leu Leu Pro Cys Lys Leu 215 220 225ggg att tgg ttt tgc ctt aca cta aaa gca tta cct cac ctc atc cag 836Gly Ile Trp Phe Cys Leu Thr Leu Lys Ala Leu Pro His Leu Ile Gln 230 235 240gat gct ggg cag ttt tat gct aaa tat aaa gaa aca aga ttg aag gaa 884Asp Ala Gly Gln Phe Tyr Ala Lys Tyr Lys Glu Thr Arg Leu Lys Glu 245 250 255aag gaa gat gca ctg

act aga act gaa ctt gaa aca ctt caa aaa cag 932Lys Glu Asp Ala Leu Thr Arg Thr Glu Leu Glu Thr Leu Gln Lys Gln260 265 270 275aag aaa gtt aaa aaa cca aaa cct gaa ttt cct gta tac aca cct tta 980Lys Lys Val Lys Lys Pro Lys Pro Glu Phe Pro Val Tyr Thr Pro Leu 280 285 290gaa act aca tat att cag tct tat gat cat gga act tcc ata gaa gaa 1028Glu Thr Thr Tyr Ile Gln Ser Tyr Asp His Gly Thr Ser Ile Glu Glu 295 300 305att gag gaa caa atg gat gat tgg ttg gaa aac agg aac cga aca cag 1076Ile Glu Glu Gln Met Asp Asp Trp Leu Glu Asn Arg Asn Arg Thr Gln 310 315 320aaa aaa cag gca cct gaa tgg aca gaa gag gac ctc agc caa ctg aca 1124Lys Lys Gln Ala Pro Glu Trp Thr Glu Glu Asp Leu Ser Gln Leu Thr 325 330 335aga agt atg gtt aag ttc cca gga ggg act cca ggt cga tgg gaa aag 1172Arg Ser Met Val Lys Phe Pro Gly Gly Thr Pro Gly Arg Trp Glu Lys340 345 350 355att gcc cac gaa ttg ggt cga tct gtg aca gat gtg aca acc aaa gcc 1220Ile Ala His Glu Leu Gly Arg Ser Val Thr Asp Val Thr Thr Lys Ala 360 365 370aag caa ctg aag gat tca gtg acc tgc tcc cca gga atg gtt aga ctc 1268Lys Gln Leu Lys Asp Ser Val Thr Cys Ser Pro Gly Met Val Arg Leu 375 380 385tcc gaa ctc aaa tcg aca gtt cag aat tcc agg ccc atc aaa acg gcc 1316Ser Glu Leu Lys Ser Thr Val Gln Asn Ser Arg Pro Ile Lys Thr Ala 390 395 400acc acc ttg ccc gat gac atg atc acc cag cga gag gac gca gag ggg 1364Thr Thr Leu Pro Asp Asp Met Ile Thr Gln Arg Glu Asp Ala Glu Gly 405 410 415gtg gca gcg gag gag gag cag gag gga gac tcc ggt gag cag gag acc 1412Val Ala Ala Glu Glu Glu Gln Glu Gly Asp Ser Gly Glu Gln Glu Thr420 425 430 435ggg gcc act gat gcc cgg cct cgg agg cgg aag cca gcc agg ctg ctg 1460Gly Ala Thr Asp Ala Arg Pro Arg Arg Arg Lys Pro Ala Arg Leu Leu 440 445 450gag gct aca gcg aag ccg gag cca gag gag aag tcc aga gcc aag cgg 1508Glu Ala Thr Ala Lys Pro Glu Pro Glu Glu Lys Ser Arg Ala Lys Arg 455 460 465cag aag gac ttt gac ata gca gaa caa aac gag tcc agc gac gag gag 1556Gln Lys Asp Phe Asp Ile Ala Glu Gln Asn Glu Ser Ser Asp Glu Glu 470 475 480agc ctg aga aaa gag aga gct cgg tct gca gag gag ccg tgg act caa 1604Ser Leu Arg Lys Glu Arg Ala Arg Ser Ala Glu Glu Pro Trp Thr Gln 485 490 495aat caa cag aaa ctt ctg gaa ctg gcg ttg cag cag tac cca agg gga 1652Asn Gln Gln Lys Leu Leu Glu Leu Ala Leu Gln Gln Tyr Pro Arg Gly500 505 510 515tcc tct gac cgc tgg gac aaa ata gcc aga tgt gtc ccg tcc aag agc 1700Ser Ser Asp Arg Trp Asp Lys Ile Ala Arg Cys Val Pro Ser Lys Ser 520 525 530aag gaa gac tgt atc gct agg tac aag ttg ctg gtt gaa ctg gtc caa 1748Lys Glu Asp Cys Ile Ala Arg Tyr Lys Leu Leu Val Glu Leu Val Gln 535 540 545aag aaa aaa caa gct aaa agc tga atattctggg agatgatgtt caccttcatt 1802Lys Lys Lys Gln Ala Lys Ser * 550ttccaaaatg aatatcttaa aaatcttatg cagaaatttg cattttgtac ctcaatattt 1862ctacgtcatg tgccttagt 188118554PRThuman 18Met Thr Ala Pro Cys Ser Gln Pro Ala Gln Leu Pro Gly Arg Arg Gln1 5 10 15Leu Gly Leu Val Pro Phe Pro Pro Pro Pro Pro Arg Thr Pro Leu Leu 20 25 30Trp Leu Leu Leu Leu Leu Leu Ala Ala Val Ala Pro Ala Arg Gly Trp 35 40 45Glu Ser Gly Asp Leu Glu Leu Phe Asp Leu Val Glu Glu Val Gln Leu 50 55 60Asn Phe Tyr Gln Phe Leu Gly Val Gln Gln Asp Ala Ser Ser Ala Asp65 70 75 80Ile Arg Lys Ala Tyr Arg Lys Leu Ser Leu Thr Leu His Pro Asp Lys 85 90 95Asn Lys Asp Glu Asn Ala Glu Thr Gln Phe Arg Gln Leu Val Ala Ile 100 105 110Tyr Glu Val Leu Lys Asp Asp Glu Arg Arg Gln Arg Tyr Asp Asp Ile 115 120 125Leu Ile Asn Gly Leu Pro Asp Trp Arg Gln Pro Val Phe Tyr Tyr Arg 130 135 140Arg Val Arg Lys Met Ser Asn Ala Glu Leu Ala Leu Leu Leu Phe Ile145 150 155 160Ile Leu Thr Val Gly His Tyr Ala Val Val Trp Ser Ile Tyr Leu Glu 165 170 175Lys Gln Leu Asp Glu Leu Leu Ser Arg Lys Lys Arg Glu Lys Lys Lys 180 185 190Lys Thr Gly Ser Lys Ser Val Asp Val Ser Lys Leu Gly Ala Ser Glu 195 200 205Lys Asn Glu Arg Leu Leu Met Lys Pro Gln Trp His Asp Leu Leu Pro 210 215 220Cys Lys Leu Gly Ile Trp Phe Cys Leu Thr Leu Lys Ala Leu Pro His225 230 235 240Leu Ile Gln Asp Ala Gly Gln Phe Tyr Ala Lys Tyr Lys Glu Thr Arg 245 250 255Leu Lys Glu Lys Glu Asp Ala Leu Thr Arg Thr Glu Leu Glu Thr Leu 260 265 270Gln Lys Gln Lys Lys Val Lys Lys Pro Lys Pro Glu Phe Pro Val Tyr 275 280 285Thr Pro Leu Glu Thr Thr Tyr Ile Gln Ser Tyr Asp His Gly Thr Ser 290 295 300Ile Glu Glu Ile Glu Glu Gln Met Asp Asp Trp Leu Glu Asn Arg Asn305 310 315 320Arg Thr Gln Lys Lys Gln Ala Pro Glu Trp Thr Glu Glu Asp Leu Ser 325 330 335Gln Leu Thr Arg Ser Met Val Lys Phe Pro Gly Gly Thr Pro Gly Arg 340 345 350Trp Glu Lys Ile Ala His Glu Leu Gly Arg Ser Val Thr Asp Val Thr 355 360 365Thr Lys Ala Lys Gln Leu Lys Asp Ser Val Thr Cys Ser Pro Gly Met 370 375 380Val Arg Leu Ser Glu Leu Lys Ser Thr Val Gln Asn Ser Arg Pro Ile385 390 395 400Lys Thr Ala Thr Thr Leu Pro Asp Asp Met Ile Thr Gln Arg Glu Asp 405 410 415Ala Glu Gly Val Ala Ala Glu Glu Glu Gln Glu Gly Asp Ser Gly Glu 420 425 430Gln Glu Thr Gly Ala Thr Asp Ala Arg Pro Arg Arg Arg Lys Pro Ala 435 440 445Arg Leu Leu Glu Ala Thr Ala Lys Pro Glu Pro Glu Glu Lys Ser Arg 450 455 460Ala Lys Arg Gln Lys Asp Phe Asp Ile Ala Glu Gln Asn Glu Ser Ser465 470 475 480Asp Glu Glu Ser Leu Arg Lys Glu Arg Ala Arg Ser Ala Glu Glu Pro 485 490 495Trp Thr Gln Asn Gln Gln Lys Leu Leu Glu Leu Ala Leu Gln Gln Tyr 500 505 510Pro Arg Gly Ser Ser Asp Arg Trp Asp Lys Ile Ala Arg Cys Val Pro 515 520 525Ser Lys Ser Lys Glu Asp Cys Ile Ala Arg Tyr Lys Leu Leu Val Glu 530 535 540Leu Val Gln Lys Lys Lys Gln Ala Lys Ser545 550194252DNAhumanCDS(528)...(3053) 19tttatttacg cctacctccc agcccttggc aatctgacta ataacaaact gagctaacaa 60gaaatactag aaaaggagga aggagaacat tgctgtagct tggatctaca acctaagaaa 120gcaagagtga tcaatctcag ctctgttaaa catcttgttt acttactgca ttcagcagct 180tgcaaatggt taactatatg caaaaaagtc agcatagctg tgaagtatgc cgtgaatttt 240aattgaggga aaaagggaca attgcttcag gatgctctag tatgcactct gcttgaaata 300ttttcaatga aatgctcagt attctatctt tgaccagagg ttttaacttt atgaagctat 360gggacttgac aaaaagtgat atttgagaag aaagtacgca gtggttggtg ttttcttttt 420tttaataaag gaattgaatt actttgaaca cctcttccag ctgtgcatta cagataacgt 480caggaagagt ctctgcttta cagaatcgga tttcatcaca tgacaac atg aag ctg 536 Met Lys Leu 1tgg att cat ctc ttt tat tca tct ctc ctt gcc tgt ata tct tta cac 584Trp Ile His Leu Phe Tyr Ser Ser Leu Leu Ala Cys Ile Ser Leu His 5 10 15tcc caa act cca gtg ctc tca tcc aga ggc tct tgt gat tct ctt tgc 632Ser Gln Thr Pro Val Leu Ser Ser Arg Gly Ser Cys Asp Ser Leu Cys20 25 30 35aat tgt gag gaa aaa gat ggc aca atg cta ata aat tgt gaa gca aaa 680Asn Cys Glu Glu Lys Asp Gly Thr Met Leu Ile Asn Cys Glu Ala Lys 40 45 50ggt atc aag atg gta tct gaa ata agt gtg cca cca tca cga cct ttc 728Gly Ile Lys Met Val Ser Glu Ile Ser Val Pro Pro Ser Arg Pro Phe 55 60 65caa cta agc tta tta aat aac ggc ttg acg atg ctt cac aca aat gac 776Gln Leu Ser Leu Leu Asn Asn Gly Leu Thr Met Leu His Thr Asn Asp 70 75 80ttt tct ggg ctt acc aat gct att tca ata cac ctt gga ttt aac aat 824Phe Ser Gly Leu Thr Asn Ala Ile Ser Ile His Leu Gly Phe Asn Asn 85 90 95att gca gat att gag ata ggt gca ttt aat ggc ctt ggc ctc ctg aaa 872Ile Ala Asp Ile Glu Ile Gly Ala Phe Asn Gly Leu Gly Leu Leu Lys100 105 110 115caa ctt cat atc aat cac aat tct tta gaa att ctt aaa gag gat act 920Gln Leu His Ile Asn His Asn Ser Leu Glu Ile Leu Lys Glu Asp Thr 120 125 130ttc cat gga ctg gaa aac ctg gaa ttc ctg caa gca gat aac aat ttt 968Phe His Gly Leu Glu Asn Leu Glu Phe Leu Gln Ala Asp Asn Asn Phe 135 140 145atc aca gtg att gaa cca agt gcc ttt agc aag ctc aac aga ctc aaa 1016Ile Thr Val Ile Glu Pro Ser Ala Phe Ser Lys Leu Asn Arg Leu Lys 150 155 160gtg tta att tta aat gac aat gct att gag agt ctt cct cca aac atc 1064Val Leu Ile Leu Asn Asp Asn Ala Ile Glu Ser Leu Pro Pro Asn Ile 165 170 175ttc cga ttt gtt cct tta acc cat cta gat ctt cgt gga aat caa tta 1112Phe Arg Phe Val Pro Leu Thr His Leu Asp Leu Arg Gly Asn Gln Leu180 185 190 195caa aca ttg cct tat gtt ggt ttt ctc gaa cac att ggc cga ata ttg 1160Gln Thr Leu Pro Tyr Val Gly Phe Leu Glu His Ile Gly Arg Ile Leu 200 205 210gat ctt cag ttg gag gac aac aaa tgg gcc tgc aat tgt gac tta ttg 1208Asp Leu Gln Leu Glu Asp Asn Lys Trp Ala Cys Asn Cys Asp Leu Leu 215 220 225cag tta aaa act tgg ttg gag aac atg cct cca cag tct ata att ggt 1256Gln Leu Lys Thr Trp Leu Glu Asn Met Pro Pro Gln Ser Ile Ile Gly 230 235 240gat gtt gtc tgc aac agc cct cca ttt ttt aaa gga agt ata ctc agt 1304Asp Val Val Cys Asn Ser Pro Pro Phe Phe Lys Gly Ser Ile Leu Ser 245 250 255aga cta aag aag gaa tct att tgc cct act cca cca gtg tat gaa gaa 1352Arg Leu Lys Lys Glu Ser Ile Cys Pro Thr Pro Pro Val Tyr Glu Glu260 265 270 275cat gag gat cct tca gga tca tta cat ctg gca gca aca tct tca ata 1400His Glu Asp Pro Ser Gly Ser Leu His Leu Ala Ala Thr Ser Ser Ile 280 285 290aat gat agt cgc atg tca act aag acc acg tcc att cta aaa cta ccc 1448Asn Asp Ser Arg Met Ser Thr Lys Thr Thr Ser Ile Leu Lys Leu Pro 295 300 305acc aaa gca cca ggt ttg ata cct tat att aca aag cca tcc act caa 1496Thr Lys Ala Pro Gly Leu Ile Pro Tyr Ile Thr Lys Pro Ser Thr Gln 310 315 320ctt cca gga cct tac tgc cct att cct tgt aac tgc aaa gtc cta tcc 1544Leu Pro Gly Pro Tyr Cys Pro Ile Pro Cys Asn Cys Lys Val Leu Ser 325 330 335cca tca gga ctt cta ata cat tgt cag gag cgc aac att gaa agc tta 1592Pro Ser Gly Leu Leu Ile His Cys Gln Glu Arg Asn Ile Glu Ser Leu340 345 350 355tca gat ctg aga cct cct ccg caa aat cct aga aag ctc att cta gcg 1640Ser Asp Leu Arg Pro Pro Pro Gln Asn Pro Arg Lys Leu Ile Leu Ala 360 365 370gga aat att att cac agt tta atg aag tct gat cta gtg gaa tat ttc 1688Gly Asn Ile Ile His Ser Leu Met Lys Ser Asp Leu Val Glu Tyr Phe 375 380 385act ttg gaa atg ctt cac ttg gga aac aat cgt att gaa gtt ctt gaa 1736Thr Leu Glu Met Leu His Leu Gly Asn Asn Arg Ile Glu Val Leu Glu 390 395 400gaa gga tcg ttt atg aac cta acg aga tta caa aaa ctc tat cta aat 1784Glu Gly Ser Phe Met Asn Leu Thr Arg Leu Gln Lys Leu Tyr Leu Asn 405 410 415ggt aac cac ctg acc aaa tta agt aaa ggc atg ttc ctt ggt ctc cat 1832Gly Asn His Leu Thr Lys Leu Ser Lys Gly Met Phe Leu Gly Leu His420 425 430 435aat ctt gaa tac tta tat ctt gaa tac aat gcc att aag gaa ata ctg 1880Asn Leu Glu Tyr Leu Tyr Leu Glu Tyr Asn Ala Ile Lys Glu Ile Leu 440 445 450cca gga acc ttt aat cca atg cct aaa ctt aaa gtc ctg tat tta aat 1928Pro Gly Thr Phe Asn Pro Met Pro Lys Leu Lys Val Leu Tyr Leu Asn 455 460 465aac aac ctc ctc caa gtt tta cca cca cat att ttt tca ggg gtt cct 1976Asn Asn Leu Leu Gln Val Leu Pro Pro His Ile Phe Ser Gly Val Pro 470 475 480cta act aag gta aat ctt aaa aca aac cag ttt acc cat cta cct gta 2024Leu Thr Lys Val Asn Leu Lys Thr Asn Gln Phe Thr His Leu Pro Val 485 490 495agt aat att ttg gat gat ctt gat tta cta acc cag att gac ctt gag 2072Ser Asn Ile Leu Asp Asp Leu Asp Leu Leu Thr Gln Ile Asp Leu Glu500 505 510 515gat aac ccc tgg gac tgc tcc tgt gac ctg gtt gga ctg cag caa tgg 2120Asp Asn Pro Trp Asp Cys Ser Cys Asp Leu Val Gly Leu Gln Gln Trp 520 525 530ata caa aag tta agc aag aac aca gtg aca gat gac atc ctc tgc act 2168Ile Gln Lys Leu Ser Lys Asn Thr Val Thr Asp Asp Ile Leu Cys Thr 535 540 545tcc ccc ggg cat ctc gac aaa aag gaa ttg aaa gcc cta aat agt gaa 2216Ser Pro Gly His Leu Asp Lys Lys Glu Leu Lys Ala Leu Asn Ser Glu 550 555 560att ctc tgt cca ggt tta gta aat aac cca tcc atg cca aca cag act 2264Ile Leu Cys Pro Gly Leu Val Asn Asn Pro Ser Met Pro Thr Gln Thr 565 570 575agt tac ctt atg gtc acc act cct gca aca aca aca aat acg gct gat 2312Ser Tyr Leu Met Val Thr Thr Pro Ala Thr Thr Thr Asn Thr Ala Asp580 585 590 595act att tta cga tct ctt acg gac gct gtg cca ctg tct gtt cta ata 2360Thr Ile Leu Arg Ser Leu Thr Asp Ala Val Pro Leu Ser Val Leu Ile 600 605 610ttg gga ctt ctg att atg ttc atc act att gtt ttc tgt gct gca ggg 2408Leu Gly Leu Leu Ile Met Phe Ile Thr Ile Val Phe Cys Ala Ala Gly 615 620 625ata gtg gtt ctt gtt ctt cac cgc agg aga aga tac aaa aag aaa caa 2456Ile Val Val Leu Val Leu His Arg Arg Arg Arg Tyr Lys Lys Lys Gln 630 635 640gta gat gag caa atg aga gac aac agt cct gtg cat ctt cag tac agc 2504Val Asp Glu Gln Met Arg Asp Asn Ser Pro Val His Leu Gln Tyr Ser 645 650 655atg tat ggc cat aaa acc act cat cac act act gaa aga ccc tct gcc 2552Met Tyr Gly His Lys Thr Thr His His Thr Thr Glu Arg Pro Ser Ala660 665 670 675tca ctc tat gaa cag cac atg gtg agc ccc atg gtt cat gtc tat aga 2600Ser Leu Tyr Glu Gln His Met Val Ser Pro Met Val His Val Tyr Arg 680 685 690agt cca tcc ttt ggt cca aag cat ctg gaa gag gaa gaa gag agg aat 2648Ser Pro Ser Phe Gly Pro Lys His Leu Glu Glu Glu Glu Glu Arg Asn 695 700 705gag aaa gaa gga agt gat gca aaa cat ctc caa aga agt ctt ttg gaa 2696Glu Lys Glu Gly Ser Asp Ala Lys His Leu Gln Arg Ser Leu Leu Glu 710 715 720cag gaa aat cat tca cca ctc aca ggg tca aat atg aaa tac aaa acc 2744Gln Glu Asn His Ser Pro Leu Thr Gly Ser Asn Met Lys Tyr Lys Thr 725 730 735acg aac caa tca aca gaa ttt tta tcc ttc caa gat gcc agc tca ttg 2792Thr Asn Gln Ser Thr Glu Phe Leu Ser Phe Gln Asp Ala Ser Ser Leu740 745 750 755tac aga aac att tta gaa aaa gaa agg gaa ctt cag caa ctg gga atc 2840Tyr Arg Asn Ile Leu Glu Lys Glu Arg Glu Leu Gln Gln Leu Gly Ile 760 765 770aca gaa tac cta agg aaa aac att gct cag ctc cag cct gat atg gag 2888Thr Glu Tyr Leu Arg Lys Asn Ile Ala Gln Leu Gln Pro Asp Met Glu 775 780 785gca cat tat cct gga gcc cac gaa gag ctg aag tta atg gaa aca tta 2936Ala His Tyr Pro Gly Ala His Glu Glu Leu Lys Leu Met Glu Thr Leu 790 795 800atg tac tca cgt cca agg aag gta tta gtg gaa cag aca aaa aat gag 2984Met Tyr Ser Arg Pro Arg Lys Val Leu Val Glu Gln Thr Lys Asn Glu 805 810 815tat ttt gaa ctt aaa gct aat tta cat gct gaa cct gac tat tta gaa

3032Tyr Phe Glu Leu Lys Ala Asn Leu His Ala Glu Pro Asp Tyr Leu Glu820 825 830 835gtc ctg gag cag caa aca tag atggagagtt tgagggcttt cgcagaaatg 3083Val Leu Glu Gln Gln Thr * 840ctgtgattct gttttaagtc cataccttgt aaataagtgc cttacgtgag tgtgtcatca 3143atcagaacct aagcacagca gtaaactatg gggaaaaaaa aagaagaaga aaaagaaact 3203cagggatcac tgggagaagc catggcatta tcttcaggca atttagtctg tcccaaataa 3263aataaatcct tgcatgtaaa tcattcaagg attatagtaa tatttcatat actgaaaagt 3323gtctcatagg agtcctcttg cacatctaaa aaggctgaac atttaagtat cccgaatttt 3383cttgaattgc tttccctata gattaattac aattggattt catcatttaa aaaccatact 3443tgtatatgta gttataatat gtaaggaata cattgtttat aaccagtatg tacttcaaaa 3503atgtgtattg tcaaacatac ctaactttct tgcaataaat gcaaaagaaa ctggaacttg 3563acaattataa atagtaatag tgaagaaaaa atagaaaggt tgcaattata taggccatgg 3623gtggctcaaa actttgaaca tttgagctta aacaaatgcc actctcatgc attctaaatt 3683aaaaagttaa aatgattaat agttcaggtg gaagaaataa gcatactttt tgggttttct 3743acacattttg tgtagacaat tttaatgtca gtgctgctgt gaactaaagt atgtcattta 3803tgctcaaagt ttaattcttc ttcttgggat attttaaaaa tgctactgag attctgctgt 3863aaatatgact agagaatata ttgggtttgc tttatttcat aggcttaatt ctttgtaaat 3923ctgaatgacc ataatagaaa tacatttctt gtggcaagta attcacagtt gtaaagtaaa 3983taggaaaaat tattttattt ttattgatgt acattgatag atgccataaa tcagtagcaa 4043aaggcacttc taaaggtaag tggtttaagt tgcctcaaga gagggacaat gtagctttat 4103tttacaagaa ggcatagtta gatttctatg aaatatttat tctgtacagt tttatatagt 4163tttggttcac aaaagtaatt attcttgggt gcctttcaag aaaattaaaa atactactca 4223ctacaataaa actaaaatga aaactcttt 425220841PRThuman 20Met Lys Leu Trp Ile His Leu Phe Tyr Ser Ser Leu Leu Ala Cys Ile1 5 10 15Ser Leu His Ser Gln Thr Pro Val Leu Ser Ser Arg Gly Ser Cys Asp 20 25 30Ser Leu Cys Asn Cys Glu Glu Lys Asp Gly Thr Met Leu Ile Asn Cys 35 40 45Glu Ala Lys Gly Ile Lys Met Val Ser Glu Ile Ser Val Pro Pro Ser 50 55 60Arg Pro Phe Gln Leu Ser Leu Leu Asn Asn Gly Leu Thr Met Leu His65 70 75 80Thr Asn Asp Phe Ser Gly Leu Thr Asn Ala Ile Ser Ile His Leu Gly 85 90 95Phe Asn Asn Ile Ala Asp Ile Glu Ile Gly Ala Phe Asn Gly Leu Gly 100 105 110Leu Leu Lys Gln Leu His Ile Asn His Asn Ser Leu Glu Ile Leu Lys 115 120 125Glu Asp Thr Phe His Gly Leu Glu Asn Leu Glu Phe Leu Gln Ala Asp 130 135 140Asn Asn Phe Ile Thr Val Ile Glu Pro Ser Ala Phe Ser Lys Leu Asn145 150 155 160Arg Leu Lys Val Leu Ile Leu Asn Asp Asn Ala Ile Glu Ser Leu Pro 165 170 175Pro Asn Ile Phe Arg Phe Val Pro Leu Thr His Leu Asp Leu Arg Gly 180 185 190Asn Gln Leu Gln Thr Leu Pro Tyr Val Gly Phe Leu Glu His Ile Gly 195 200 205Arg Ile Leu Asp Leu Gln Leu Glu Asp Asn Lys Trp Ala Cys Asn Cys 210 215 220Asp Leu Leu Gln Leu Lys Thr Trp Leu Glu Asn Met Pro Pro Gln Ser225 230 235 240Ile Ile Gly Asp Val Val Cys Asn Ser Pro Pro Phe Phe Lys Gly Ser 245 250 255Ile Leu Ser Arg Leu Lys Lys Glu Ser Ile Cys Pro Thr Pro Pro Val 260 265 270Tyr Glu Glu His Glu Asp Pro Ser Gly Ser Leu His Leu Ala Ala Thr 275 280 285Ser Ser Ile Asn Asp Ser Arg Met Ser Thr Lys Thr Thr Ser Ile Leu 290 295 300Lys Leu Pro Thr Lys Ala Pro Gly Leu Ile Pro Tyr Ile Thr Lys Pro305 310 315 320Ser Thr Gln Leu Pro Gly Pro Tyr Cys Pro Ile Pro Cys Asn Cys Lys 325 330 335Val Leu Ser Pro Ser Gly Leu Leu Ile His Cys Gln Glu Arg Asn Ile 340 345 350Glu Ser Leu Ser Asp Leu Arg Pro Pro Pro Gln Asn Pro Arg Lys Leu 355 360 365Ile Leu Ala Gly Asn Ile Ile His Ser Leu Met Lys Ser Asp Leu Val 370 375 380Glu Tyr Phe Thr Leu Glu Met Leu His Leu Gly Asn Asn Arg Ile Glu385 390 395 400Val Leu Glu Glu Gly Ser Phe Met Asn Leu Thr Arg Leu Gln Lys Leu 405 410 415Tyr Leu Asn Gly Asn His Leu Thr Lys Leu Ser Lys Gly Met Phe Leu 420 425 430Gly Leu His Asn Leu Glu Tyr Leu Tyr Leu Glu Tyr Asn Ala Ile Lys 435 440 445Glu Ile Leu Pro Gly Thr Phe Asn Pro Met Pro Lys Leu Lys Val Leu 450 455 460Tyr Leu Asn Asn Asn Leu Leu Gln Val Leu Pro Pro His Ile Phe Ser465 470 475 480Gly Val Pro Leu Thr Lys Val Asn Leu Lys Thr Asn Gln Phe Thr His 485 490 495Leu Pro Val Ser Asn Ile Leu Asp Asp Leu Asp Leu Leu Thr Gln Ile 500 505 510Asp Leu Glu Asp Asn Pro Trp Asp Cys Ser Cys Asp Leu Val Gly Leu 515 520 525Gln Gln Trp Ile Gln Lys Leu Ser Lys Asn Thr Val Thr Asp Asp Ile 530 535 540Leu Cys Thr Ser Pro Gly His Leu Asp Lys Lys Glu Leu Lys Ala Leu545 550 555 560Asn Ser Glu Ile Leu Cys Pro Gly Leu Val Asn Asn Pro Ser Met Pro 565 570 575Thr Gln Thr Ser Tyr Leu Met Val Thr Thr Pro Ala Thr Thr Thr Asn 580 585 590Thr Ala Asp Thr Ile Leu Arg Ser Leu Thr Asp Ala Val Pro Leu Ser 595 600 605Val Leu Ile Leu Gly Leu Leu Ile Met Phe Ile Thr Ile Val Phe Cys 610 615 620Ala Ala Gly Ile Val Val Leu Val Leu His Arg Arg Arg Arg Tyr Lys625 630 635 640Lys Lys Gln Val Asp Glu Gln Met Arg Asp Asn Ser Pro Val His Leu 645 650 655Gln Tyr Ser Met Tyr Gly His Lys Thr Thr His His Thr Thr Glu Arg 660 665 670Pro Ser Ala Ser Leu Tyr Glu Gln His Met Val Ser Pro Met Val His 675 680 685Val Tyr Arg Ser Pro Ser Phe Gly Pro Lys His Leu Glu Glu Glu Glu 690 695 700Glu Arg Asn Glu Lys Glu Gly Ser Asp Ala Lys His Leu Gln Arg Ser705 710 715 720Leu Leu Glu Gln Glu Asn His Ser Pro Leu Thr Gly Ser Asn Met Lys 725 730 735Tyr Lys Thr Thr Asn Gln Ser Thr Glu Phe Leu Ser Phe Gln Asp Ala 740 745 750Ser Ser Leu Tyr Arg Asn Ile Leu Glu Lys Glu Arg Glu Leu Gln Gln 755 760 765Leu Gly Ile Thr Glu Tyr Leu Arg Lys Asn Ile Ala Gln Leu Gln Pro 770 775 780Asp Met Glu Ala His Tyr Pro Gly Ala His Glu Glu Leu Lys Leu Met785 790 795 800Glu Thr Leu Met Tyr Ser Arg Pro Arg Lys Val Leu Val Glu Gln Thr 805 810 815Lys Asn Glu Tyr Phe Glu Leu Lys Ala Asn Leu His Ala Glu Pro Asp 820 825 830Tyr Leu Glu Val Leu Glu Gln Gln Thr 835 840213609DNAhumanCDS(282)...(2549) 21cgaagggggc ggtggttccc cgcggcgctg cgcgcggcgg taattagtga ttgtcttcca 60gcttcgcgaa ggctaggggc gcggctgccg ggtggctgcg cggcgctgcc cccggaccga 120ggggcagcca atccaatgaa accaccgcgt gttcgcgcct ggtagagatt tctcgaagac 180accagtgggc ccgttccgag ccctctggac cgcccgtgtg gaaccaaacc tgcgcgcgtg 240gccgggccgt gggacaacga ggccgcggag acgaaggcgc a atg gcg agg aag tta 296 Met Ala Arg Lys Leu 1 5tct gta atc ttg atc ctg acc ttt gcc ctc tct gtc aca aat ccc ctt 344Ser Val Ile Leu Ile Leu Thr Phe Ala Leu Ser Val Thr Asn Pro Leu 10 15 20cat gaa cta aaa gca gct gct ttc ccc cag acc act gag aaa att agt 392His Glu Leu Lys Ala Ala Ala Phe Pro Gln Thr Thr Glu Lys Ile Ser 25 30 35ccg aat tgg gaa tct ggc att aat gtt gac ttg gca att tcc aca cgg 440Pro Asn Trp Glu Ser Gly Ile Asn Val Asp Leu Ala Ile Ser Thr Arg 40 45 50caa tat cat cta caa cag ctt ttc tac cgc tat gga gaa aat aat tct 488Gln Tyr His Leu Gln Gln Leu Phe Tyr Arg Tyr Gly Glu Asn Asn Ser 55 60 65ttg tca gtt gaa ggg ttc aga aaa tta ctt caa aat ata ggc ata gat 536Leu Ser Val Glu Gly Phe Arg Lys Leu Leu Gln Asn Ile Gly Ile Asp70 75 80 85aag att aaa aga atc cat ata cac cat gac cac gac cat cac tca gac 584Lys Ile Lys Arg Ile His Ile His His Asp His Asp His His Ser Asp 90 95 100cac gag cat cac tca gac cat gag cgt cac tca gac cat gag cat cac 632His Glu His His Ser Asp His Glu Arg His Ser Asp His Glu His His 105 110 115tca gac cac gag cat cac tct gac cat gat cat cac tct cac cat aat 680Ser Asp His Glu His His Ser Asp His Asp His His Ser His His Asn 120 125 130cat gct gct tct ggt aaa aat aag cga aaa gct ctt tgc cca gac cat 728His Ala Ala Ser Gly Lys Asn Lys Arg Lys Ala Leu Cys Pro Asp His 135 140 145gac tca gat agt tca ggt aaa gat cct aga aac agc cag ggg aaa gga 776Asp Ser Asp Ser Ser Gly Lys Asp Pro Arg Asn Ser Gln Gly Lys Gly150 155 160 165gct cac cga cca gaa cat gcc agt ggt aga agg aat gtc aag gac agt 824Ala His Arg Pro Glu His Ala Ser Gly Arg Arg Asn Val Lys Asp Ser 170 175 180gtt agt gct agt gaa gtg acc tca act gtg tac aac act gtc tct gaa 872Val Ser Ala Ser Glu Val Thr Ser Thr Val Tyr Asn Thr Val Ser Glu 185 190 195gga act cac ttt cta gag aca ata gag act cca aga cct gga aaa ctc 920Gly Thr His Phe Leu Glu Thr Ile Glu Thr Pro Arg Pro Gly Lys Leu 200 205 210ttc ccc aaa gat gta agc agc tcc act cca ccc agt gtc aca tca aag 968Phe Pro Lys Asp Val Ser Ser Ser Thr Pro Pro Ser Val Thr Ser Lys 215 220 225agc cgg gtg agc cgg ctg gct ggt agg aaa aca aat gaa tct gtg agt 1016Ser Arg Val Ser Arg Leu Ala Gly Arg Lys Thr Asn Glu Ser Val Ser230 235 240 245gag ccc cga aaa ggc ttt atg tat tcc aga aac aca aat gaa aat cct 1064Glu Pro Arg Lys Gly Phe Met Tyr Ser Arg Asn Thr Asn Glu Asn Pro 250 255 260cag gag tgt ttc aat gca tca aag cta ctg aca tct cat ggc atg ggc 1112Gln Glu Cys Phe Asn Ala Ser Lys Leu Leu Thr Ser His Gly Met Gly 265 270 275atc cag gtt ccg ctg aat gca aca gag ttc aac tat ctc tgt cca gcc 1160Ile Gln Val Pro Leu Asn Ala Thr Glu Phe Asn Tyr Leu Cys Pro Ala 280 285 290atc atc aac caa att gat gct aga tct tgt ctg att cat aca agt gaa 1208Ile Ile Asn Gln Ile Asp Ala Arg Ser Cys Leu Ile His Thr Ser Glu 295 300 305aag aag gct gaa atc cct cca aag acc tat tca tta caa ata gcc tgg 1256Lys Lys Ala Glu Ile Pro Pro Lys Thr Tyr Ser Leu Gln Ile Ala Trp310 315 320 325gtt ggt ggt ttt ata gcc att tcc atc atc agt ttc ctg tct ctg ctg 1304Val Gly Gly Phe Ile Ala Ile Ser Ile Ile Ser Phe Leu Ser Leu Leu 330 335 340ggg gtt atc tta gtg cct ctc atg aat cgg gtg ttt ttc aaa ttt ctc 1352Gly Val Ile Leu Val Pro Leu Met Asn Arg Val Phe Phe Lys Phe Leu 345 350 355ctg agt ttc ctt gtg gca ctg gcc gtt ggg act ttg agt ggt gat gct 1400Leu Ser Phe Leu Val Ala Leu Ala Val Gly Thr Leu Ser Gly Asp Ala 360 365 370ttt tta cac ctt ctt cca cat tct cat gca agt cac cac cat agt cat 1448Phe Leu His Leu Leu Pro His Ser His Ala Ser His His His Ser His 375 380 385agc cat gaa gaa cca gca atg gaa atg aaa aga gga cca ctt ttc agt 1496Ser His Glu Glu Pro Ala Met Glu Met Lys Arg Gly Pro Leu Phe Ser390 395 400 405cat ctg tct tct caa aac ata gaa gaa agt gcc tat ttt gat tcc acg 1544His Leu Ser Ser Gln Asn Ile Glu Glu Ser Ala Tyr Phe Asp Ser Thr 410 415 420tgg aag ggt cta aca gct cta gga ggc ctg tat ttc atg ttt ctt gtt 1592Trp Lys Gly Leu Thr Ala Leu Gly Gly Leu Tyr Phe Met Phe Leu Val 425 430 435gaa cat gtc ctc aca ttg atc aaa caa ttt aaa gat aag aag aaa aag 1640Glu His Val Leu Thr Leu Ile Lys Gln Phe Lys Asp Lys Lys Lys Lys 440 445 450aat cag aag aaa cct gaa aat gat gat gat gtg gag att aag aag cag 1688Asn Gln Lys Lys Pro Glu Asn Asp Asp Asp Val Glu Ile Lys Lys Gln 455 460 465ttg tcc aag tat gaa tct caa ctt tca aca aat gag gag aaa gta gat 1736Leu Ser Lys Tyr Glu Ser Gln Leu Ser Thr Asn Glu Glu Lys Val Asp470 475 480 485aca gat gat cga act gaa ggc tat tta cga gca gac tca caa gag ccc 1784Thr Asp Asp Arg Thr Glu Gly Tyr Leu Arg Ala Asp Ser Gln Glu Pro 490 495 500tcc cac ttt gat tct cag cag cct gca gtc ttg gaa gaa gaa gag gtc 1832Ser His Phe Asp Ser Gln Gln Pro Ala Val Leu Glu Glu Glu Glu Val 505 510 515atg ata gct cat gct cat cca cag gaa gtc tac aat gaa tat gta ccc 1880Met Ile Ala His Ala His Pro Gln Glu Val Tyr Asn Glu Tyr Val Pro 520 525 530aga ggg tgc aag aat aaa tgc cat tca cat ttc cac gat aca ctc ggc 1928Arg Gly Cys Lys Asn Lys Cys His Ser His Phe His Asp Thr Leu Gly 535 540 545cag tca gac gat ctc att cac cac cat cat gac tac cat cat att ctc 1976Gln Ser Asp Asp Leu Ile His His His His Asp Tyr His His Ile Leu550 555 560 565cat cat cac cac cac caa aac cac cat cct cac agt cac agc cag cgc 2024His His His His His Gln Asn His His Pro His Ser His Ser Gln Arg 570 575 580tac tct cgg gag gag ctg aaa gat gcc ggc gtc gcc act ctg gcc tgg 2072Tyr Ser Arg Glu Glu Leu Lys Asp Ala Gly Val Ala Thr Leu Ala Trp 585 590 595atg gtg ata atg ggt gat ggc ctg cac aat ttc agc gat ggc cta gca 2120Met Val Ile Met Gly Asp Gly Leu His Asn Phe Ser Asp Gly Leu Ala 600 605 610att ggt gct gct ttt act gaa ggc tta tca agt ggt tta agt act tct 2168Ile Gly Ala Ala Phe Thr Glu Gly Leu Ser Ser Gly Leu Ser Thr Ser 615 620 625gtt gct gtg ttc tgt cat gag ttg cct cat gaa tta ggt gac ttt gct 2216Val Ala Val Phe Cys His Glu Leu Pro His Glu Leu Gly Asp Phe Ala630 635 640 645gtt cta cta aag gct ggc atg acc gtt aag cag gct gtc ctt tat aat 2264Val Leu Leu Lys Ala Gly Met Thr Val Lys Gln Ala Val Leu Tyr Asn 650 655 660gca ttg tca gcc atg ctg gcg tat ctt gga atg gca aca gga att ttc 2312Ala Leu Ser Ala Met Leu Ala Tyr Leu Gly Met Ala Thr Gly Ile Phe 665 670 675att ggt cat tat gct gaa aat gtt tct atg tgg ata ttt gca ctt act 2360Ile Gly His Tyr Ala Glu Asn Val Ser Met Trp Ile Phe Ala Leu Thr 680 685 690gct ggc tta ttc atg tat gtt gct ctg gtt gat atg gta cct gaa atg 2408Ala Gly Leu Phe Met Tyr Val Ala Leu Val Asp Met Val Pro Glu Met 695 700 705ctg cac aat gat gct agt gac cat gga tgt agc cgc tgg ggg tat ttc 2456Leu His Asn Asp Ala Ser Asp His Gly Cys Ser Arg Trp Gly Tyr Phe710 715 720 725ttt tta cag aat gct ggg atg ctt ttg ggt ttt gga att atg tta ctt 2504Phe Leu Gln Asn Ala Gly Met Leu Leu Gly Phe Gly Ile Met Leu Leu 730 735 740att tcc ata ttt gaa cat aaa atc gtg ttt cgt ata aat ttc tag 2549Ile Ser Ile Phe Glu His Lys Ile Val Phe Arg Ile Asn Phe * 745 750 755ttaaggttta aatgctagag tagcttaaaa agttgtcata gtttcagtag gtcataggga 2609gatgagtttg tatgctgtac tatgcagcgt ttaaagttag tgggttttgt gattttttat 2669tgaatattgc tgtctgttac aaagtcagtt aaaggtacgt tttaatattt aagttattct 2729atcttggaga taaaatctgt atgtgcaatt caccggtatt accagtttat tatgtaaaca 2789agagatttgg catgacatgt tctgtatgtt tcagggaaaa atgtctttaa tgctttttca 2849agaactaaca cagttattcc tatactggat tttaggtctc tgaagaactg ctggtgttta 2909ggaataagaa tgtgcatgaa gcctaaaata ccaagaaagc ttatactgaa tttaagcaaa 2969gaaataaagg agaaaagaga agaatctgag aattggggag gcatagattc ttataaaaat 3029cacaaaattt gttgtaaatt agaggggaga aatttagaat taagtataaa aaggcagaat 3089tagtatagag tacattcatt aaacattttt gtcaggatta tttcccgtaa aaacgtagtg 3149agcacttttc atatactaat ttagttgtac atttaacttt gtataataca gaaatctaaa 3209tatatttaat gaattcaagc aatatatcac ttgaccaaga aattggaatt tcaaaatgtt 3269cgtgcgggta tataccagat

gagtacagtg agtagtttta tgtatcacca gactgggtta 3329ttgccaagtt atatatcacc aaaagctgta tgactggatg ttctggttac ctggtttaca 3389aaattatcag agtagtaaaa ctttgatata tatgaggata ttaaaactac actaagtatc 3449atttgattcg attcagaaag tactttgata tctctcagtg cttcagtgct atcattgtga 3509gcaattgtct tttatatacg gtactgtagc catactaggc ctgtctgtgg cattctctag 3569atgtttcttt tttacacaat aaattcctta tatcagcttg 360922755PRThuman 22Met Ala Arg Lys Leu Ser Val Ile Leu Ile Leu Thr Phe Ala Leu Ser1 5 10 15Val Thr Asn Pro Leu His Glu Leu Lys Ala Ala Ala Phe Pro Gln Thr 20 25 30Thr Glu Lys Ile Ser Pro Asn Trp Glu Ser Gly Ile Asn Val Asp Leu 35 40 45Ala Ile Ser Thr Arg Gln Tyr His Leu Gln Gln Leu Phe Tyr Arg Tyr 50 55 60Gly Glu Asn Asn Ser Leu Ser Val Glu Gly Phe Arg Lys Leu Leu Gln65 70 75 80Asn Ile Gly Ile Asp Lys Ile Lys Arg Ile His Ile His His Asp His 85 90 95Asp His His Ser Asp His Glu His His Ser Asp His Glu Arg His Ser 100 105 110Asp His Glu His His Ser Asp His Glu His His Ser Asp His Asp His 115 120 125His Ser His His Asn His Ala Ala Ser Gly Lys Asn Lys Arg Lys Ala 130 135 140Leu Cys Pro Asp His Asp Ser Asp Ser Ser Gly Lys Asp Pro Arg Asn145 150 155 160Ser Gln Gly Lys Gly Ala His Arg Pro Glu His Ala Ser Gly Arg Arg 165 170 175Asn Val Lys Asp Ser Val Ser Ala Ser Glu Val Thr Ser Thr Val Tyr 180 185 190Asn Thr Val Ser Glu Gly Thr His Phe Leu Glu Thr Ile Glu Thr Pro 195 200 205Arg Pro Gly Lys Leu Phe Pro Lys Asp Val Ser Ser Ser Thr Pro Pro 210 215 220Ser Val Thr Ser Lys Ser Arg Val Ser Arg Leu Ala Gly Arg Lys Thr225 230 235 240Asn Glu Ser Val Ser Glu Pro Arg Lys Gly Phe Met Tyr Ser Arg Asn 245 250 255Thr Asn Glu Asn Pro Gln Glu Cys Phe Asn Ala Ser Lys Leu Leu Thr 260 265 270Ser His Gly Met Gly Ile Gln Val Pro Leu Asn Ala Thr Glu Phe Asn 275 280 285Tyr Leu Cys Pro Ala Ile Ile Asn Gln Ile Asp Ala Arg Ser Cys Leu 290 295 300Ile His Thr Ser Glu Lys Lys Ala Glu Ile Pro Pro Lys Thr Tyr Ser305 310 315 320Leu Gln Ile Ala Trp Val Gly Gly Phe Ile Ala Ile Ser Ile Ile Ser 325 330 335Phe Leu Ser Leu Leu Gly Val Ile Leu Val Pro Leu Met Asn Arg Val 340 345 350Phe Phe Lys Phe Leu Leu Ser Phe Leu Val Ala Leu Ala Val Gly Thr 355 360 365Leu Ser Gly Asp Ala Phe Leu His Leu Leu Pro His Ser His Ala Ser 370 375 380His His His Ser His Ser His Glu Glu Pro Ala Met Glu Met Lys Arg385 390 395 400Gly Pro Leu Phe Ser His Leu Ser Ser Gln Asn Ile Glu Glu Ser Ala 405 410 415Tyr Phe Asp Ser Thr Trp Lys Gly Leu Thr Ala Leu Gly Gly Leu Tyr 420 425 430Phe Met Phe Leu Val Glu His Val Leu Thr Leu Ile Lys Gln Phe Lys 435 440 445Asp Lys Lys Lys Lys Asn Gln Lys Lys Pro Glu Asn Asp Asp Asp Val 450 455 460Glu Ile Lys Lys Gln Leu Ser Lys Tyr Glu Ser Gln Leu Ser Thr Asn465 470 475 480Glu Glu Lys Val Asp Thr Asp Asp Arg Thr Glu Gly Tyr Leu Arg Ala 485 490 495Asp Ser Gln Glu Pro Ser His Phe Asp Ser Gln Gln Pro Ala Val Leu 500 505 510Glu Glu Glu Glu Val Met Ile Ala His Ala His Pro Gln Glu Val Tyr 515 520 525Asn Glu Tyr Val Pro Arg Gly Cys Lys Asn Lys Cys His Ser His Phe 530 535 540His Asp Thr Leu Gly Gln Ser Asp Asp Leu Ile His His His His Asp545 550 555 560Tyr His His Ile Leu His His His His His Gln Asn His His Pro His 565 570 575Ser His Ser Gln Arg Tyr Ser Arg Glu Glu Leu Lys Asp Ala Gly Val 580 585 590Ala Thr Leu Ala Trp Met Val Ile Met Gly Asp Gly Leu His Asn Phe 595 600 605Ser Asp Gly Leu Ala Ile Gly Ala Ala Phe Thr Glu Gly Leu Ser Ser 610 615 620Gly Leu Ser Thr Ser Val Ala Val Phe Cys His Glu Leu Pro His Glu625 630 635 640Leu Gly Asp Phe Ala Val Leu Leu Lys Ala Gly Met Thr Val Lys Gln 645 650 655Ala Val Leu Tyr Asn Ala Leu Ser Ala Met Leu Ala Tyr Leu Gly Met 660 665 670Ala Thr Gly Ile Phe Ile Gly His Tyr Ala Glu Asn Val Ser Met Trp 675 680 685Ile Phe Ala Leu Thr Ala Gly Leu Phe Met Tyr Val Ala Leu Val Asp 690 695 700Met Val Pro Glu Met Leu His Asn Asp Ala Ser Asp His Gly Cys Ser705 710 715 720Arg Trp Gly Tyr Phe Phe Leu Gln Asn Ala Gly Met Leu Leu Gly Phe 725 730 735Gly Ile Met Leu Leu Ile Ser Ile Phe Glu His Lys Ile Val Phe Arg 740 745 750Ile Asn Phe 755232811DNAhumanCDS(309)...(1751) 23cgaagggggc ggtggttccc cgcggcgctg cgcgcggcgg taattagtga ttgtcttcca 60gcttcgcgaa ggctaggggc gcggctgccg ggtggctgcg cggcgctgcc cccggaccga 120ggggcagcca atccaatgaa accaccgcgt gttcgcgcct ggtagagatt tctcgaagac 180accagtgggc ccgttccgag ccctctggac cgcccgtgtg gaaccaaacc tgcgcgcgtg 240gccgggccgt gggacaacga ggccgcggag actgtttcaa tgcatcaaag ctactgacat 300ctcatggc atg ggc atc cag gtt ccg ctg aat gca aca gag ttc aac tat 350 Met Gly Ile Gln Val Pro Leu Asn Ala Thr Glu Phe Asn Tyr 1 5 10ctc tgt cca gcc atc atc aac caa att gat gct aga tct tgt ctg att 398Leu Cys Pro Ala Ile Ile Asn Gln Ile Asp Ala Arg Ser Cys Leu Ile15 20 25 30cat aca agt gaa aag aag gct gaa atc cct cca aag acc tat tca tta 446His Thr Ser Glu Lys Lys Ala Glu Ile Pro Pro Lys Thr Tyr Ser Leu 35 40 45caa ata gcc tgg gtt ggt ggt ttt ata gcc att tcc atc atc agt ttc 494Gln Ile Ala Trp Val Gly Gly Phe Ile Ala Ile Ser Ile Ile Ser Phe 50 55 60ctg tct ctg ctg ggg gtt atc tta gtg cct ctc atg aat cgg gtg ttt 542Leu Ser Leu Leu Gly Val Ile Leu Val Pro Leu Met Asn Arg Val Phe 65 70 75ttc aaa ttt ctc ctg agt ttc ctt gtg gca ctg gcc gtt ggg act ttg 590Phe Lys Phe Leu Leu Ser Phe Leu Val Ala Leu Ala Val Gly Thr Leu 80 85 90agt ggt gat gct ttt tta cac ctt ctt cca cat tct cat gca agt cac 638Ser Gly Asp Ala Phe Leu His Leu Leu Pro His Ser His Ala Ser His95 100 105 110cac cat agt cat agc cat gaa gaa cca gca atg gaa atg aaa aga gga 686His His Ser His Ser His Glu Glu Pro Ala Met Glu Met Lys Arg Gly 115 120 125cca ctt ttc agt cat ctg tct tct caa aac ata gaa gaa agt gcc tat 734Pro Leu Phe Ser His Leu Ser Ser Gln Asn Ile Glu Glu Ser Ala Tyr 130 135 140ttt gat tcc acg tgg aag ggt cta aca gct cta gga ggc ctg tat ttc 782Phe Asp Ser Thr Trp Lys Gly Leu Thr Ala Leu Gly Gly Leu Tyr Phe 145 150 155atg ttt ctt gtt gaa cat gtc ctc aca ttg atc aaa caa ttt aaa gat 830Met Phe Leu Val Glu His Val Leu Thr Leu Ile Lys Gln Phe Lys Asp 160 165 170aag aag aaa aag aat cag aag aaa cct gaa aat gat gat gat gtg gag 878Lys Lys Lys Lys Asn Gln Lys Lys Pro Glu Asn Asp Asp Asp Val Glu175 180 185 190att aag aag cag ttg tcc aag tat gaa tct caa ctt tca aca aat gag 926Ile Lys Lys Gln Leu Ser Lys Tyr Glu Ser Gln Leu Ser Thr Asn Glu 195 200 205gag aaa gta gat aca gat gat cga act gaa ggc tat tta cga gca gac 974Glu Lys Val Asp Thr Asp Asp Arg Thr Glu Gly Tyr Leu Arg Ala Asp 210 215 220tca caa gag ccc tcc cac ttt gat tct cag cag cct gca gtc ttg gaa 1022Ser Gln Glu Pro Ser His Phe Asp Ser Gln Gln Pro Ala Val Leu Glu 225 230 235gaa gaa gag gtc atg ata gct cat gct cat cca cag gaa gtc tac aat 1070Glu Glu Glu Val Met Ile Ala His Ala His Pro Gln Glu Val Tyr Asn 240 245 250gaa tat gta ccc aga ggg tgc aag aat aaa tgc cat tca cat ttc cac 1118Glu Tyr Val Pro Arg Gly Cys Lys Asn Lys Cys His Ser His Phe His255 260 265 270gat aca ctc ggc cag tca gac gat ctc att cac cac cat cat gac tac 1166Asp Thr Leu Gly Gln Ser Asp Asp Leu Ile His His His His Asp Tyr 275 280 285cat cat att ctc cat cat cac cac cac caa aac cac cat cct cac agt 1214His His Ile Leu His His His His His Gln Asn His His Pro His Ser 290 295 300cac agc cag cgc tac tct cgg gag gag ctg aaa gat gcc ggc gtc gcc 1262His Ser Gln Arg Tyr Ser Arg Glu Glu Leu Lys Asp Ala Gly Val Ala 305 310 315act ctg gcc tgg atg gtg ata atg ggt gat ggc ctg cac aat ttc agc 1310Thr Leu Ala Trp Met Val Ile Met Gly Asp Gly Leu His Asn Phe Ser 320 325 330gat ggc cta gca att ggt gct gct ttt act gaa ggc tta tca agt ggt 1358Asp Gly Leu Ala Ile Gly Ala Ala Phe Thr Glu Gly Leu Ser Ser Gly335 340 345 350tta agt act tct gtt gct gtg ttc tgt cat gag ttg cct cat gaa tta 1406Leu Ser Thr Ser Val Ala Val Phe Cys His Glu Leu Pro His Glu Leu 355 360 365ggt gac ttt gct gtt cta cta aag gct ggc atg acc gtt aag cag gct 1454Gly Asp Phe Ala Val Leu Leu Lys Ala Gly Met Thr Val Lys Gln Ala 370 375 380gtc ctt tat aat gca ttg tca gcc atg ctg gcg tat ctt gga atg gca 1502Val Leu Tyr Asn Ala Leu Ser Ala Met Leu Ala Tyr Leu Gly Met Ala 385 390 395aca gga att ttc att ggt cat tat gct gaa aat gtt tct atg tgg ata 1550Thr Gly Ile Phe Ile Gly His Tyr Ala Glu Asn Val Ser Met Trp Ile 400 405 410ttt gca ctt act gct ggc tta ttc atg tat gtt gct ctg gtt gat atg 1598Phe Ala Leu Thr Ala Gly Leu Phe Met Tyr Val Ala Leu Val Asp Met415 420 425 430gta cct gaa atg ctg cac aat gat gct agt gac cat gga tgt agc cgc 1646Val Pro Glu Met Leu His Asn Asp Ala Ser Asp His Gly Cys Ser Arg 435 440 445tgg ggg tat ttc ttt tta cag aat gct ggg atg ctt ttg ggt ttt gga 1694Trp Gly Tyr Phe Phe Leu Gln Asn Ala Gly Met Leu Leu Gly Phe Gly 450 455 460att atg tta ctt att tcc ata ttt gaa cat aaa atc gtg ttt cgt ata 1742Ile Met Leu Leu Ile Ser Ile Phe Glu His Lys Ile Val Phe Arg Ile 465 470 475aat ttc tag ttaaggttta aatgctagag tagcttaaaa agttgtcata 1791Asn Phe * 480gtttcagtag gtcataggga gatgagtttg tatgctgtac tatgcagcgt ttaaagttag 1851tgggttttgt gattttttat tgaatattgc tgtctgttac aaagtcagtt aaaggtacgt 1911tttaatattt aagttattct atcttggaga taaaatctgt atgtgcaatt caccggtatt 1971accagtttat tatgtaaaca agagatttgg catgacatgt tctgtatgtt tcagggaaaa 2031atgtctttaa tgctttttca agaactaaca cagttattcc tatactggat tttaggtctc 2091tgaagaactg ctggtgttta ggaataagaa tgtgcatgaa gcctaaaata ccaagaaagc 2151ttatactgaa tttaagcaaa gaaataaagg agaaaagaga agaatctgag aattggggag 2211gcatagattc ttataaaaat cacaaaattt gttgtaaatt agaggggaga aatttagaat 2271taagtataaa aaggcagaat tagtatagag tacattcatt aaacattttt gtcaggatta 2331tttcccgtaa aaacgtagtg agcacttttc atatactaat ttagttgtac atttaacttt 2391gtataataca gaaatctaaa tatatttaat gaattcaagc aatatatcac ttgaccaaga 2451aattggaatt tcaaaatgtt cgtgcgggta tataccagat gagtacagtg agtagtttta 2511tgtatcacca gactgggtta ttgccaagtt atatatcacc aaaagctgta tgactggatg 2571ttctggttac ctggtttaca aaattatcag agtagtaaaa ctttgatata tatgaggata 2631ttaaaactac actaagtatc atttgattcg attcagaaag tactttgata tctctcagtg 2691cttcagtgct atcattgtga gcaattgtct tttatatacg gtactgtagc catactaggc 2751ctgtctgtgg cattctctag atgtttcttt tttacacaat aaattcctta tatcagcttg 281124480PRThuman 24Met Gly Ile Gln Val Pro Leu Asn Ala Thr Glu Phe Asn Tyr Leu Cys1 5 10 15Pro Ala Ile Ile Asn Gln Ile Asp Ala Arg Ser Cys Leu Ile His Thr 20 25 30Ser Glu Lys Lys Ala Glu Ile Pro Pro Lys Thr Tyr Ser Leu Gln Ile 35 40 45Ala Trp Val Gly Gly Phe Ile Ala Ile Ser Ile Ile Ser Phe Leu Ser 50 55 60Leu Leu Gly Val Ile Leu Val Pro Leu Met Asn Arg Val Phe Phe Lys65 70 75 80Phe Leu Leu Ser Phe Leu Val Ala Leu Ala Val Gly Thr Leu Ser Gly 85 90 95Asp Ala Phe Leu His Leu Leu Pro His Ser His Ala Ser His His His 100 105 110Ser His Ser His Glu Glu Pro Ala Met Glu Met Lys Arg Gly Pro Leu 115 120 125Phe Ser His Leu Ser Ser Gln Asn Ile Glu Glu Ser Ala Tyr Phe Asp 130 135 140Ser Thr Trp Lys Gly Leu Thr Ala Leu Gly Gly Leu Tyr Phe Met Phe145 150 155 160Leu Val Glu His Val Leu Thr Leu Ile Lys Gln Phe Lys Asp Lys Lys 165 170 175Lys Lys Asn Gln Lys Lys Pro Glu Asn Asp Asp Asp Val Glu Ile Lys 180 185 190Lys Gln Leu Ser Lys Tyr Glu Ser Gln Leu Ser Thr Asn Glu Glu Lys 195 200 205Val Asp Thr Asp Asp Arg Thr Glu Gly Tyr Leu Arg Ala Asp Ser Gln 210 215 220Glu Pro Ser His Phe Asp Ser Gln Gln Pro Ala Val Leu Glu Glu Glu225 230 235 240Glu Val Met Ile Ala His Ala His Pro Gln Glu Val Tyr Asn Glu Tyr 245 250 255Val Pro Arg Gly Cys Lys Asn Lys Cys His Ser His Phe His Asp Thr 260 265 270Leu Gly Gln Ser Asp Asp Leu Ile His His His His Asp Tyr His His 275 280 285Ile Leu His His His His His Gln Asn His His Pro His Ser His Ser 290 295 300Gln Arg Tyr Ser Arg Glu Glu Leu Lys Asp Ala Gly Val Ala Thr Leu305 310 315 320Ala Trp Met Val Ile Met Gly Asp Gly Leu His Asn Phe Ser Asp Gly 325 330 335Leu Ala Ile Gly Ala Ala Phe Thr Glu Gly Leu Ser Ser Gly Leu Ser 340 345 350Thr Ser Val Ala Val Phe Cys His Glu Leu Pro His Glu Leu Gly Asp 355 360 365Phe Ala Val Leu Leu Lys Ala Gly Met Thr Val Lys Gln Ala Val Leu 370 375 380Tyr Asn Ala Leu Ser Ala Met Leu Ala Tyr Leu Gly Met Ala Thr Gly385 390 395 400Ile Phe Ile Gly His Tyr Ala Glu Asn Val Ser Met Trp Ile Phe Ala 405 410 415Leu Thr Ala Gly Leu Phe Met Tyr Val Ala Leu Val Asp Met Val Pro 420 425 430Glu Met Leu His Asn Asp Ala Ser Asp His Gly Cys Ser Arg Trp Gly 435 440 445Tyr Phe Phe Leu Gln Asn Ala Gly Met Leu Leu Gly Phe Gly Ile Met 450 455 460Leu Leu Ile Ser Ile Phe Glu His Lys Ile Val Phe Arg Ile Asn Phe465 470 475 480252260DNAhumanCDS(23)...(1489) 25aagcccagca gccccggggc gg atg gct cca gca gca tgg cta cga agt gca 52 Met Ala Pro Ala Ala Trp Leu Arg Ser Ala 1 5 10gct gct cga gca cta cta cca cct atg ctg ctg ctg ctg ctc cag ccg 100Ala Ala Arg Ala Leu Leu Pro Pro Met Leu Leu Leu Leu Leu Gln Pro 15 20 25ccg ccg ctg ctg gcc cgg gct ctg ccg ccg gac gtc cac cac ctc cat 148Pro Pro Leu Leu Ala Arg Ala Leu Pro Pro Asp Val His His Leu His 30 35 40gcc gag agg agg ggg cca cag ccc tgg cat gca gcc ctg ccc agt agc 196Ala Glu Arg Arg Gly Pro Gln Pro Trp His Ala Ala Leu Pro Ser Ser 45 50 55ccg gca cct gcc cct gcc acg cag gaa gcc ccc cgg cct gcc agc agc 244Pro Ala Pro Ala Pro Ala Thr Gln Glu Ala Pro Arg Pro Ala Ser Ser 60 65 70ctc agg cct ccc cgc tgt ggc gtg ccc gac cca tct gat ggg ctg agt 292Leu Arg Pro Pro Arg Cys Gly Val Pro Asp Pro Ser Asp Gly Leu Ser75 80 85 90gcc cgc aac cga cag aag agg ttc gtg ctt tct ggc ggg cgc tgg gag 340Ala Arg Asn Arg Gln Lys Arg

Phe Val Leu Ser Gly Gly Arg Trp Glu 95 100 105aag acg gac ctc acc tac agg atc ctt cgg ttc cca tgg cag ttg gtg 388Lys Thr Asp Leu Thr Tyr Arg Ile Leu Arg Phe Pro Trp Gln Leu Val 110 115 120cag gag cag gtg cgg cag acg atg gca gag gcc cta aag gta tgg agc 436Gln Glu Gln Val Arg Gln Thr Met Ala Glu Ala Leu Lys Val Trp Ser 125 130 135gat gtg acg cca ctc acc ttt act gag gtg cac gag ggc cgt gct gac 484Asp Val Thr Pro Leu Thr Phe Thr Glu Val His Glu Gly Arg Ala Asp 140 145 150atc atg atc gac ttc gcc agg tac tgg cat ggg gac gac ctg ccg ttt 532Ile Met Ile Asp Phe Ala Arg Tyr Trp His Gly Asp Asp Leu Pro Phe155 160 165 170gat ggg cct ggg ggc atc ctg gcc cat gcc ttc ttc ccc aag act cac 580Asp Gly Pro Gly Gly Ile Leu Ala His Ala Phe Phe Pro Lys Thr His 175 180 185cga gaa ggg gat gtc cac ttc gac tat gat gag acc tgg act atc ggg 628Arg Glu Gly Asp Val His Phe Asp Tyr Asp Glu Thr Trp Thr Ile Gly 190 195 200gat gac cag ggc aca gac ctg ctg cag gtg gca gcc cat gaa ttt ggc 676Asp Asp Gln Gly Thr Asp Leu Leu Gln Val Ala Ala His Glu Phe Gly 205 210 215cac gtg ctg ggg ctg cag cac aca aca gca gcc aag gcc ctg atg tcc 724His Val Leu Gly Leu Gln His Thr Thr Ala Ala Lys Ala Leu Met Ser 220 225 230gcc ttc tac acc ttt cgc tac cca ctg agt ctc agc cca gat gac tgc 772Ala Phe Tyr Thr Phe Arg Tyr Pro Leu Ser Leu Ser Pro Asp Asp Cys235 240 245 250agg ggc gtt caa cac cta tat ggc cag ccc tgg ccc act gtc acc tcc 820Arg Gly Val Gln His Leu Tyr Gly Gln Pro Trp Pro Thr Val Thr Ser 255 260 265agg acc cca gcc ctg ggc ccc cag gct ggg ata gac acc aat gag att 868Arg Thr Pro Ala Leu Gly Pro Gln Ala Gly Ile Asp Thr Asn Glu Ile 270 275 280gca ccg ctg gag cca gac gcc ccg cca gat gcc tgt gag gcc tcc ttt 916Ala Pro Leu Glu Pro Asp Ala Pro Pro Asp Ala Cys Glu Ala Ser Phe 285 290 295gac gcg gtc tcc acc atc cga ggc gag ctc ttt ttc ttc aaa gcg ggc 964Asp Ala Val Ser Thr Ile Arg Gly Glu Leu Phe Phe Phe Lys Ala Gly 300 305 310ttt gtg tgg cgc ctc cgt ggg ggc cag ctg cag ccc ggc tac cca gca 1012Phe Val Trp Arg Leu Arg Gly Gly Gln Leu Gln Pro Gly Tyr Pro Ala315 320 325 330ttg gcc tct cgc cac tgg cag gga ctg ccc agc cct gtg gac gct gcc 1060Leu Ala Ser Arg His Trp Gln Gly Leu Pro Ser Pro Val Asp Ala Ala 335 340 345ttc gag gat gcc cag ggc cac att tgg ttc ttc caa ggt gct cag tac 1108Phe Glu Asp Ala Gln Gly His Ile Trp Phe Phe Gln Gly Ala Gln Tyr 350 355 360tgg gtg tac gac ggt gaa aag cca gtc ctg ggc ccc gca ccc ctc acc 1156Trp Val Tyr Asp Gly Glu Lys Pro Val Leu Gly Pro Ala Pro Leu Thr 365 370 375gag ctg ggc ctg gtg agg ttc ccg gtc cat gct gcc ttg gtc tgg ggt 1204Glu Leu Gly Leu Val Arg Phe Pro Val His Ala Ala Leu Val Trp Gly 380 385 390ccc gag aag aac aag atc tac ttc ttc cga ggc agg gac tac tgg cgt 1252Pro Glu Lys Asn Lys Ile Tyr Phe Phe Arg Gly Arg Asp Tyr Trp Arg395 400 405 410ttc cac ccc agc acc cgg cgt gta gac agt ccc gtg ccc cgc agg gcc 1300Phe His Pro Ser Thr Arg Arg Val Asp Ser Pro Val Pro Arg Arg Ala 415 420 425act gac tgg aga ggg gtg ccc tct gag atc gac gct gcc ttc cag gat 1348Thr Asp Trp Arg Gly Val Pro Ser Glu Ile Asp Ala Ala Phe Gln Asp 430 435 440gct gat ggc tat gcc tac ttc ctg cgc ggc cgc ctc tac tgg aag ttt 1396Ala Asp Gly Tyr Ala Tyr Phe Leu Arg Gly Arg Leu Tyr Trp Lys Phe 445 450 455gac cct gtg aag gtg aag gct ctg gaa ggc ttc ccc cgt ctc gtg ggt 1444Asp Pro Val Lys Val Lys Ala Leu Glu Gly Phe Pro Arg Leu Val Gly 460 465 470cct gac ttc ttt ggc tgt gcc gag cct gcc aac act ttc ctc tga 1489Pro Asp Phe Phe Gly Cys Ala Glu Pro Ala Asn Thr Phe Leu *475 480 485ccatggcttg gatgccctca ggggtgctga cccctgccag gccacgaata tcaggctaga 1549gacccatggc catctttgtg gctgtgggca ccaggcatgg gactgagccc atgtctcctg 1609cagggggatg gggtggggta caaccaccat gacaactgcc gggagggcca cgcaggtcgt 1669ggtcacctgc cagcgactgt ctcagactgg gcagggaggc tttggcatga cttaagagga 1729agggcagtct tgggacccgc tatgcaggtc ctggcaaacc tggctgccct gtctcatccc 1789tgtccctcag ggtagcacca tggcaggact gggggaactg gagtgtcctt gctgtatccc 1849tgttgtgagg ttccttccag gggctggcac tgaagcaagg gtgctggggc cccatggcct 1909tcagccctgg ctgagcaact gggctgtagg gcagggccac ttcctgaggt caggtcttgg 1969taggtgcctg catctgtctg ccttctggct gacaatcctg gaaatctgtt ctccagaatc 2029caggccaaaa agttcacagt caaatgggga ggggtattct tcatgcagga gaccccaggc 2089cctggaggct gcaacatacc tcaatcctgt cccaggccgg atcctcctga agcccttttc 2149gcagcactgc tatcctccaa agccattgta aatgtgtgta cagtgtgtat aaaccttctt 2209cttctttttt ttttttaaac tgaggattgt cattaaacac agttgttttc t 226026488PRThuman 26Met Ala Pro Ala Ala Trp Leu Arg Ser Ala Ala Ala Arg Ala Leu Leu1 5 10 15Pro Pro Met Leu Leu Leu Leu Leu Gln Pro Pro Pro Leu Leu Ala Arg 20 25 30Ala Leu Pro Pro Asp Val His His Leu His Ala Glu Arg Arg Gly Pro 35 40 45Gln Pro Trp His Ala Ala Leu Pro Ser Ser Pro Ala Pro Ala Pro Ala 50 55 60Thr Gln Glu Ala Pro Arg Pro Ala Ser Ser Leu Arg Pro Pro Arg Cys65 70 75 80Gly Val Pro Asp Pro Ser Asp Gly Leu Ser Ala Arg Asn Arg Gln Lys 85 90 95Arg Phe Val Leu Ser Gly Gly Arg Trp Glu Lys Thr Asp Leu Thr Tyr 100 105 110Arg Ile Leu Arg Phe Pro Trp Gln Leu Val Gln Glu Gln Val Arg Gln 115 120 125Thr Met Ala Glu Ala Leu Lys Val Trp Ser Asp Val Thr Pro Leu Thr 130 135 140Phe Thr Glu Val His Glu Gly Arg Ala Asp Ile Met Ile Asp Phe Ala145 150 155 160Arg Tyr Trp His Gly Asp Asp Leu Pro Phe Asp Gly Pro Gly Gly Ile 165 170 175Leu Ala His Ala Phe Phe Pro Lys Thr His Arg Glu Gly Asp Val His 180 185 190Phe Asp Tyr Asp Glu Thr Trp Thr Ile Gly Asp Asp Gln Gly Thr Asp 195 200 205Leu Leu Gln Val Ala Ala His Glu Phe Gly His Val Leu Gly Leu Gln 210 215 220His Thr Thr Ala Ala Lys Ala Leu Met Ser Ala Phe Tyr Thr Phe Arg225 230 235 240Tyr Pro Leu Ser Leu Ser Pro Asp Asp Cys Arg Gly Val Gln His Leu 245 250 255Tyr Gly Gln Pro Trp Pro Thr Val Thr Ser Arg Thr Pro Ala Leu Gly 260 265 270Pro Gln Ala Gly Ile Asp Thr Asn Glu Ile Ala Pro Leu Glu Pro Asp 275 280 285Ala Pro Pro Asp Ala Cys Glu Ala Ser Phe Asp Ala Val Ser Thr Ile 290 295 300Arg Gly Glu Leu Phe Phe Phe Lys Ala Gly Phe Val Trp Arg Leu Arg305 310 315 320Gly Gly Gln Leu Gln Pro Gly Tyr Pro Ala Leu Ala Ser Arg His Trp 325 330 335Gln Gly Leu Pro Ser Pro Val Asp Ala Ala Phe Glu Asp Ala Gln Gly 340 345 350His Ile Trp Phe Phe Gln Gly Ala Gln Tyr Trp Val Tyr Asp Gly Glu 355 360 365Lys Pro Val Leu Gly Pro Ala Pro Leu Thr Glu Leu Gly Leu Val Arg 370 375 380Phe Pro Val His Ala Ala Leu Val Trp Gly Pro Glu Lys Asn Lys Ile385 390 395 400Tyr Phe Phe Arg Gly Arg Asp Tyr Trp Arg Phe His Pro Ser Thr Arg 405 410 415Arg Val Asp Ser Pro Val Pro Arg Arg Ala Thr Asp Trp Arg Gly Val 420 425 430Pro Ser Glu Ile Asp Ala Ala Phe Gln Asp Ala Asp Gly Tyr Ala Tyr 435 440 445Phe Leu Arg Gly Arg Leu Tyr Trp Lys Phe Asp Pro Val Lys Val Lys 450 455 460Ala Leu Glu Gly Phe Pro Arg Leu Val Gly Pro Asp Phe Phe Gly Cys465 470 475 480Ala Glu Pro Ala Asn Thr Phe Leu 485272778DNAhumanCDS(272)...(1426) 27agcggaatct ttaggatctg agcaggagaa ataccagcgg atcttcccca ctctgctccc 60ttccattccc acccttcctt ctttaataag caggagcgaa aaagacaaat tccaaagagg 120attgttcagt tcaagggaat gaagaattca gaataatttt ggtaaatgga ttccaatatg 180gggaataaga ataagctgaa cagttgacct gctttgaaga aacatactgt ccatttgtct 240aaaataatct ataacaacca aaccaatcaa a atg aat tca aca tta ttt tcc 292 Met Asn Ser Thr Leu Phe Ser 1 5cag gtt gaa aat cat tca gtc cac tct aat ttc tca gag aag aat gcc 340Gln Val Glu Asn His Ser Val His Ser Asn Phe Ser Glu Lys Asn Ala 10 15 20cag ctt ctg gct ttt gaa aat gat gat tgt cat ctg ccc ttg gcc atg 388Gln Leu Leu Ala Phe Glu Asn Asp Asp Cys His Leu Pro Leu Ala Met 25 30 35ata ttt acc tta gct ctt gct tat gga gct gtg atc att ctt ggt gtc 436Ile Phe Thr Leu Ala Leu Ala Tyr Gly Ala Val Ile Ile Leu Gly Val40 45 50 55tct gga aac ctg gcc ttg atc ata atc atc ttg aaa caa aag gag atg 484Ser Gly Asn Leu Ala Leu Ile Ile Ile Ile Leu Lys Gln Lys Glu Met 60 65 70aga aat gtt acc aac atc ctg att gtg aac ctt tcc ttc tca gac ttg 532Arg Asn Val Thr Asn Ile Leu Ile Val Asn Leu Ser Phe Ser Asp Leu 75 80 85ctt gtt gcc atc atg tgt ctc ccc ttt aca ttt gtc tac aca tta atg 580Leu Val Ala Ile Met Cys Leu Pro Phe Thr Phe Val Tyr Thr Leu Met 90 95 100gac cac tgg gtc ttt ggt gag gcg atg tgt aag ttg aat cct ttt gtg 628Asp His Trp Val Phe Gly Glu Ala Met Cys Lys Leu Asn Pro Phe Val 105 110 115caa tgt gtt tca atc act gtg tcc att ttc tct ctg gtt ctc att gct 676Gln Cys Val Ser Ile Thr Val Ser Ile Phe Ser Leu Val Leu Ile Ala120 125 130 135gtg gaa cga cat cag ctg ata atc aac cct cga ggg tgg aga cca aat 724Val Glu Arg His Gln Leu Ile Ile Asn Pro Arg Gly Trp Arg Pro Asn 140 145 150aat aga cat gct tat gta ggt att gct gtg att tgg gtc ctt gct gtg 772Asn Arg His Ala Tyr Val Gly Ile Ala Val Ile Trp Val Leu Ala Val 155 160 165gct tct tct ttg cct ttc ctg atc tac caa gta atg act gat gag ccg 820Ala Ser Ser Leu Pro Phe Leu Ile Tyr Gln Val Met Thr Asp Glu Pro 170 175 180ttc caa aat gta aca ctt gat gcg tac aaa gac aaa tac gtg tgc ttt 868Phe Gln Asn Val Thr Leu Asp Ala Tyr Lys Asp Lys Tyr Val Cys Phe 185 190 195gat caa ttt cca tcg gac tct cat agg ttg tct tat acc act ctc ctc 916Asp Gln Phe Pro Ser Asp Ser His Arg Leu Ser Tyr Thr Thr Leu Leu200 205 210 215ttg gtg ctg cag tat ttt ggt cca ctt tgt ttt ata ttt att tgc tac 964Leu Val Leu Gln Tyr Phe Gly Pro Leu Cys Phe Ile Phe Ile Cys Tyr 220 225 230ttc aag ata tat ata cgc cta aaa agg aga aac aac atg atg gac aag 1012Phe Lys Ile Tyr Ile Arg Leu Lys Arg Arg Asn Asn Met Met Asp Lys 235 240 245atg aga gac aat aag tac agg tcc agt gaa acc aaa aga atc aat atc 1060Met Arg Asp Asn Lys Tyr Arg Ser Ser Glu Thr Lys Arg Ile Asn Ile 250 255 260atg ctg ctc tcc att gtg gta gca ttt gca gtc tgc tgg ctc cct ctt 1108Met Leu Leu Ser Ile Val Val Ala Phe Ala Val Cys Trp Leu Pro Leu 265 270 275acc atc ttt aac act gtg ttt gat tgg aat cat cag atc att gct acc 1156Thr Ile Phe Asn Thr Val Phe Asp Trp Asn His Gln Ile Ile Ala Thr280 285 290 295tgc aac cac aat ctg tta ttc ctg ctc tgc cac ctc aca gca atg ata 1204Cys Asn His Asn Leu Leu Phe Leu Leu Cys His Leu Thr Ala Met Ile 300 305 310tcc act tgt gtc aac ccc ata ttt tat ggg ttc ctg aac aaa aac ttc 1252Ser Thr Cys Val Asn Pro Ile Phe Tyr Gly Phe Leu Asn Lys Asn Phe 315 320 325cag aga gac ttg cag ttc ttc ttc aac ttt tgt gat ttc cgg tct cgg 1300Gln Arg Asp Leu Gln Phe Phe Phe Asn Phe Cys Asp Phe Arg Ser Arg 330 335 340gat gat gat tat gaa aca ata gcc atg tcc acg atg cac aca gat gtt 1348Asp Asp Asp Tyr Glu Thr Ile Ala Met Ser Thr Met His Thr Asp Val 345 350 355tcc aaa act tct ttg aag caa gca agc cca gtc gca ttt aaa aaa atc 1396Ser Lys Thr Ser Leu Lys Gln Ala Ser Pro Val Ala Phe Lys Lys Ile360 365 370 375aac aac aat gat gat aat gaa aaa atc tga aactacttat agcctatggt 1446Asn Asn Asn Asp Asp Asn Glu Lys Ile * 380cccggatgac atctgtttaa aaacaagcac aacctgcaac atactttgat tacctgttct 1506cccaaggaat ggggttgaaa tcatttgaaa atgactaaga ttttcttgtc ttgcttttta 1566ctgcttttgt tgtagttgtc ataattacat ttggaacaaa aggtgtgggc tttggggtct 1626tctggaaata gttttgacca gacatctttg aagtgctttt tgtgaattta tgcatataat 1686ataaagactt ttatactgta cttattggaa tgaaatttct ttaaagtatt actattaact 1746gacttcagaa gtacctgcca tccaatacgg tcattagatt gggtcatctt gattagatta 1806gattagatta gattgtcaac agattgggcc atccttactt tatgataggc atcattttag 1866tgtgttacaa tagtaacagt atgcaaaagc agcattcagg agccgaaaga tagtctgaag 1926tcattcagaa gtggtttgag gtttctgttt tttggtggtt tttgtttgtt tttttttttt 1986caccttaagg gaggatttaa tttgctccca actgattgtc acttaaatga aaatttaaaa 2046atgaataaaa agacatactt ctcagctgca aatattatgg agaattgggg cacccacagg 2106aatgaagaga gaaagcagct ccctaacttc aaaaccattt tggtacctga caacaagagc 2166attttagagt aattaattta ataaagtaaa ttagtattgc tgcaaatagc taaattatat 2226ttatttgaat tgatggtcaa gagattttcc atttttttta cagactgttc agtgtttgtc 2286aagctttctg gcataaatat gtactcaaaa ggcatttccg cttacaattt gtagaaacac 2346aaaatgcgtt ttccatacag cagtgcctat atagtgactg atttttaact ttcaatgtcc 2406atctttcaaa ggaagtaaca ccaaggtaca atgttaaagg aatattcact ttacctagca 2466gggaaaaata cacaaaaact gcagatactt catatagccc attttaactt gtataaactg 2526tgtgacttgt ggcgtcttat aaataatgca ctgtaaagat tactgaatag ttgtgtcatg 2586ttaatgtgcc taatttcatg tatcttgtaa tcatgattga gcctcagaat catttggaga 2646aactatattt taaagaacaa gacatacttc aatgtattat acagataaag tattacatgt 2706gtttgatttt aaaagggcgg acattttatt aaaatcaata ttgtttttgc tttttcaaaa 2766aaaaaaaaaa aa 277828384PRThuman 28Met Asn Ser Thr Leu Phe Ser Gln Val Glu Asn His Ser Val His Ser1 5 10 15Asn Phe Ser Glu Lys Asn Ala Gln Leu Leu Ala Phe Glu Asn Asp Asp 20 25 30Cys His Leu Pro Leu Ala Met Ile Phe Thr Leu Ala Leu Ala Tyr Gly 35 40 45Ala Val Ile Ile Leu Gly Val Ser Gly Asn Leu Ala Leu Ile Ile Ile 50 55 60Ile Leu Lys Gln Lys Glu Met Arg Asn Val Thr Asn Ile Leu Ile Val65 70 75 80Asn Leu Ser Phe Ser Asp Leu Leu Val Ala Ile Met Cys Leu Pro Phe 85 90 95Thr Phe Val Tyr Thr Leu Met Asp His Trp Val Phe Gly Glu Ala Met 100 105 110Cys Lys Leu Asn Pro Phe Val Gln Cys Val Ser Ile Thr Val Ser Ile 115 120 125Phe Ser Leu Val Leu Ile Ala Val Glu Arg His Gln Leu Ile Ile Asn 130 135 140Pro Arg Gly Trp Arg Pro Asn Asn Arg His Ala Tyr Val Gly Ile Ala145 150 155 160Val Ile Trp Val Leu Ala Val Ala Ser Ser Leu Pro Phe Leu Ile Tyr 165 170 175Gln Val Met Thr Asp Glu Pro Phe Gln Asn Val Thr Leu Asp Ala Tyr 180 185 190Lys Asp Lys Tyr Val Cys Phe Asp Gln Phe Pro Ser Asp Ser His Arg 195 200 205Leu Ser Tyr Thr Thr Leu Leu Leu Val Leu Gln Tyr Phe Gly Pro Leu 210 215 220Cys Phe Ile Phe Ile Cys Tyr Phe Lys Ile Tyr Ile Arg Leu Lys Arg225 230 235 240Arg Asn Asn Met Met Asp Lys Met Arg Asp Asn Lys Tyr Arg Ser Ser 245 250 255Glu Thr Lys Arg Ile Asn Ile Met Leu Leu Ser Ile Val Val Ala Phe 260 265 270Ala Val Cys Trp Leu Pro Leu Thr Ile Phe Asn Thr Val Phe Asp Trp 275 280 285Asn His Gln Ile Ile Ala Thr Cys Asn His Asn Leu Leu Phe Leu Leu 290 295 300Cys His Leu Thr Ala Met Ile Ser Thr Cys Val Asn Pro Ile Phe Tyr305 310 315 320Gly Phe Leu Asn Lys Asn Phe Gln Arg Asp Leu Gln Phe Phe Phe Asn

325 330 335Phe Cys Asp Phe Arg Ser Arg Asp Asp Asp Tyr Glu Thr Ile Ala Met 340 345 350Ser Thr Met His Thr Asp Val Ser Lys Thr Ser Leu Lys Gln Ala Ser 355 360 365Pro Val Ala Phe Lys Lys Ile Asn Asn Asn Asp Asp Asn Glu Lys Ile 370 375 380292881DNAhumanCDS(241)...(1005) 29ttttcacttt aaagagttct gtgagtcaga agtcattttg actgccctca ataaaattag 60taatgcaatt ggtcattttc tctttacaga ttgttcagtt caagggaatg aagaattcag 120aataattttg gtaaatggat tccaatatcg ggaataagaa taagctgaac agttgacctg 180ctttgaagaa acatactgtc catttgtcta aaataatcta taacaaccaa accaatcaaa 240atg aat tca aca tta ttt tcc cag gtt gaa aat cat tca gtc cac tct 288Met Asn Ser Thr Leu Phe Ser Gln Val Glu Asn His Ser Val His Ser1 5 10 15aat ttc tca gag aag aat gcc cag ctt ctg gct ttt gaa aat gat gat 336Asn Phe Ser Glu Lys Asn Ala Gln Leu Leu Ala Phe Glu Asn Asp Asp 20 25 30tgt cat ctg ccc ttg gcc atg ata ttt acc tta gct ctt gct tat gga 384Cys His Leu Pro Leu Ala Met Ile Phe Thr Leu Ala Leu Ala Tyr Gly 35 40 45gct gtg atc att ctt ggt gtc tct gga aac ctg gcc ttg atc ata atc 432Ala Val Ile Ile Leu Gly Val Ser Gly Asn Leu Ala Leu Ile Ile Ile 50 55 60atc ttg aaa caa aag gag atg aga aat gtt acc aac atc ctg att gtg 480Ile Leu Lys Gln Lys Glu Met Arg Asn Val Thr Asn Ile Leu Ile Val65 70 75 80aac ctt tcc ttc tca gac ttg ctt gtt gcc atc atg tgt ctc ccc ttt 528Asn Leu Ser Phe Ser Asp Leu Leu Val Ala Ile Met Cys Leu Pro Phe 85 90 95aca ttt gtc tac aca tta atg gac cac tgg gtc ttt ggt gag gcg atg 576Thr Phe Val Tyr Thr Leu Met Asp His Trp Val Phe Gly Glu Ala Met 100 105 110tgt aag ttg aat cct ttt gtg caa tgt gtt tca atc act gtg tcc att 624Cys Lys Leu Asn Pro Phe Val Gln Cys Val Ser Ile Thr Val Ser Ile 115 120 125ttc tct ctg gtt ctc att gct gtg gaa cga cat cag ctg ata atc aac 672Phe Ser Leu Val Leu Ile Ala Val Glu Arg His Gln Leu Ile Ile Asn 130 135 140cct cga ggg tgg aga cca aat aat aga cat gct tat gta ggt att gct 720Pro Arg Gly Trp Arg Pro Asn Asn Arg His Ala Tyr Val Gly Ile Ala145 150 155 160gtg att tgg gtc ctt gct gtg gct tct tct ttg cct ttc ctg atc tac 768Val Ile Trp Val Leu Ala Val Ala Ser Ser Leu Pro Phe Leu Ile Tyr 165 170 175caa gta atg act gat gag ccg ttc caa aat gta aca ctt gat gcg tac 816Gln Val Met Thr Asp Glu Pro Phe Gln Asn Val Thr Leu Asp Ala Tyr 180 185 190aaa gac aaa tac gtg tgc ttt gat caa ttt cca tcg gac tct cat agg 864Lys Asp Lys Tyr Val Cys Phe Asp Gln Phe Pro Ser Asp Ser His Arg 195 200 205ttg tct tat acc act ctc ctc ttg gtg ctg cag tat ttt ggt cca ctt 912Leu Ser Tyr Thr Thr Leu Leu Leu Val Leu Gln Tyr Phe Gly Pro Leu 210 215 220tgt ttt ata ttt att tgc tac ttc aag gta aga aaa ctt ttt ttc tat 960Cys Phe Ile Phe Ile Cys Tyr Phe Lys Val Arg Lys Leu Phe Phe Tyr225 230 235 240 cat ttc cat ttt tac ctt ctt tac aca gaa ttc ctc atc aaa tga 1005His Phe His Phe Tyr Leu Leu Tyr Thr Glu Phe Leu Ile Lys * 245 250gtgtttctat ttaaactttt ttcttccata gatatatata cgcctaaaaa ggagaaacaa 1065catgatggac aagatgagag acaataagta caggtccagt gaaaccaaaa gaatcaatat 1125catgctgctc tccattgtgg tagcatttgc agtctgctgg ctccctctta ccatctttaa 1185cactgtgttt gattggaatc atcagatcat tgctacctgc aaccacaatc tgttattcct 1245gctctgccac ctcacagcaa tgatatccac ttgtgtcaac cccatatttt atgggttcct 1305gaacaaaaac ttccagagag acttgcagtt cttcttcaac ttttgtgatt tccggtctcg 1365ggatgatgat tatgaaacaa tagccatgtc cacgatgcac acagatgttt ccaaaacttc 1425tttgaagcaa gcaagcccag tcgcatttaa aaaaatcaac aacaatgatg ataatgaaaa 1485aatctgaaac tacttatagc ctatggtccc ggatgacatc tgtttaaaaa caagcacaac 1545ctgcaacata ctttgattac ctgttctccc aaggaatggg gttgaaatca tttgaaaatg 1605actaagattt tcttgtcttg ctttttactg cttttgttgt agttgtcata attacatttg 1665gaacaaaagg tgtgggcttt ggggtcttct ggaaatagtt ttgaccagac atctttgaag 1725tgctttttgt gaatttatgc atataatata aagactttta tactgtactt attggaatga 1785aatttcttta aagtattacg atgcgctgac ttcagaagta cctgccatcc aatacggtca 1845ttagattggg tcatcttgat tagattagat tagattagat tgtcaacaga ttgggccatc 1905cttactttat gataggcatc attttagtgt gttacaatag taacagtatg caaaagcagc 1965attcaggagc cgaaagatag tcttgaagtc attcagaagt ggtttgaggt ttctgttttt 2025tggtggtttt tgtttgtttt tttttttttt caccttaagg gaggctttca tttcctcccg 2085actgattgtc acttaaatca aaatttaaaa atgaataaaa agacatactt ctcagctgca 2145aatattatgg agaattgggc acccacagga atgaagagag aaagcagctc cccaacttca 2205aaaccatttt ggtacctgac aacaagagca ttttagagta attaatttaa taaagtaaat 2265tagtattgct gcaaatagct aaattatatt tatttgaatt gatggtcaag agattttcca 2325ttttttttac agactgttca gtgtttgtca agcttctggt ctaatatgta ctcgaaagac 2385tttccgctta caatttgtag aaacacaaat atcgttttcc atacagcagt gcctatatag 2445tgactgattt taactttcaa tgtccatctt tcaaaggaag taacaccaag gtacaatgtt 2505aaaggaatat tcactttacc tagcagggaa aaatacacaa aaactgcaga tacttcatat 2565agcccatttt aacttgtata aactgtgtga cttgtggcgt cttataaata atgcactgta 2625aagattactg aatagttgtg tcatgttaat gtgcctaatt tcatgtatct tgtaatcatg 2685attgagcctc agaatcattt ggagaaacta tattttaaag aacaagacat acttcaatgt 2745attatacaga taaagtatta catgtgtttg attttaaaag ggcggacatt ttattaaaat 2805caatattgtt tttgcttttt ctgaggagtc tctttcagtt tcattttttc tcatcccatg 2865acttccctcc gatggt 288130254PRThuman 30Met Asn Ser Thr Leu Phe Ser Gln Val Glu Asn His Ser Val His Ser1 5 10 15Asn Phe Ser Glu Lys Asn Ala Gln Leu Leu Ala Phe Glu Asn Asp Asp 20 25 30Cys His Leu Pro Leu Ala Met Ile Phe Thr Leu Ala Leu Ala Tyr Gly 35 40 45Ala Val Ile Ile Leu Gly Val Ser Gly Asn Leu Ala Leu Ile Ile Ile 50 55 60Ile Leu Lys Gln Lys Glu Met Arg Asn Val Thr Asn Ile Leu Ile Val65 70 75 80Asn Leu Ser Phe Ser Asp Leu Leu Val Ala Ile Met Cys Leu Pro Phe 85 90 95Thr Phe Val Tyr Thr Leu Met Asp His Trp Val Phe Gly Glu Ala Met 100 105 110Cys Lys Leu Asn Pro Phe Val Gln Cys Val Ser Ile Thr Val Ser Ile 115 120 125Phe Ser Leu Val Leu Ile Ala Val Glu Arg His Gln Leu Ile Ile Asn 130 135 140Pro Arg Gly Trp Arg Pro Asn Asn Arg His Ala Tyr Val Gly Ile Ala145 150 155 160Val Ile Trp Val Leu Ala Val Ala Ser Ser Leu Pro Phe Leu Ile Tyr 165 170 175Gln Val Met Thr Asp Glu Pro Phe Gln Asn Val Thr Leu Asp Ala Tyr 180 185 190Lys Asp Lys Tyr Val Cys Phe Asp Gln Phe Pro Ser Asp Ser His Arg 195 200 205Leu Ser Tyr Thr Thr Leu Leu Leu Val Leu Gln Tyr Phe Gly Pro Leu 210 215 220Cys Phe Ile Phe Ile Cys Tyr Phe Lys Val Arg Lys Leu Phe Phe Tyr225 230 235 240His Phe His Phe Tyr Leu Leu Tyr Thr Glu Phe Leu Ile Lys 245 250312492DNAhumanCDS(272)...(700) 31agcggaatct ttaggatctg agcaggagaa ataccagcgg atcttcccca ctctgctccc 60ttccattccc acccttcctt ctttaataag caggagcgaa aaagacaaat tccaaagagg 120attgttcagt tcaagggaat gaagaattca gaataatttt ggtaaatgga ttccaatatg 180gggaataaga ataagctgaa cagttgacct gctttgaaga aacatactgt ccatttgtct 240aaaataatct ataacaacca aaccaatcaa a atg aat tca aca tta ttt tcc 292 Met Asn Ser Thr Leu Phe Ser 1 5cag gtt gaa aat cat tca gtc cac tct aat ttc tca gag aag aat gcc 340Gln Val Glu Asn His Ser Val His Ser Asn Phe Ser Glu Lys Asn Ala 10 15 20cag ctt ctg gct ttt gaa aat gat gat tgt cat ctg ccc ttg gcc atg 388Gln Leu Leu Ala Phe Glu Asn Asp Asp Cys His Leu Pro Leu Ala Met 25 30 35ata ttt acc tta gct ctt gct tat gga gct gtg atc att ctt ggt gtc 436Ile Phe Thr Leu Ala Leu Ala Tyr Gly Ala Val Ile Ile Leu Gly Val40 45 50 55tct gga aac ctg gcc ttg atc ata atc atc ttg aaa caa aag gag atg 484Ser Gly Asn Leu Ala Leu Ile Ile Ile Ile Leu Lys Gln Lys Glu Met 60 65 70aga aat gtt acc aac atc ctg att gtg aac ctt tcc ttc tca gac ttg 532Arg Asn Val Thr Asn Ile Leu Ile Val Asn Leu Ser Phe Ser Asp Leu 75 80 85ctt gtt gcc atc atg tgt ctc ccc ttt aca ttt gtc tac aca tta atg 580Leu Val Ala Ile Met Cys Leu Pro Phe Thr Phe Val Tyr Thr Leu Met 90 95 100gac cac tgg gtc ttt ggt gag gcg atg tgt tgt ctt ata cca ctc tcc 628Asp His Trp Val Phe Gly Glu Ala Met Cys Cys Leu Ile Pro Leu Ser 105 110 115tct tgg tgc tgc agt att ttg gtc cac ttt gtt tta tat tta ttt gct 676Ser Trp Cys Cys Ser Ile Leu Val His Phe Val Leu Tyr Leu Phe Ala120 125 130 135act tca aga tat ata tac gcc taa aaaggagaaa caacatgatg gacaagatga 730Thr Ser Arg Tyr Ile Tyr Ala * 140gagacaataa gtacaggtcc agtgaaacca aaagaatcaa tatcatgctg ctctccattg 790tggtagcatt tgcagtctgc tggctccctc ttaccatctt taacactgtg tttgattgga 850atcatcagat cattgctacc tgcaaccaca atctgttatt cctgctctgc cacctcacag 910caatgatatc cacttgtgtc aaccccatat tttatgggtt cctgaacaaa aacttccaga 970gagacttgca gttcttcttc aacttttgtg atttccggtc tcgggatgat gattatgaaa 1030caatagccat gtccacgatg cacacagatg tttccaaaac ttctttgaag caagcaagcc 1090cagtcgcatt taaaaaaatc aacaacaatg atgataatga aaaaatctga aactacttat 1150agcctatggt cccggatgac atctgtttaa aaacaagcac aacctgcaac atactttgat 1210tacctgttct cccaaggaat ggggttgaaa tcatttgaaa atgactaaga ttttcttgtc 1270ttgcttttta ctgcttttgt tgtagttgtc ataattacat ttggaacaaa aggtgtgggc 1330tttggggtct tctggaaata gttttgacca gacatctttg aagtgctttt tgtgaattta 1390tgcatataat ataaagactt ttatactgta cttattggaa tgaaatttct ttaaagtatt 1450actattaact gacttcagaa gtacctgcca tccaatacgg tcattagatt gggtcatctt 1510gattagatta gattagatta gattgtcaac agattgggcc atccttactt tatgataggc 1570atcattttag tgtgttacaa tagtaacagt atgcaaaagc agcattcagg agccgaaaga 1630tagtctgaag tcattcagaa gtggtttgag gtttctgttt tttggtggtt tttgtttgtt 1690tttttttttt caccttaagg gaggatttaa tttgctccca actgattgtc acttaaatga 1750aaatttaaaa atgaataaaa agacatactt ctcagctgca aatattatgg agaattgggg 1810cacccacagg aatgaagaga gaaagcagct ccctaacttc aaaaccattt tggtacctga 1870caacaagagc attttagagt aattaattta ataaagtaaa ttagtattgc tgcaaatagc 1930taaattatat ttatttgaat tgatggtcaa gagattttcc atttttttta cagactgttc 1990agtgtttgtc aagctttctg gcataaatat gtactcaaaa ggcatttccg cttacaattt 2050gtagaaacac aaaatgcgtt ttccatacag cagtgcctat atagtgactg atttttaact 2110ttcaatgtcc atctttcaaa ggaagtaaca ccaaggtaca atgttaaagg aatattcact 2170ttacctagca gggaaaaata cacaaaaact gcagatactt catatagccc attttaactt 2230gtataaactg tgtgacttgt ggcgtcttat aaataatgca ctgtaaagat tactgaatag 2290ttgtgtcatg ttaatgtgcc taatttcatg tatcttgtaa tcatgattga gcctcagaat 2350catttggaga aactatattt taaagaacaa gacatacttc aatgtattat acagataaag 2410tattacatgt gtttgatttt aaaagggcgg acattttatt aaaatcaata ttgtttttgc 2470tttttcaaaa aaaaaaaaaa aa 249232142PRThuman 32Met Asn Ser Thr Leu Phe Ser Gln Val Glu Asn His Ser Val His Ser1 5 10 15Asn Phe Ser Glu Lys Asn Ala Gln Leu Leu Ala Phe Glu Asn Asp Asp 20 25 30Cys His Leu Pro Leu Ala Met Ile Phe Thr Leu Ala Leu Ala Tyr Gly 35 40 45Ala Val Ile Ile Leu Gly Val Ser Gly Asn Leu Ala Leu Ile Ile Ile 50 55 60Ile Leu Lys Gln Lys Glu Met Arg Asn Val Thr Asn Ile Leu Ile Val65 70 75 80Asn Leu Ser Phe Ser Asp Leu Leu Val Ala Ile Met Cys Leu Pro Phe 85 90 95Thr Phe Val Tyr Thr Leu Met Asp His Trp Val Phe Gly Glu Ala Met 100 105 110Cys Cys Leu Ile Pro Leu Ser Ser Trp Cys Cys Ser Ile Leu Val His 115 120 125Phe Val Leu Tyr Leu Phe Ala Thr Ser Arg Tyr Ile Tyr Ala 130 135 140334458DNAhumanCDS(100)...(4125) 33ctagtctata ccagcaacga ctcctacatc gtccactctg gggatcttag aaagatccat 60aaagctgcct cccggggaca agtccggaag ctggagaag atg aca aag agg aag 114 Met Thr Lys Arg Lys 1 5aag acc atc aac ctt aat ata caa gac gcc cag aag agg act gct cta 162Lys Thr Ile Asn Leu Asn Ile Gln Asp Ala Gln Lys Arg Thr Ala Leu 10 15 20cac tgg gcc tgt gtc aat ggc cat gag gaa gta gta aca ttt ctg gta 210His Trp Ala Cys Val Asn Gly His Glu Glu Val Val Thr Phe Leu Val 25 30 35gac aga aag tgc cag ctt gac gtc ctt gat ggc gaa cac agg aca cct 258Asp Arg Lys Cys Gln Leu Asp Val Leu Asp Gly Glu His Arg Thr Pro 40 45 50ctg atg aag gct cta caa tgc cat cag gag gct tgt gca aat att ctg 306Leu Met Lys Ala Leu Gln Cys His Gln Glu Ala Cys Ala Asn Ile Leu 55 60 65ata gat tct ggt gcc gat ata aat ctc gta gat gtg tat ggc aac atg 354Ile Asp Ser Gly Ala Asp Ile Asn Leu Val Asp Val Tyr Gly Asn Met70 75 80 85gct ctc cat tat gct gtt tat agt gag att ttg tca gtg gtg gca aaa 402Ala Leu His Tyr Ala Val Tyr Ser Glu Ile Leu Ser Val Val Ala Lys 90 95 100ctg ctg tcc cat ggt gca gtc atc gaa gtg cac aac aag gct agc ctc 450Leu Leu Ser His Gly Ala Val Ile Glu Val His Asn Lys Ala Ser Leu 105 110 115aca cca ctt tta cta tcc ata acg aaa aga agt gag caa att gtg gaa 498Thr Pro Leu Leu Leu Ser Ile Thr Lys Arg Ser Glu Gln Ile Val Glu 120 125 130ttt ttg ctg ata aaa aat gca aat gcg aat gca gtt aat aag tat aaa 546Phe Leu Leu Ile Lys Asn Ala Asn Ala Asn Ala Val Asn Lys Tyr Lys 135 140 145tgc aca gcc ctc atg ctt gct gta tgt cat gga tca tca gag ata gtt 594Cys Thr Ala Leu Met Leu Ala Val Cys His Gly Ser Ser Glu Ile Val150 155 160 165ggc atg ctt ctt cag caa aat gtt gac gtc ttt gct gca gat ata tgt 642Gly Met Leu Leu Gln Gln Asn Val Asp Val Phe Ala Ala Asp Ile Cys 170 175 180gga gta act gca gaa cat tat gct gtt act tgt gga ttt cat cac att 690Gly Val Thr Ala Glu His Tyr Ala Val Thr Cys Gly Phe His His Ile 185 190 195cat gaa caa att atg gaa tat ata cga aaa tta tct aaa aat cat caa 738His Glu Gln Ile Met Glu Tyr Ile Arg Lys Leu Ser Lys Asn His Gln 200 205 210aat acc aat cca gaa gga aca tct gca gga aca cct gat gag gct gca 786Asn Thr Asn Pro Glu Gly Thr Ser Ala Gly Thr Pro Asp Glu Ala Ala 215 220 225ccc ttg gcg gaa aga aca cct gac aca gct gaa agc ttg gtg gaa aaa 834Pro Leu Ala Glu Arg Thr Pro Asp Thr Ala Glu Ser Leu Val Glu Lys230 235 240 245aca cct gat gag gct gca ccc ttg gtg gaa aga aca cct gac acg gct 882Thr Pro Asp Glu Ala Ala Pro Leu Val Glu Arg Thr Pro Asp Thr Ala 250 255 260gaa agc ttg gtg gaa aaa aca cct gat gag gct gca tcc ttg gtg gag 930Glu Ser Leu Val Glu Lys Thr Pro Asp Glu Ala Ala Ser Leu Val Glu 265 270 275gga aca tct gac aaa att caa tgt ttg gag aaa gcg aca tct gga aag 978Gly Thr Ser Asp Lys Ile Gln Cys Leu Glu Lys Ala Thr Ser Gly Lys 280 285 290ttc gaa cag tca gca gaa gaa aca cct agg gaa att acg agt cct gca 1026Phe Glu Gln Ser Ala Glu Glu Thr Pro Arg Glu Ile Thr Ser Pro Ala 295 300 305aaa gaa aca tct gag aaa ttt acg tgg cca gca aaa gga aga cct agg 1074Lys Glu Thr Ser Glu Lys Phe Thr Trp Pro Ala Lys Gly Arg Pro Arg310 315 320 325aag atc gca tgg gag aaa aaa gaa gac aca cct agg gaa att atg agt 1122Lys Ile Ala Trp Glu Lys Lys Glu Asp Thr Pro Arg Glu Ile Met Ser 330 335 340ccc gca aaa gaa aca tct gag aaa ttt acg tgg gca gca aaa gga aga 1170Pro Ala Lys Glu Thr Ser Glu Lys Phe Thr Trp Ala Ala Lys Gly Arg 345 350 355cct agg aag atc gca tgg gag aaa aaa gaa aca cct gta aag act gga 1218Pro Arg Lys Ile Ala Trp Glu Lys Lys Glu Thr Pro Val Lys Thr Gly 360 365 370tgc gtg gca aga gta aca tct aat aaa act aaa gtt ttg gaa aaa gga 1266Cys Val Ala Arg Val Thr Ser Asn Lys Thr Lys Val Leu Glu Lys Gly 375 380 385aga tct aag atg att gca tgt cct aca aaa gaa tca tct aca aaa gca 1314Arg Ser Lys Met Ile

Ala Cys Pro Thr Lys Glu Ser Ser Thr Lys Ala390 395 400 405agt gcc aat gat cag agg ttc cca tca gaa tcc aaa caa gag gaa gat 1362Ser Ala Asn Asp Gln Arg Phe Pro Ser Glu Ser Lys Gln Glu Glu Asp 410 415 420gaa gaa tat tct tgt gat tct cgg agt ctc ttt gag agt tct gca aag 1410Glu Glu Tyr Ser Cys Asp Ser Arg Ser Leu Phe Glu Ser Ser Ala Lys 425 430 435att caa gtg tgt ata cct gag tct ata tat caa aaa gta atg gag ata 1458Ile Gln Val Cys Ile Pro Glu Ser Ile Tyr Gln Lys Val Met Glu Ile 440 445 450aat aga gaa gta gaa gag cct cct aag aag cca tct gcc ttc aag cct 1506Asn Arg Glu Val Glu Glu Pro Pro Lys Lys Pro Ser Ala Phe Lys Pro 455 460 465gcc att gaa atg caa aac tct gtt cca aat aaa gcc ttt gaa ttg aag 1554Ala Ile Glu Met Gln Asn Ser Val Pro Asn Lys Ala Phe Glu Leu Lys470 475 480 485aat gaa caa aca ttg aga gca gat ccg atg ttc cca cca gaa tcc aaa 1602Asn Glu Gln Thr Leu Arg Ala Asp Pro Met Phe Pro Pro Glu Ser Lys 490 495 500caa aag gac tat gaa gaa aat tct tgg gat tct gag agt ctc tgt gag 1650Gln Lys Asp Tyr Glu Glu Asn Ser Trp Asp Ser Glu Ser Leu Cys Glu 505 510 515act gtt tca cag aag gat gtg tgt tta ccc aag gct aca cat caa aaa 1698Thr Val Ser Gln Lys Asp Val Cys Leu Pro Lys Ala Thr His Gln Lys 520 525 530gaa ata gat aaa ata aat gga aaa tta gaa gag tct cct aat aaa gat 1746Glu Ile Asp Lys Ile Asn Gly Lys Leu Glu Glu Ser Pro Asn Lys Asp 535 540 545ggt ctt ctg aag gct acc tgc gga atg aaa gtt tct att cca act aaa 1794Gly Leu Leu Lys Ala Thr Cys Gly Met Lys Val Ser Ile Pro Thr Lys550 555 560 565gcc tta gaa ttg aag gac atg caa act ttc aaa gcg gag cct ccg ggg 1842Ala Leu Glu Leu Lys Asp Met Gln Thr Phe Lys Ala Glu Pro Pro Gly 570 575 580aag cca tct gcc ttc gag cct gcc act gaa atg caa aag tct gtc cca 1890Lys Pro Ser Ala Phe Glu Pro Ala Thr Glu Met Gln Lys Ser Val Pro 585 590 595aat aaa gcc ttg gaa ttg aaa aat gaa caa aca tgg aga gca gat gag 1938Asn Lys Ala Leu Glu Leu Lys Asn Glu Gln Thr Trp Arg Ala Asp Glu 600 605 610ata ctc cca tca gaa tcc aaa caa aag gac tat gaa gaa aat tct tgg 1986Ile Leu Pro Ser Glu Ser Lys Gln Lys Asp Tyr Glu Glu Asn Ser Trp 615 620 625gat act gag agt ctc tgt gag act gtt tca cag aag gat gtg tgt tta 2034Asp Thr Glu Ser Leu Cys Glu Thr Val Ser Gln Lys Asp Val Cys Leu630 635 640 645ccc aag gct gcg cat caa aaa gaa ata gat aaa ata aat gga aaa tta 2082Pro Lys Ala Ala His Gln Lys Glu Ile Asp Lys Ile Asn Gly Lys Leu 650 655 660gaa ggg tct cct gtt aaa gat ggt ctt ctg aag gct aac tgc gga atg 2130Glu Gly Ser Pro Val Lys Asp Gly Leu Leu Lys Ala Asn Cys Gly Met 665 670 675aaa gtt tct att cca act aaa gcc tta gaa ttg atg gac atg caa act 2178Lys Val Ser Ile Pro Thr Lys Ala Leu Glu Leu Met Asp Met Gln Thr 680 685 690ttc aaa gca gag cct ccc gag aag cca tct gcc ttc gag cct gcc att 2226Phe Lys Ala Glu Pro Pro Glu Lys Pro Ser Ala Phe Glu Pro Ala Ile 695 700 705gaa atg caa aag tct gtt cca aat aaa gcc ttg gaa ttg aag aat gaa 2274Glu Met Gln Lys Ser Val Pro Asn Lys Ala Leu Glu Leu Lys Asn Glu710 715 720 725caa aca ttg aga gca gat gag ata ctc cca tca gaa tcc aaa caa aag 2322Gln Thr Leu Arg Ala Asp Glu Ile Leu Pro Ser Glu Ser Lys Gln Lys 730 735 740gac tat gaa gaa agt tct tgg gat tct gag agt ctc tgt gag act gtt 2370Asp Tyr Glu Glu Ser Ser Trp Asp Ser Glu Ser Leu Cys Glu Thr Val 745 750 755tca cag aag gat gtg tgt tta ccc aag gct aca cat caa aaa gaa ata 2418Ser Gln Lys Asp Val Cys Leu Pro Lys Ala Thr His Gln Lys Glu Ile 760 765 770gat aaa ata aat gga aaa tta gaa gag tct cct gat aat gat ggt ttt 2466Asp Lys Ile Asn Gly Lys Leu Glu Glu Ser Pro Asp Asn Asp Gly Phe 775 780 785ctg aag gct ccc tgc aga atg aaa gtt tct att cca act aaa gcc tta 2514Leu Lys Ala Pro Cys Arg Met Lys Val Ser Ile Pro Thr Lys Ala Leu790 795 800 805gaa ttg atg gac atg caa act ttc aaa gca gag cct ccc gag aag cca 2562Glu Leu Met Asp Met Gln Thr Phe Lys Ala Glu Pro Pro Glu Lys Pro 810 815 820tct gcc ttc gag cct gcc att gaa atg caa aag tct gtt cca aat aaa 2610Ser Ala Phe Glu Pro Ala Ile Glu Met Gln Lys Ser Val Pro Asn Lys 825 830 835gcc ttg gaa ttg aag aat gaa caa aca ttg aga gca gat cag atg ttc 2658Ala Leu Glu Leu Lys Asn Glu Gln Thr Leu Arg Ala Asp Gln Met Phe 840 845 850cct tca gaa tca aaa caa aag aag gtt gaa gaa aat tct tgg gat tct 2706Pro Ser Glu Ser Lys Gln Lys Lys Val Glu Glu Asn Ser Trp Asp Ser 855 860 865gag agt ctc cgt gag act gtt tca cag aag gat gtg tgt gta ccc aag 2754Glu Ser Leu Arg Glu Thr Val Ser Gln Lys Asp Val Cys Val Pro Lys870 875 880 885gct aca cat caa aaa gaa atg gat aaa ata agt gga aaa tta gaa gat 2802Ala Thr His Gln Lys Glu Met Asp Lys Ile Ser Gly Lys Leu Glu Asp 890 895 900tca act agc cta tca aaa atc ttg gat aca gtt cat tct tgt gaa aga 2850Ser Thr Ser Leu Ser Lys Ile Leu Asp Thr Val His Ser Cys Glu Arg 905 910 915gca agg gaa ctt caa aaa gat cac tgt gaa caa cgt aca gga aaa atg 2898Ala Arg Glu Leu Gln Lys Asp His Cys Glu Gln Arg Thr Gly Lys Met 920 925 930gaa caa atg aaa aag aag ttt tgt gta ctg aaa aag aaa ctg tca gaa 2946Glu Gln Met Lys Lys Lys Phe Cys Val Leu Lys Lys Lys Leu Ser Glu 935 940 945gca aaa gaa ata aaa tca cag tta gag aac caa aaa gtt aaa tgg gaa 2994Ala Lys Glu Ile Lys Ser Gln Leu Glu Asn Gln Lys Val Lys Trp Glu950 955 960 965caa gag ctc tgc agt gtg aga ttg act tta aac caa gaa gaa gag aag 3042Gln Glu Leu Cys Ser Val Arg Leu Thr Leu Asn Gln Glu Glu Glu Lys 970 975 980aga aga aat gcc gat ata tta aat gaa aaa att agg gaa gaa tta gga 3090Arg Arg Asn Ala Asp Ile Leu Asn Glu Lys Ile Arg Glu Glu Leu Gly 985 990 995aga atc gaa gag cag cat agg aaa gag tta gaa gtg aaa caa caa ctt 3138Arg Ile Glu Glu Gln His Arg Lys Glu Leu Glu Val Lys Gln Gln Leu 1000 1005 1010gaa cag gct ctc aga ata caa gat ata gaa ttg aag agt gta gaa agt 3186Glu Gln Ala Leu Arg Ile Gln Asp Ile Glu Leu Lys Ser Val Glu Ser 1015 1020 1025aat ttg aat cag gtt tct cac act cat gaa aat gaa aat tat ctc tta 3234Asn Leu Asn Gln Val Ser His Thr His Glu Asn Glu Asn Tyr Leu Leu1030 1035 1040 1045cat gaa aat tgc atg ttg aaa aag gaa att gcc atg cta aaa ctg gaa 3282His Glu Asn Cys Met Leu Lys Lys Glu Ile Ala Met Leu Lys Leu Glu 1050 1055 1060ata gcc aca ctg aaa cac caa tac cag gaa aag gaa aat aaa tac ttt 3330Ile Ala Thr Leu Lys His Gln Tyr Gln Glu Lys Glu Asn Lys Tyr Phe 1065 1070 1075gag gac att aag att tta aaa gaa aag aat gct gaa ctt cag atg acc 3378Glu Asp Ile Lys Ile Leu Lys Glu Lys Asn Ala Glu Leu Gln Met Thr 1080 1085 1090cta aaa ctg aaa gag gaa tca tta act aaa agg gca tct caa tat agt 3426Leu Lys Leu Lys Glu Glu Ser Leu Thr Lys Arg Ala Ser Gln Tyr Ser 1095 1100 1105ggg cag ctt aaa gtt ctg ata gct gag aac aca atg ctc act tct aaa 3474Gly Gln Leu Lys Val Leu Ile Ala Glu Asn Thr Met Leu Thr Ser Lys1110 1115 1120 1125ttg aag gaa aaa caa gac aaa gaa ata cta gag gca gaa att gaa tca 3522Leu Lys Glu Lys Gln Asp Lys Glu Ile Leu Glu Ala Glu Ile Glu Ser 1130 1135 1140cac cat cct aga ctg gct tct gct gta caa gac cat gat caa att gtg 3570His His Pro Arg Leu Ala Ser Ala Val Gln Asp His Asp Gln Ile Val 1145 1150 1155aca tca aga aaa agt caa gaa cct gct ttc cac att gca gga gat gct 3618Thr Ser Arg Lys Ser Gln Glu Pro Ala Phe His Ile Ala Gly Asp Ala 1160 1165 1170tgt ttg caa aga aaa atg aat gtt gat gtg agt agt acg ata tat aac 3666Cys Leu Gln Arg Lys Met Asn Val Asp Val Ser Ser Thr Ile Tyr Asn 1175 1180 1185aat gag gtg ctc cat caa cca ctt tct gaa gct caa agg aaa tcc aaa 3714Asn Glu Val Leu His Gln Pro Leu Ser Glu Ala Gln Arg Lys Ser Lys1190 1195 1200 1205agc cta aaa att aat ctc aat tat gca gga gat gct cta aga gaa aat 3762Ser Leu Lys Ile Asn Leu Asn Tyr Ala Gly Asp Ala Leu Arg Glu Asn 1210 1215 1220aca ttg gtt tca gaa cat gca caa aga gac caa cgt gaa aca cag tgt 3810Thr Leu Val Ser Glu His Ala Gln Arg Asp Gln Arg Glu Thr Gln Cys 1225 1230 1235caa atg aag gaa gct gaa cac atg tat caa aac gaa caa gat aat gtg 3858Gln Met Lys Glu Ala Glu His Met Tyr Gln Asn Glu Gln Asp Asn Val 1240 1245 1250aac aaa cac act gaa cag cag gag tct cta gat cag aaa tta ttt caa 3906Asn Lys His Thr Glu Gln Gln Glu Ser Leu Asp Gln Lys Leu Phe Gln 1255 1260 1265cta caa agc aaa aat atg tgg ctt caa cag caa tta gtt cat gca cat 3954Leu Gln Ser Lys Asn Met Trp Leu Gln Gln Gln Leu Val His Ala His1270 1275 1280 1285aag aaa gct gac aac aaa agc aag ata aca att gat att cat ttt ctt 4002Lys Lys Ala Asp Asn Lys Ser Lys Ile Thr Ile Asp Ile His Phe Leu 1290 1295 1300gag agg aaa atg caa cat cat ctc cta aaa gag aaa aat gag gag ata 4050Glu Arg Lys Met Gln His His Leu Leu Lys Glu Lys Asn Glu Glu Ile 1305 1310 1315ttt aat tac aat aac cat tta aaa aac cgt ata tat caa tat gaa aaa 4098Phe Asn Tyr Asn Asn His Leu Lys Asn Arg Ile Tyr Gln Tyr Glu Lys 1320 1325 1330gag aaa gca gaa aca gaa aac tca tga gagacaagca gtaagaaact 4145Glu Lys Ala Glu Thr Glu Asn Ser * 1335 1340tcttttggag aaacaacaga ccagatcttt actcacaact catgctagga ggccagtcct 4205agcatcacct tatgttgaaa atcttaccaa tagtctgtgt caacagaata cttattttag 4265aagaaaaatt catgatttct tcctgaagcc tacagacata aaataacagt gtgaagaatt 4325acttgttcac gaattgcata aagctgcaca ggattcccat ctaccctgat gatgcagcag 4385acatcattca atccaaccag aatctcgctc tgcactccag cctaggtgac agagtgagac 4445tccacctcgg aaa 4458341341PRThuman 34Met Thr Lys Arg Lys Lys Thr Ile Asn Leu Asn Ile Gln Asp Ala Gln1 5 10 15Lys Arg Thr Ala Leu His Trp Ala Cys Val Asn Gly His Glu Glu Val 20 25 30Val Thr Phe Leu Val Asp Arg Lys Cys Gln Leu Asp Val Leu Asp Gly 35 40 45Glu His Arg Thr Pro Leu Met Lys Ala Leu Gln Cys His Gln Glu Ala 50 55 60Cys Ala Asn Ile Leu Ile Asp Ser Gly Ala Asp Ile Asn Leu Val Asp65 70 75 80Val Tyr Gly Asn Met Ala Leu His Tyr Ala Val Tyr Ser Glu Ile Leu 85 90 95Ser Val Val Ala Lys Leu Leu Ser His Gly Ala Val Ile Glu Val His 100 105 110Asn Lys Ala Ser Leu Thr Pro Leu Leu Leu Ser Ile Thr Lys Arg Ser 115 120 125Glu Gln Ile Val Glu Phe Leu Leu Ile Lys Asn Ala Asn Ala Asn Ala 130 135 140Val Asn Lys Tyr Lys Cys Thr Ala Leu Met Leu Ala Val Cys His Gly145 150 155 160Ser Ser Glu Ile Val Gly Met Leu Leu Gln Gln Asn Val Asp Val Phe 165 170 175Ala Ala Asp Ile Cys Gly Val Thr Ala Glu His Tyr Ala Val Thr Cys 180 185 190Gly Phe His His Ile His Glu Gln Ile Met Glu Tyr Ile Arg Lys Leu 195 200 205Ser Lys Asn His Gln Asn Thr Asn Pro Glu Gly Thr Ser Ala Gly Thr 210 215 220Pro Asp Glu Ala Ala Pro Leu Ala Glu Arg Thr Pro Asp Thr Ala Glu225 230 235 240Ser Leu Val Glu Lys Thr Pro Asp Glu Ala Ala Pro Leu Val Glu Arg 245 250 255Thr Pro Asp Thr Ala Glu Ser Leu Val Glu Lys Thr Pro Asp Glu Ala 260 265 270Ala Ser Leu Val Glu Gly Thr Ser Asp Lys Ile Gln Cys Leu Glu Lys 275 280 285Ala Thr Ser Gly Lys Phe Glu Gln Ser Ala Glu Glu Thr Pro Arg Glu 290 295 300Ile Thr Ser Pro Ala Lys Glu Thr Ser Glu Lys Phe Thr Trp Pro Ala305 310 315 320Lys Gly Arg Pro Arg Lys Ile Ala Trp Glu Lys Lys Glu Asp Thr Pro 325 330 335Arg Glu Ile Met Ser Pro Ala Lys Glu Thr Ser Glu Lys Phe Thr Trp 340 345 350Ala Ala Lys Gly Arg Pro Arg Lys Ile Ala Trp Glu Lys Lys Glu Thr 355 360 365Pro Val Lys Thr Gly Cys Val Ala Arg Val Thr Ser Asn Lys Thr Lys 370 375 380Val Leu Glu Lys Gly Arg Ser Lys Met Ile Ala Cys Pro Thr Lys Glu385 390 395 400Ser Ser Thr Lys Ala Ser Ala Asn Asp Gln Arg Phe Pro Ser Glu Ser 405 410 415Lys Gln Glu Glu Asp Glu Glu Tyr Ser Cys Asp Ser Arg Ser Leu Phe 420 425 430Glu Ser Ser Ala Lys Ile Gln Val Cys Ile Pro Glu Ser Ile Tyr Gln 435 440 445Lys Val Met Glu Ile Asn Arg Glu Val Glu Glu Pro Pro Lys Lys Pro 450 455 460Ser Ala Phe Lys Pro Ala Ile Glu Met Gln Asn Ser Val Pro Asn Lys465 470 475 480Ala Phe Glu Leu Lys Asn Glu Gln Thr Leu Arg Ala Asp Pro Met Phe 485 490 495Pro Pro Glu Ser Lys Gln Lys Asp Tyr Glu Glu Asn Ser Trp Asp Ser 500 505 510Glu Ser Leu Cys Glu Thr Val Ser Gln Lys Asp Val Cys Leu Pro Lys 515 520 525Ala Thr His Gln Lys Glu Ile Asp Lys Ile Asn Gly Lys Leu Glu Glu 530 535 540Ser Pro Asn Lys Asp Gly Leu Leu Lys Ala Thr Cys Gly Met Lys Val545 550 555 560Ser Ile Pro Thr Lys Ala Leu Glu Leu Lys Asp Met Gln Thr Phe Lys 565 570 575Ala Glu Pro Pro Gly Lys Pro Ser Ala Phe Glu Pro Ala Thr Glu Met 580 585 590Gln Lys Ser Val Pro Asn Lys Ala Leu Glu Leu Lys Asn Glu Gln Thr 595 600 605Trp Arg Ala Asp Glu Ile Leu Pro Ser Glu Ser Lys Gln Lys Asp Tyr 610 615 620Glu Glu Asn Ser Trp Asp Thr Glu Ser Leu Cys Glu Thr Val Ser Gln625 630 635 640Lys Asp Val Cys Leu Pro Lys Ala Ala His Gln Lys Glu Ile Asp Lys 645 650 655Ile Asn Gly Lys Leu Glu Gly Ser Pro Val Lys Asp Gly Leu Leu Lys 660 665 670Ala Asn Cys Gly Met Lys Val Ser Ile Pro Thr Lys Ala Leu Glu Leu 675 680 685Met Asp Met Gln Thr Phe Lys Ala Glu Pro Pro Glu Lys Pro Ser Ala 690 695 700Phe Glu Pro Ala Ile Glu Met Gln Lys Ser Val Pro Asn Lys Ala Leu705 710 715 720Glu Leu Lys Asn Glu Gln Thr Leu Arg Ala Asp Glu Ile Leu Pro Ser 725 730 735Glu Ser Lys Gln Lys Asp Tyr Glu Glu Ser Ser Trp Asp Ser Glu Ser 740 745 750Leu Cys Glu Thr Val Ser Gln Lys Asp Val Cys Leu Pro Lys Ala Thr 755 760 765His Gln Lys Glu Ile Asp Lys Ile Asn Gly Lys Leu Glu Glu Ser Pro 770 775 780Asp Asn Asp Gly Phe Leu Lys Ala Pro Cys Arg Met Lys Val Ser Ile785 790 795 800Pro Thr Lys Ala Leu Glu Leu Met Asp Met Gln Thr Phe Lys Ala Glu 805 810 815Pro Pro Glu Lys Pro Ser Ala Phe Glu Pro Ala Ile Glu Met Gln Lys 820 825 830Ser Val Pro Asn Lys Ala Leu Glu Leu Lys Asn Glu Gln Thr Leu Arg 835 840 845Ala Asp Gln Met Phe Pro Ser Glu Ser Lys Gln Lys Lys Val Glu Glu 850 855 860Asn Ser Trp Asp Ser Glu Ser Leu Arg Glu Thr Val Ser Gln Lys Asp865 870 875 880Val Cys Val Pro Lys Ala Thr His Gln Lys

Glu Met Asp Lys Ile Ser 885 890 895Gly Lys Leu Glu Asp Ser Thr Ser Leu Ser Lys Ile Leu Asp Thr Val 900 905 910His Ser Cys Glu Arg Ala Arg Glu Leu Gln Lys Asp His Cys Glu Gln 915 920 925Arg Thr Gly Lys Met Glu Gln Met Lys Lys Lys Phe Cys Val Leu Lys 930 935 940Lys Lys Leu Ser Glu Ala Lys Glu Ile Lys Ser Gln Leu Glu Asn Gln945 950 955 960Lys Val Lys Trp Glu Gln Glu Leu Cys Ser Val Arg Leu Thr Leu Asn 965 970 975Gln Glu Glu Glu Lys Arg Arg Asn Ala Asp Ile Leu Asn Glu Lys Ile 980 985 990Arg Glu Glu Leu Gly Arg Ile Glu Glu Gln His Arg Lys Glu Leu Glu 995 1000 1005Val Lys Gln Gln Leu Glu Gln Ala Leu Arg Ile Gln Asp Ile Glu Leu 1010 1015 1020Lys Ser Val Glu Ser Asn Leu Asn Gln Val Ser His Thr His Glu Asn1025 1030 1035 1040Glu Asn Tyr Leu Leu His Glu Asn Cys Met Leu Lys Lys Glu Ile Ala 1045 1050 1055Met Leu Lys Leu Glu Ile Ala Thr Leu Lys His Gln Tyr Gln Glu Lys 1060 1065 1070Glu Asn Lys Tyr Phe Glu Asp Ile Lys Ile Leu Lys Glu Lys Asn Ala 1075 1080 1085Glu Leu Gln Met Thr Leu Lys Leu Lys Glu Glu Ser Leu Thr Lys Arg 1090 1095 1100Ala Ser Gln Tyr Ser Gly Gln Leu Lys Val Leu Ile Ala Glu Asn Thr1105 1110 1115 1120Met Leu Thr Ser Lys Leu Lys Glu Lys Gln Asp Lys Glu Ile Leu Glu 1125 1130 1135Ala Glu Ile Glu Ser His His Pro Arg Leu Ala Ser Ala Val Gln Asp 1140 1145 1150His Asp Gln Ile Val Thr Ser Arg Lys Ser Gln Glu Pro Ala Phe His 1155 1160 1165Ile Ala Gly Asp Ala Cys Leu Gln Arg Lys Met Asn Val Asp Val Ser 1170 1175 1180Ser Thr Ile Tyr Asn Asn Glu Val Leu His Gln Pro Leu Ser Glu Ala1185 1190 1195 1200Gln Arg Lys Ser Lys Ser Leu Lys Ile Asn Leu Asn Tyr Ala Gly Asp 1205 1210 1215Ala Leu Arg Glu Asn Thr Leu Val Ser Glu His Ala Gln Arg Asp Gln 1220 1225 1230Arg Glu Thr Gln Cys Gln Met Lys Glu Ala Glu His Met Tyr Gln Asn 1235 1240 1245Glu Gln Asp Asn Val Asn Lys His Thr Glu Gln Gln Glu Ser Leu Asp 1250 1255 1260Gln Lys Leu Phe Gln Leu Gln Ser Lys Asn Met Trp Leu Gln Gln Gln1265 1270 1275 1280Leu Val His Ala His Lys Lys Ala Asp Asn Lys Ser Lys Ile Thr Ile 1285 1290 1295Asp Ile His Phe Leu Glu Arg Lys Met Gln His His Leu Leu Lys Glu 1300 1305 1310Lys Asn Glu Glu Ile Phe Asn Tyr Asn Asn His Leu Lys Asn Arg Ile 1315 1320 1325Tyr Gln Tyr Glu Lys Glu Lys Ala Glu Thr Glu Asn Ser 1330 1335 1340353213DNAhumanCDS(12)...(2522) 35agagactcaa g atg att ccc ttt tta ccc atg ttt tct cta cta ttg ctg 50 Met Ile Pro Phe Leu Pro Met Phe Ser Leu Leu Leu Leu 1 5 10ctt att gtt aac cct ata aac gcc aac aat cat tat gac aag atc ttg 98Leu Ile Val Asn Pro Ile Asn Ala Asn Asn His Tyr Asp Lys Ile Leu 15 20 25gct cat agt cgt atc agg ggt cgg gac caa ggc cca aat gtc tgt gcc 146Ala His Ser Arg Ile Arg Gly Arg Asp Gln Gly Pro Asn Val Cys Ala30 35 40 45ctt caa cag att ttg ggc acc aaa aag aaa tac ttc agc act tgt aag 194Leu Gln Gln Ile Leu Gly Thr Lys Lys Lys Tyr Phe Ser Thr Cys Lys 50 55 60aac tgg tat aaa aag tcc atc tgt gga cag aaa acg act gtg tta tat 242Asn Trp Tyr Lys Lys Ser Ile Cys Gly Gln Lys Thr Thr Val Leu Tyr 65 70 75gaa tgt tgc cct ggt tat atg aga atg gaa gga atg aaa ggc tgc cca 290Glu Cys Cys Pro Gly Tyr Met Arg Met Glu Gly Met Lys Gly Cys Pro 80 85 90gca gtt ttg ccc att gac cat gtt tat ggc act ctg ggc atc gtg gga 338Ala Val Leu Pro Ile Asp His Val Tyr Gly Thr Leu Gly Ile Val Gly 95 100 105gcc acc aca acg cag cgc tat tct gac gcc tca aaa ctg agg gag gag 386Ala Thr Thr Thr Gln Arg Tyr Ser Asp Ala Ser Lys Leu Arg Glu Glu110 115 120 125atc gag gga aag gga tcc ttc act tac ttt gca ccg agt aat gag gct 434Ile Glu Gly Lys Gly Ser Phe Thr Tyr Phe Ala Pro Ser Asn Glu Ala 130 135 140tgg gac aac ttg gat tct gat atc cgt aga ggt ttg gag agc aac gtg 482Trp Asp Asn Leu Asp Ser Asp Ile Arg Arg Gly Leu Glu Ser Asn Val 145 150 155aat gtt gaa tta ctg aat gct tta cat agt cac atg att aat aag aga 530Asn Val Glu Leu Leu Asn Ala Leu His Ser His Met Ile Asn Lys Arg 160 165 170atg ttg acc aag gac tta aaa aat ggc atg att att cct tca atg tat 578Met Leu Thr Lys Asp Leu Lys Asn Gly Met Ile Ile Pro Ser Met Tyr 175 180 185aac aat ttg ggg ctt ttc att aac cat tat cct aat ggg gtt gtc act 626Asn Asn Leu Gly Leu Phe Ile Asn His Tyr Pro Asn Gly Val Val Thr190 195 200 205gtt aat tgt gct cga atc atc cat ggg aac cag att gca aca aat ggt 674Val Asn Cys Ala Arg Ile Ile His Gly Asn Gln Ile Ala Thr Asn Gly 210 215 220gtt gtc cat gtc att gac cgt gtg ctt aca caa att ggt acc tca att 722Val Val His Val Ile Asp Arg Val Leu Thr Gln Ile Gly Thr Ser Ile 225 230 235caa gac ttc att gaa gca gaa gat gac ctt tca tct ttt aga gca gct 770Gln Asp Phe Ile Glu Ala Glu Asp Asp Leu Ser Ser Phe Arg Ala Ala 240 245 250gcc atc aca tcg gac ata ttg gag gcc ctt gga aga gac ggt cac ttc 818Ala Ile Thr Ser Asp Ile Leu Glu Ala Leu Gly Arg Asp Gly His Phe 255 260 265aca ctc ttt gct ccc acc aat gag gct ttt gag aaa ctt cca cga ggt 866Thr Leu Phe Ala Pro Thr Asn Glu Ala Phe Glu Lys Leu Pro Arg Gly270 275 280 285gtc cta gaa agg atc atg gga gac aaa gtg gct tcc gaa gct ctt atg 914Val Leu Glu Arg Ile Met Gly Asp Lys Val Ala Ser Glu Ala Leu Met 290 295 300aag tac cac atc tta aat act ctc cag tgt tct gag tct att atg gga 962Lys Tyr His Ile Leu Asn Thr Leu Gln Cys Ser Glu Ser Ile Met Gly 305 310 315gga gca gtc ttt gag acg ctg gaa gga aat aca att gag ata gga tgt 1010Gly Ala Val Phe Glu Thr Leu Glu Gly Asn Thr Ile Glu Ile Gly Cys 320 325 330gac ggt gac agt ata aca gta aat gga atc aaa atg gtg aac aaa aag 1058Asp Gly Asp Ser Ile Thr Val Asn Gly Ile Lys Met Val Asn Lys Lys 335 340 345gat att gtg aca aat aat ggt gtg atc cat ttg att gat cag gtc cta 1106Asp Ile Val Thr Asn Asn Gly Val Ile His Leu Ile Asp Gln Val Leu350 355 360 365att cct gat tct gcc aaa caa gtt att gag ctg gct gga aaa cag caa 1154Ile Pro Asp Ser Ala Lys Gln Val Ile Glu Leu Ala Gly Lys Gln Gln 370 375 380acc acc ttc acg gat ctt gtg gcc caa tta ggc ttg gca tct gct ctg 1202Thr Thr Phe Thr Asp Leu Val Ala Gln Leu Gly Leu Ala Ser Ala Leu 385 390 395agg cca gat gga gaa tac act ttg ctg gca cct gtg aat aat gca ttt 1250Arg Pro Asp Gly Glu Tyr Thr Leu Leu Ala Pro Val Asn Asn Ala Phe 400 405 410tct gat gat act ctc agc atg gat cag cgc ctc ctt aaa tta att ctg 1298Ser Asp Asp Thr Leu Ser Met Asp Gln Arg Leu Leu Lys Leu Ile Leu 415 420 425cag aat cac ata ttg aaa gta aaa gtt ggc ctt aat gag ctt tac aac 1346Gln Asn His Ile Leu Lys Val Lys Val Gly Leu Asn Glu Leu Tyr Asn430 435 440 445ggg caa ata ctg gaa acc atc gga ggc aaa cag ctc aga gtc ttc gta 1394Gly Gln Ile Leu Glu Thr Ile Gly Gly Lys Gln Leu Arg Val Phe Val 450 455 460tat cgt aca gct gtc tgc att gaa aat tca tgc atg gag aaa ggg agt 1442Tyr Arg Thr Ala Val Cys Ile Glu Asn Ser Cys Met Glu Lys Gly Ser 465 470 475aag caa ggg aga aac ggt gcg att cac ata ttc cgc gag atc atc aag 1490Lys Gln Gly Arg Asn Gly Ala Ile His Ile Phe Arg Glu Ile Ile Lys 480 485 490cca gca gag aaa tcc ctc cat gaa aag tta aaa caa gat aag cgc ttt 1538Pro Ala Glu Lys Ser Leu His Glu Lys Leu Lys Gln Asp Lys Arg Phe 495 500 505agc acc ttc ctc agc cta ctt gaa gct gca gac ttg aaa gag ctc ctg 1586Ser Thr Phe Leu Ser Leu Leu Glu Ala Ala Asp Leu Lys Glu Leu Leu510 515 520 525aca caa cct gga gac tgg aca tta ttt gtg cca acc aat gat gct ttt 1634Thr Gln Pro Gly Asp Trp Thr Leu Phe Val Pro Thr Asn Asp Ala Phe 530 535 540aag gga atg act agt gaa gaa aaa gaa att ctg ata cgg gac aaa aat 1682Lys Gly Met Thr Ser Glu Glu Lys Glu Ile Leu Ile Arg Asp Lys Asn 545 550 555gct ctt caa aac atc att ctt tat cac ctg aca cca gga gtt ttc att 1730Ala Leu Gln Asn Ile Ile Leu Tyr His Leu Thr Pro Gly Val Phe Ile 560 565 570gga aaa gga ttt gaa cct ggt gtt act aac att tta aag acc aca caa 1778Gly Lys Gly Phe Glu Pro Gly Val Thr Asn Ile Leu Lys Thr Thr Gln 575 580 585gga agc aaa atc ttt ctg aaa gaa gta aat gat aca ctt ctg gtg aat 1826Gly Ser Lys Ile Phe Leu Lys Glu Val Asn Asp Thr Leu Leu Val Asn590 595 600 605gaa ttg aaa tca aaa gaa tct gac atc atg aca aca aat ggt gta att 1874Glu Leu Lys Ser Lys Glu Ser Asp Ile Met Thr Thr Asn Gly Val Ile 610 615 620cat gtt gta gat aaa ctc ctc tat cca gca gac aca cct gtt gga aat 1922His Val Val Asp Lys Leu Leu Tyr Pro Ala Asp Thr Pro Val Gly Asn 625 630 635gat caa ctg ctg gaa ata ctt aat aaa tta atc aaa tac atc caa att 1970Asp Gln Leu Leu Glu Ile Leu Asn Lys Leu Ile Lys Tyr Ile Gln Ile 640 645 650aag ttt gtt cgt ggt agc acc ttc aaa gaa atc ccc gtg act gtc tat 2018Lys Phe Val Arg Gly Ser Thr Phe Lys Glu Ile Pro Val Thr Val Tyr 655 660 665aca act aaa att ata acc aaa gtt gtg gaa cca aaa att aaa gtg att 2066Thr Thr Lys Ile Ile Thr Lys Val Val Glu Pro Lys Ile Lys Val Ile670 675 680 685gaa ggc agt ctt cag cct att atc aaa act gaa gga ccc aca cta aca 2114Glu Gly Ser Leu Gln Pro Ile Ile Lys Thr Glu Gly Pro Thr Leu Thr 690 695 700aaa gtc aaa att gaa ggt gaa cct gaa ttc aga ctg att aaa gaa ggt 2162Lys Val Lys Ile Glu Gly Glu Pro Glu Phe Arg Leu Ile Lys Glu Gly 705 710 715gaa aca ata act gaa gtg atc cat gga gag cca att att aaa aaa tac 2210Glu Thr Ile Thr Glu Val Ile His Gly Glu Pro Ile Ile Lys Lys Tyr 720 725 730acc aaa atc att gat gga gtg cct gtg gaa ata act gaa aaa gag aca 2258Thr Lys Ile Ile Asp Gly Val Pro Val Glu Ile Thr Glu Lys Glu Thr 735 740 745cga gaa gaa cga atc att aca ggt cct gaa ata aaa tac act agg att 2306Arg Glu Glu Arg Ile Ile Thr Gly Pro Glu Ile Lys Tyr Thr Arg Ile750 755 760 765tct act gga ggt gga gaa aca gaa gaa act ctg aag aaa ttg tta caa 2354Ser Thr Gly Gly Gly Glu Thr Glu Glu Thr Leu Lys Lys Leu Leu Gln 770 775 780gaa gag gtc acc aag gtc acc aaa ttc att gaa ggt ggt gat ggt cat 2402Glu Glu Val Thr Lys Val Thr Lys Phe Ile Glu Gly Gly Asp Gly His 785 790 795tta ttt gaa gat gaa gaa att aaa aga ctg ctt cag gga gac aca ccc 2450Leu Phe Glu Asp Glu Glu Ile Lys Arg Leu Leu Gln Gly Asp Thr Pro 800 805 810gtg agg aag ttg caa gcc aac aaa aaa gtt caa gga tct aga aga cga 2498Val Arg Lys Leu Gln Ala Asn Lys Lys Val Gln Gly Ser Arg Arg Arg 815 820 825tta agg gaa ggt cgt tct cag tga aaatccaaaa accagaaaaa aatgtttata 2552Leu Arg Glu Gly Arg Ser Gln *830 835caaccctaag tcaataacct gaccttagaa aattgtgaga gccaagttga cttcaggaac 2612tgaaacatca gcacaaagaa gcaatcatca aataattctg aacacaaatt taatattttt 2672ttttctgaat gagaaacatg agggaaattg tggagttagc ctcctgtggt aaaggaattg 2732aagaaaatat aacaccttac accctttttc atcttgacat taaaagttct ggctaacttt 2792ggaatccatt agagaaaaat ccttgtcacc agattcatta caattcaaat cgaagagttg 2852tgaactgtta tcccattgaa aagaccgagc cttgtatgta tgttatggat acataaaatg 2912cacgcaagcc attatctctc catgggaagc taagttataa aaataggtgc ttggtgtaca 2972aaacttttta tatcaaaagg ctttgcacat ttctatatga gtgggtttac tggtaaatta 3032tgttattttt tacaactaat tttgtactct cagaatgttt gtcatatgct tcttgcaatg 3092catatttttt aatctcaaac gtttcaataa aaccattttt cagatataaa gagaattact 3152tcaaattgag taattcagaa aaactcaaga tttaagttaa aaagtggttt ggacttggga 3212a 321336836PRThuman 36Met Ile Pro Phe Leu Pro Met Phe Ser Leu Leu Leu Leu Leu Ile Val1 5 10 15Asn Pro Ile Asn Ala Asn Asn His Tyr Asp Lys Ile Leu Ala His Ser 20 25 30Arg Ile Arg Gly Arg Asp Gln Gly Pro Asn Val Cys Ala Leu Gln Gln 35 40 45Ile Leu Gly Thr Lys Lys Lys Tyr Phe Ser Thr Cys Lys Asn Trp Tyr 50 55 60Lys Lys Ser Ile Cys Gly Gln Lys Thr Thr Val Leu Tyr Glu Cys Cys65 70 75 80Pro Gly Tyr Met Arg Met Glu Gly Met Lys Gly Cys Pro Ala Val Leu 85 90 95Pro Ile Asp His Val Tyr Gly Thr Leu Gly Ile Val Gly Ala Thr Thr 100 105 110Thr Gln Arg Tyr Ser Asp Ala Ser Lys Leu Arg Glu Glu Ile Glu Gly 115 120 125Lys Gly Ser Phe Thr Tyr Phe Ala Pro Ser Asn Glu Ala Trp Asp Asn 130 135 140Leu Asp Ser Asp Ile Arg Arg Gly Leu Glu Ser Asn Val Asn Val Glu145 150 155 160Leu Leu Asn Ala Leu His Ser His Met Ile Asn Lys Arg Met Leu Thr 165 170 175Lys Asp Leu Lys Asn Gly Met Ile Ile Pro Ser Met Tyr Asn Asn Leu 180 185 190Gly Leu Phe Ile Asn His Tyr Pro Asn Gly Val Val Thr Val Asn Cys 195 200 205Ala Arg Ile Ile His Gly Asn Gln Ile Ala Thr Asn Gly Val Val His 210 215 220Val Ile Asp Arg Val Leu Thr Gln Ile Gly Thr Ser Ile Gln Asp Phe225 230 235 240Ile Glu Ala Glu Asp Asp Leu Ser Ser Phe Arg Ala Ala Ala Ile Thr 245 250 255Ser Asp Ile Leu Glu Ala Leu Gly Arg Asp Gly His Phe Thr Leu Phe 260 265 270Ala Pro Thr Asn Glu Ala Phe Glu Lys Leu Pro Arg Gly Val Leu Glu 275 280 285Arg Ile Met Gly Asp Lys Val Ala Ser Glu Ala Leu Met Lys Tyr His 290 295 300Ile Leu Asn Thr Leu Gln Cys Ser Glu Ser Ile Met Gly Gly Ala Val305 310 315 320Phe Glu Thr Leu Glu Gly Asn Thr Ile Glu Ile Gly Cys Asp Gly Asp 325 330 335Ser Ile Thr Val Asn Gly Ile Lys Met Val Asn Lys Lys Asp Ile Val 340 345 350Thr Asn Asn Gly Val Ile His Leu Ile Asp Gln Val Leu Ile Pro Asp 355 360 365Ser Ala Lys Gln Val Ile Glu Leu Ala Gly Lys Gln Gln Thr Thr Phe 370 375 380Thr Asp Leu Val Ala Gln Leu Gly Leu Ala Ser Ala Leu Arg Pro Asp385 390 395 400Gly Glu Tyr Thr Leu Leu Ala Pro Val Asn Asn Ala Phe Ser Asp Asp 405 410 415Thr Leu Ser Met Asp Gln Arg Leu Leu Lys Leu Ile Leu Gln Asn His 420 425 430Ile Leu Lys Val Lys Val Gly Leu Asn Glu Leu Tyr Asn Gly Gln Ile 435 440 445Leu Glu Thr Ile Gly Gly Lys Gln Leu Arg Val Phe Val Tyr Arg Thr 450 455 460Ala Val Cys Ile Glu Asn Ser Cys Met Glu Lys Gly Ser Lys Gln Gly465 470 475 480Arg Asn Gly Ala Ile His Ile Phe Arg Glu Ile Ile Lys Pro Ala Glu 485 490 495Lys Ser Leu His Glu Lys Leu Lys Gln Asp Lys Arg Phe Ser Thr Phe 500 505 510Leu Ser Leu Leu Glu Ala Ala Asp Leu Lys Glu Leu Leu Thr Gln Pro 515 520 525Gly Asp Trp Thr Leu Phe Val Pro Thr Asn Asp Ala Phe Lys Gly Met 530 535

540Thr Ser Glu Glu Lys Glu Ile Leu Ile Arg Asp Lys Asn Ala Leu Gln545 550 555 560Asn Ile Ile Leu Tyr His Leu Thr Pro Gly Val Phe Ile Gly Lys Gly 565 570 575Phe Glu Pro Gly Val Thr Asn Ile Leu Lys Thr Thr Gln Gly Ser Lys 580 585 590Ile Phe Leu Lys Glu Val Asn Asp Thr Leu Leu Val Asn Glu Leu Lys 595 600 605Ser Lys Glu Ser Asp Ile Met Thr Thr Asn Gly Val Ile His Val Val 610 615 620Asp Lys Leu Leu Tyr Pro Ala Asp Thr Pro Val Gly Asn Asp Gln Leu625 630 635 640Leu Glu Ile Leu Asn Lys Leu Ile Lys Tyr Ile Gln Ile Lys Phe Val 645 650 655Arg Gly Ser Thr Phe Lys Glu Ile Pro Val Thr Val Tyr Thr Thr Lys 660 665 670Ile Ile Thr Lys Val Val Glu Pro Lys Ile Lys Val Ile Glu Gly Ser 675 680 685Leu Gln Pro Ile Ile Lys Thr Glu Gly Pro Thr Leu Thr Lys Val Lys 690 695 700Ile Glu Gly Glu Pro Glu Phe Arg Leu Ile Lys Glu Gly Glu Thr Ile705 710 715 720Thr Glu Val Ile His Gly Glu Pro Ile Ile Lys Lys Tyr Thr Lys Ile 725 730 735Ile Asp Gly Val Pro Val Glu Ile Thr Glu Lys Glu Thr Arg Glu Glu 740 745 750Arg Ile Ile Thr Gly Pro Glu Ile Lys Tyr Thr Arg Ile Ser Thr Gly 755 760 765Gly Gly Glu Thr Glu Glu Thr Leu Lys Lys Leu Leu Gln Glu Glu Val 770 775 780Thr Lys Val Thr Lys Phe Ile Glu Gly Gly Asp Gly His Leu Phe Glu785 790 795 800Asp Glu Glu Ile Lys Arg Leu Leu Gln Gly Asp Thr Pro Val Arg Lys 805 810 815Leu Gln Ala Asn Lys Lys Val Gln Gly Ser Arg Arg Arg Leu Arg Glu 820 825 830Gly Arg Ser Gln 835373129DNAhumanCDS(12)...(2438) 37agagactcaa g atg att ccc ttt tta ccc atg ttt tct cta cta ttg ctg 50 Met Ile Pro Phe Leu Pro Met Phe Ser Leu Leu Leu Leu 1 5 10ctt att gtt aac cct ata aac gcc aac aat cat tat gac aag atc ttg 98Leu Ile Val Asn Pro Ile Asn Ala Asn Asn His Tyr Asp Lys Ile Leu 15 20 25gct cat agt cgt atc agg ggt cgg gac caa ggc cca aat gtc tgt gcc 146Ala His Ser Arg Ile Arg Gly Arg Asp Gln Gly Pro Asn Val Cys Ala30 35 40 45ctt caa cag att ttg ggc acc aaa aag aaa tac ttc agc act tgt aag 194Leu Gln Gln Ile Leu Gly Thr Lys Lys Lys Tyr Phe Ser Thr Cys Lys 50 55 60aac tgg tat aaa aag tcc atc tgt gga cag aaa acg act gtg tta tat 242Asn Trp Tyr Lys Lys Ser Ile Cys Gly Gln Lys Thr Thr Val Leu Tyr 65 70 75gaa tgt tgc cct ggt tat atg aga atg gaa gga atg aaa ggc tgc cca 290Glu Cys Cys Pro Gly Tyr Met Arg Met Glu Gly Met Lys Gly Cys Pro 80 85 90gca gtt ttg ccc att gac cat gtt tat ggc act ctg ggc atc gtg gga 338Ala Val Leu Pro Ile Asp His Val Tyr Gly Thr Leu Gly Ile Val Gly 95 100 105gcc acc aca acg cag cgc tat tct gac gcc tca aaa ctg agg gag gag 386Ala Thr Thr Thr Gln Arg Tyr Ser Asp Ala Ser Lys Leu Arg Glu Glu110 115 120 125atc gag gga aag gga tcc ttc act tac ttt gca ccg agt aat gag gct 434Ile Glu Gly Lys Gly Ser Phe Thr Tyr Phe Ala Pro Ser Asn Glu Ala 130 135 140tgg gac aac ttg gat tct gat atc cgt aga ggt ttg gag agc aac gtg 482Trp Asp Asn Leu Asp Ser Asp Ile Arg Arg Gly Leu Glu Ser Asn Val 145 150 155aat gtt gaa tta ctg aat gct tta cat agt cac atg att aat aag aga 530Asn Val Glu Leu Leu Asn Ala Leu His Ser His Met Ile Asn Lys Arg 160 165 170atg ttg acc aag gac tta aaa aat ggc atg att att cct tca atg tat 578Met Leu Thr Lys Asp Leu Lys Asn Gly Met Ile Ile Pro Ser Met Tyr 175 180 185aac aat ttg ggg ctt ttc att aac cat tat cct aat ggg gtt gtc act 626Asn Asn Leu Gly Leu Phe Ile Asn His Tyr Pro Asn Gly Val Val Thr190 195 200 205gtt aat tgt gct cga atc atc cat ggg aac cag att gca aca aat ggt 674Val Asn Cys Ala Arg Ile Ile His Gly Asn Gln Ile Ala Thr Asn Gly 210 215 220gtt gtc cat gtc att gac cgt gtg ctt aca caa att ggt acc tca att 722Val Val His Val Ile Asp Arg Val Leu Thr Gln Ile Gly Thr Ser Ile 225 230 235caa gac ttc att gaa gca gaa gat gac ctt tca tct ttt aga gca gct 770Gln Asp Phe Ile Glu Ala Glu Asp Asp Leu Ser Ser Phe Arg Ala Ala 240 245 250gcc atc aca tcg gac ata ttg gag gcc ctt gga aga gac ggt cac ttc 818Ala Ile Thr Ser Asp Ile Leu Glu Ala Leu Gly Arg Asp Gly His Phe 255 260 265aca ctc ttt gct ccc acc aat gag gct ttt gag aaa ctt cca cga ggt 866Thr Leu Phe Ala Pro Thr Asn Glu Ala Phe Glu Lys Leu Pro Arg Gly270 275 280 285gtc cta gaa agg atc atg gga gac aaa gtg gct tcc gaa gct ctt atg 914Val Leu Glu Arg Ile Met Gly Asp Lys Val Ala Ser Glu Ala Leu Met 290 295 300aag tac cac atc tta aat act ctc cag tgt tct gag tct att atg gga 962Lys Tyr His Ile Leu Asn Thr Leu Gln Cys Ser Glu Ser Ile Met Gly 305 310 315gga gca gtc ttt gag acg ctg gaa gga aat aca att gag ata gga tgt 1010Gly Ala Val Phe Glu Thr Leu Glu Gly Asn Thr Ile Glu Ile Gly Cys 320 325 330gac ggt gac agt ata aca gta aat gga atc aaa atg gtg aac aaa aag 1058Asp Gly Asp Ser Ile Thr Val Asn Gly Ile Lys Met Val Asn Lys Lys 335 340 345gat att gtg aca aat aat ggt gtg atc cat ttg att gat cag gtc cta 1106Asp Ile Val Thr Asn Asn Gly Val Ile His Leu Ile Asp Gln Val Leu350 355 360 365att cct gat tct gcc aaa caa gtt att gag ctg gct gga aaa cag caa 1154Ile Pro Asp Ser Ala Lys Gln Val Ile Glu Leu Ala Gly Lys Gln Gln 370 375 380acc acc ttc acg gat ctt gtg gcc caa tta ggc ttg gca tct gct ctg 1202Thr Thr Phe Thr Asp Leu Val Ala Gln Leu Gly Leu Ala Ser Ala Leu 385 390 395agg cca gat gga gaa tac act ttg ctg gca cct gtg aat aat gca ttt 1250Arg Pro Asp Gly Glu Tyr Thr Leu Leu Ala Pro Val Asn Asn Ala Phe 400 405 410tct gat gat act ctc agc atg gat cag cgc ctc ctt aaa tta att ctg 1298Ser Asp Asp Thr Leu Ser Met Asp Gln Arg Leu Leu Lys Leu Ile Leu 415 420 425cag aat cac ata ttg aaa gta aaa gtt ggc ctt aat gag ctt tac aac 1346Gln Asn His Ile Leu Lys Val Lys Val Gly Leu Asn Glu Leu Tyr Asn430 435 440 445ggg caa ata ctg gaa acc atc gga ggc aaa cag ctc aga gtc ttc gta 1394Gly Gln Ile Leu Glu Thr Ile Gly Gly Lys Gln Leu Arg Val Phe Val 450 455 460tat cgt aca gct gtc tgc att gaa aat tca tgc atg gag aaa ggg agt 1442Tyr Arg Thr Ala Val Cys Ile Glu Asn Ser Cys Met Glu Lys Gly Ser 465 470 475aag caa ggg aga aac ggt gcg att cac ata ttc cgc gag atc atc aag 1490Lys Gln Gly Arg Asn Gly Ala Ile His Ile Phe Arg Glu Ile Ile Lys 480 485 490cca gca gag aaa tcc ctc cat gaa aag tta aaa caa gat aag cgc ttt 1538Pro Ala Glu Lys Ser Leu His Glu Lys Leu Lys Gln Asp Lys Arg Phe 495 500 505agc acc ttc ctc agc cta ctt gaa gct gca gac ttg aaa gag ctc ctg 1586Ser Thr Phe Leu Ser Leu Leu Glu Ala Ala Asp Leu Lys Glu Leu Leu510 515 520 525aca caa cct gga gac tgg aca tta ttt gtg cca acc aat gat gct ttt 1634Thr Gln Pro Gly Asp Trp Thr Leu Phe Val Pro Thr Asn Asp Ala Phe 530 535 540aag gga atg act agt gaa gaa aaa gaa att ctg ata cgg gac aaa aat 1682Lys Gly Met Thr Ser Glu Glu Lys Glu Ile Leu Ile Arg Asp Lys Asn 545 550 555gct ctt caa aac atc att ctt tat cac ctg aca cca gga gtt ttc att 1730Ala Leu Gln Asn Ile Ile Leu Tyr His Leu Thr Pro Gly Val Phe Ile 560 565 570gga aaa gga ttt gaa cct ggt gtt act aac att tta aag acc aca caa 1778Gly Lys Gly Phe Glu Pro Gly Val Thr Asn Ile Leu Lys Thr Thr Gln 575 580 585gga agc aaa atc ttt ctg aaa gaa gta aat gat aca ctt ctg gtg aat 1826Gly Ser Lys Ile Phe Leu Lys Glu Val Asn Asp Thr Leu Leu Val Asn590 595 600 605gaa ttg aaa tca aaa gaa tct gac atc atg aca aca aat ggt gta att 1874Glu Leu Lys Ser Lys Glu Ser Asp Ile Met Thr Thr Asn Gly Val Ile 610 615 620cat gtt gta gat aaa ctc ctc tat cca gca gac aca cct gtt gga aat 1922His Val Val Asp Lys Leu Leu Tyr Pro Ala Asp Thr Pro Val Gly Asn 625 630 635gat caa ctg ctg gaa ata ctt aat aaa tta atc aaa tac atc caa att 1970Asp Gln Leu Leu Glu Ile Leu Asn Lys Leu Ile Lys Tyr Ile Gln Ile 640 645 650aag ttt gtt cgt ggt agc acc ttc aaa gaa atc ccc gtg act gtc tat 2018Lys Phe Val Arg Gly Ser Thr Phe Lys Glu Ile Pro Val Thr Val Tyr 655 660 665aca act aaa att ata acc aaa gtt gtg gaa cca aaa att aaa gtg att 2066Thr Thr Lys Ile Ile Thr Lys Val Val Glu Pro Lys Ile Lys Val Ile670 675 680 685gaa ggc agt ctt cag cct att atc aaa act gaa gga ccc aca cta aca 2114Glu Gly Ser Leu Gln Pro Ile Ile Lys Thr Glu Gly Pro Thr Leu Thr 690 695 700aaa gtc aaa att gaa ggt gaa cct gaa ttc aga ctg att aaa gaa ggt 2162Lys Val Lys Ile Glu Gly Glu Pro Glu Phe Arg Leu Ile Lys Glu Gly 705 710 715gaa aca ata act gaa gtg atc cat gga gag cca att att aaa aaa tac 2210Glu Thr Ile Thr Glu Val Ile His Gly Glu Pro Ile Ile Lys Lys Tyr 720 725 730acc aaa atc att gat gga gtg cct gtg gaa ata act gaa aaa gag aca 2258Thr Lys Ile Ile Asp Gly Val Pro Val Glu Ile Thr Glu Lys Glu Thr 735 740 745cga gaa gaa cga atc att aca ggt cct gaa ata aaa tac act agg att 2306Arg Glu Glu Arg Ile Ile Thr Gly Pro Glu Ile Lys Tyr Thr Arg Ile750 755 760 765tct act gga ggt gga gaa aca gaa gaa act ctg aag aaa ttg tta caa 2354Ser Thr Gly Gly Gly Glu Thr Glu Glu Thr Leu Lys Lys Leu Leu Gln 770 775 780gaa gac aca ccc gtg agg aag ttg caa gcc aac aaa aaa gtt caa gga 2402Glu Asp Thr Pro Val Arg Lys Leu Gln Ala Asn Lys Lys Val Gln Gly 785 790 795tct aga aga cga tta agg gaa ggt cgt tct cag tga aaatccaaaa 2448Ser Arg Arg Arg Leu Arg Glu Gly Arg Ser Gln * 800 805accagaaaaa aatgtttata caaccctaag tcaataacct gaccttagaa aattgtgaga 2508gccaagttga cttcaggaac tgaaacatca gcacaaagaa gcaatcatca aataattctg 2568aacacaaatt taatattttt ttttctgaat gagaaacatg agggaaattg tggagttagc 2628ctcctgtggt aaaggaattg aagaaaatat aacaccttac accctttttc atcttgacat 2688taaaagttct ggctaacttt ggaatccatt agagaaaaat ccttgtcacc agattcatta 2748caattcaaat cgaagagttg tgaactgtta tcccattgaa aagaccgagc cttgtatgta 2808tgttatggat acataaaatg cacgcaagcc attatctctc catgggaagc taagttataa 2868aaataggtgc ttggtgtaca aaacttttta tatcaaaagg ctttgcacat ttctatatga 2928gtgggtttac tggtaaatta tgttattttt tacaactaat tttgtactct cagaatgttt 2988gtcatatgct tcttgcaatg catatttttt aatctcaaac gtttcaataa aaccattttt 3048cagatataaa gagaattact tcaaattgag taattcagaa aaactcaaga tttaagttaa 3108aaagtggttt ggacttggga a 312938808PRThuman 38Met Ile Pro Phe Leu Pro Met Phe Ser Leu Leu Leu Leu Leu Ile Val1 5 10 15Asn Pro Ile Asn Ala Asn Asn His Tyr Asp Lys Ile Leu Ala His Ser 20 25 30Arg Ile Arg Gly Arg Asp Gln Gly Pro Asn Val Cys Ala Leu Gln Gln 35 40 45Ile Leu Gly Thr Lys Lys Lys Tyr Phe Ser Thr Cys Lys Asn Trp Tyr 50 55 60Lys Lys Ser Ile Cys Gly Gln Lys Thr Thr Val Leu Tyr Glu Cys Cys65 70 75 80Pro Gly Tyr Met Arg Met Glu Gly Met Lys Gly Cys Pro Ala Val Leu 85 90 95Pro Ile Asp His Val Tyr Gly Thr Leu Gly Ile Val Gly Ala Thr Thr 100 105 110Thr Gln Arg Tyr Ser Asp Ala Ser Lys Leu Arg Glu Glu Ile Glu Gly 115 120 125Lys Gly Ser Phe Thr Tyr Phe Ala Pro Ser Asn Glu Ala Trp Asp Asn 130 135 140Leu Asp Ser Asp Ile Arg Arg Gly Leu Glu Ser Asn Val Asn Val Glu145 150 155 160Leu Leu Asn Ala Leu His Ser His Met Ile Asn Lys Arg Met Leu Thr 165 170 175Lys Asp Leu Lys Asn Gly Met Ile Ile Pro Ser Met Tyr Asn Asn Leu 180 185 190Gly Leu Phe Ile Asn His Tyr Pro Asn Gly Val Val Thr Val Asn Cys 195 200 205Ala Arg Ile Ile His Gly Asn Gln Ile Ala Thr Asn Gly Val Val His 210 215 220Val Ile Asp Arg Val Leu Thr Gln Ile Gly Thr Ser Ile Gln Asp Phe225 230 235 240Ile Glu Ala Glu Asp Asp Leu Ser Ser Phe Arg Ala Ala Ala Ile Thr 245 250 255Ser Asp Ile Leu Glu Ala Leu Gly Arg Asp Gly His Phe Thr Leu Phe 260 265 270Ala Pro Thr Asn Glu Ala Phe Glu Lys Leu Pro Arg Gly Val Leu Glu 275 280 285Arg Ile Met Gly Asp Lys Val Ala Ser Glu Ala Leu Met Lys Tyr His 290 295 300Ile Leu Asn Thr Leu Gln Cys Ser Glu Ser Ile Met Gly Gly Ala Val305 310 315 320Phe Glu Thr Leu Glu Gly Asn Thr Ile Glu Ile Gly Cys Asp Gly Asp 325 330 335Ser Ile Thr Val Asn Gly Ile Lys Met Val Asn Lys Lys Asp Ile Val 340 345 350Thr Asn Asn Gly Val Ile His Leu Ile Asp Gln Val Leu Ile Pro Asp 355 360 365Ser Ala Lys Gln Val Ile Glu Leu Ala Gly Lys Gln Gln Thr Thr Phe 370 375 380Thr Asp Leu Val Ala Gln Leu Gly Leu Ala Ser Ala Leu Arg Pro Asp385 390 395 400Gly Glu Tyr Thr Leu Leu Ala Pro Val Asn Asn Ala Phe Ser Asp Asp 405 410 415Thr Leu Ser Met Asp Gln Arg Leu Leu Lys Leu Ile Leu Gln Asn His 420 425 430Ile Leu Lys Val Lys Val Gly Leu Asn Glu Leu Tyr Asn Gly Gln Ile 435 440 445Leu Glu Thr Ile Gly Gly Lys Gln Leu Arg Val Phe Val Tyr Arg Thr 450 455 460Ala Val Cys Ile Glu Asn Ser Cys Met Glu Lys Gly Ser Lys Gln Gly465 470 475 480Arg Asn Gly Ala Ile His Ile Phe Arg Glu Ile Ile Lys Pro Ala Glu 485 490 495Lys Ser Leu His Glu Lys Leu Lys Gln Asp Lys Arg Phe Ser Thr Phe 500 505 510Leu Ser Leu Leu Glu Ala Ala Asp Leu Lys Glu Leu Leu Thr Gln Pro 515 520 525Gly Asp Trp Thr Leu Phe Val Pro Thr Asn Asp Ala Phe Lys Gly Met 530 535 540Thr Ser Glu Glu Lys Glu Ile Leu Ile Arg Asp Lys Asn Ala Leu Gln545 550 555 560Asn Ile Ile Leu Tyr His Leu Thr Pro Gly Val Phe Ile Gly Lys Gly 565 570 575Phe Glu Pro Gly Val Thr Asn Ile Leu Lys Thr Thr Gln Gly Ser Lys 580 585 590Ile Phe Leu Lys Glu Val Asn Asp Thr Leu Leu Val Asn Glu Leu Lys 595 600 605Ser Lys Glu Ser Asp Ile Met Thr Thr Asn Gly Val Ile His Val Val 610 615 620Asp Lys Leu Leu Tyr Pro Ala Asp Thr Pro Val Gly Asn Asp Gln Leu625 630 635 640Leu Glu Ile Leu Asn Lys Leu Ile Lys Tyr Ile Gln Ile Lys Phe Val 645 650 655Arg Gly Ser Thr Phe Lys Glu Ile Pro Val Thr Val Tyr Thr Thr Lys 660 665 670Ile Ile Thr Lys Val Val Glu Pro Lys Ile Lys Val Ile Glu Gly Ser 675 680 685Leu Gln Pro Ile Ile Lys Thr Glu Gly Pro Thr Leu Thr Lys Val Lys 690 695 700Ile Glu Gly Glu Pro Glu Phe Arg Leu Ile Lys Glu Gly Glu Thr Ile705 710 715 720Thr Glu Val Ile His Gly Glu Pro Ile Ile Lys Lys Tyr Thr Lys Ile 725 730 735Ile Asp Gly Val Pro Val Glu Ile Thr Glu Lys Glu Thr Arg Glu Glu 740

745 750Arg Ile Ile Thr Gly Pro Glu Ile Lys Tyr Thr Arg Ile Ser Thr Gly 755 760 765Gly Gly Glu Thr Glu Glu Thr Leu Lys Lys Leu Leu Gln Glu Asp Thr 770 775 780Pro Val Arg Lys Leu Gln Ala Asn Lys Lys Val Gln Gly Ser Arg Arg785 790 795 800Arg Leu Arg Glu Gly Arg Ser Gln 805393132DNAhumanCDS(12)...(2441) 39agagactcaa g atg att ccc ttt tta ccc atg ttt tct cta cta ttg ctg 50 Met Ile Pro Phe Leu Pro Met Phe Ser Leu Leu Leu Leu 1 5 10ctt att gtt aac cct ata aac gcc aac aat cat tat gac aag atc ttg 98Leu Ile Val Asn Pro Ile Asn Ala Asn Asn His Tyr Asp Lys Ile Leu 15 20 25gct cat agt cgt atc agg ggt cgg gac caa ggc cca aat gtc tgt gcc 146Ala His Ser Arg Ile Arg Gly Arg Asp Gln Gly Pro Asn Val Cys Ala30 35 40 45ctt caa cag att ttg ggc acc aaa aag aaa tac ttc agc act tgt aag 194Leu Gln Gln Ile Leu Gly Thr Lys Lys Lys Tyr Phe Ser Thr Cys Lys 50 55 60aac tgg tat aaa aag tcc atc tgt gga cag aaa acg act gtg tta tat 242Asn Trp Tyr Lys Lys Ser Ile Cys Gly Gln Lys Thr Thr Val Leu Tyr 65 70 75gaa tgt tgc cct ggt tat atg aga atg gaa gga atg aaa ggc tgc cca 290Glu Cys Cys Pro Gly Tyr Met Arg Met Glu Gly Met Lys Gly Cys Pro 80 85 90gca gtt ttg ccc att gac cat gtt tat ggc act ctg ggc atc gtg gga 338Ala Val Leu Pro Ile Asp His Val Tyr Gly Thr Leu Gly Ile Val Gly 95 100 105gcc acc aca acg cag cgc tat tct gac gcc tca aaa ctg agg gag gag 386Ala Thr Thr Thr Gln Arg Tyr Ser Asp Ala Ser Lys Leu Arg Glu Glu110 115 120 125atc gag gga aag gga tcc ttc act tac ttt gca ccg agt aat gag gct 434Ile Glu Gly Lys Gly Ser Phe Thr Tyr Phe Ala Pro Ser Asn Glu Ala 130 135 140tgg gac aac ttg gat tct gat atc cgt aga ggt ttg gag agc aac gtg 482Trp Asp Asn Leu Asp Ser Asp Ile Arg Arg Gly Leu Glu Ser Asn Val 145 150 155aat gtt gaa tta ctg aat gct tta cat agt cac atg att aat aag aga 530Asn Val Glu Leu Leu Asn Ala Leu His Ser His Met Ile Asn Lys Arg 160 165 170atg ttg acc aag gac tta aaa aat ggc atg att att cct tca atg tat 578Met Leu Thr Lys Asp Leu Lys Asn Gly Met Ile Ile Pro Ser Met Tyr 175 180 185aac aat ttg ggg ctt ttc att aac cat tat cct aat ggg gtt gtc act 626Asn Asn Leu Gly Leu Phe Ile Asn His Tyr Pro Asn Gly Val Val Thr190 195 200 205gtt aat tgt gct cga atc atc cat ggg aac cag att gca aca aat ggt 674Val Asn Cys Ala Arg Ile Ile His Gly Asn Gln Ile Ala Thr Asn Gly 210 215 220gtt gtc cat gtc att gac cgt gtg ctt aca caa att ggt acc tca att 722Val Val His Val Ile Asp Arg Val Leu Thr Gln Ile Gly Thr Ser Ile 225 230 235caa gac ttc att gaa gca gaa gat gac ctt tca tct ttt aga gca gct 770Gln Asp Phe Ile Glu Ala Glu Asp Asp Leu Ser Ser Phe Arg Ala Ala 240 245 250gcc atc aca tcg gac ata ttg gag gcc ctt gga aga gac ggt cac ttc 818Ala Ile Thr Ser Asp Ile Leu Glu Ala Leu Gly Arg Asp Gly His Phe 255 260 265aca ctc ttt gct ccc acc aat gag gct ttt gag aaa ctt cca cga ggt 866Thr Leu Phe Ala Pro Thr Asn Glu Ala Phe Glu Lys Leu Pro Arg Gly270 275 280 285gtc cta gaa agg atc atg gga gac aaa gtg gct tcc gaa gct ctt atg 914Val Leu Glu Arg Ile Met Gly Asp Lys Val Ala Ser Glu Ala Leu Met 290 295 300aag tac cac atc tta aat act ctc cag tgt tct gag tct att atg gga 962Lys Tyr His Ile Leu Asn Thr Leu Gln Cys Ser Glu Ser Ile Met Gly 305 310 315gga gca gtc ttt gag acg ctg gaa gga aat aca att gag ata gga tgt 1010Gly Ala Val Phe Glu Thr Leu Glu Gly Asn Thr Ile Glu Ile Gly Cys 320 325 330gac ggt gac agt ata aca gta aat gga atc aaa atg gtg aac aaa aag 1058Asp Gly Asp Ser Ile Thr Val Asn Gly Ile Lys Met Val Asn Lys Lys 335 340 345gat att gtg aca aat aat ggt gtg atc cat ttg att gat cag gtc cta 1106Asp Ile Val Thr Asn Asn Gly Val Ile His Leu Ile Asp Gln Val Leu350 355 360 365att cct gat tct gcc aaa caa gtt att gag ctg gct gga aaa cag caa 1154Ile Pro Asp Ser Ala Lys Gln Val Ile Glu Leu Ala Gly Lys Gln Gln 370 375 380acc acc ttc acg gat ctt gtg gcc caa tta ggc ttg gca tct gct ctg 1202Thr Thr Phe Thr Asp Leu Val Ala Gln Leu Gly Leu Ala Ser Ala Leu 385 390 395agg cca gat gga gaa tac act ttg ctg gca cct gtg aat aat gca ttt 1250Arg Pro Asp Gly Glu Tyr Thr Leu Leu Ala Pro Val Asn Asn Ala Phe 400 405 410tct gat gat act ctc agc atg gat cag cgc ctc ctt aaa tta att ctg 1298Ser Asp Asp Thr Leu Ser Met Asp Gln Arg Leu Leu Lys Leu Ile Leu 415 420 425cag aat cac ata ttg aaa gta aaa gtt ggc ctt aat gag ctt tac aac 1346Gln Asn His Ile Leu Lys Val Lys Val Gly Leu Asn Glu Leu Tyr Asn430 435 440 445ggg caa ata ctg gaa acc atc gga ggc aaa cag ctc aga gtc ttc gta 1394Gly Gln Ile Leu Glu Thr Ile Gly Gly Lys Gln Leu Arg Val Phe Val 450 455 460tat cgt aca gct gtc tgc att gaa aat tca tgc atg gag aaa ggg agt 1442Tyr Arg Thr Ala Val Cys Ile Glu Asn Ser Cys Met Glu Lys Gly Ser 465 470 475aag caa ggg aga aac ggt gcg att cac ata ttc cgc gag atc atc aag 1490Lys Gln Gly Arg Asn Gly Ala Ile His Ile Phe Arg Glu Ile Ile Lys 480 485 490cca gca gag aaa tcc ctc cat gaa aag tta aaa caa gat aag cgc ttt 1538Pro Ala Glu Lys Ser Leu His Glu Lys Leu Lys Gln Asp Lys Arg Phe 495 500 505agc acc ttc ctc agc cta ctt gaa gct gca gac ttg aaa gag ctc ctg 1586Ser Thr Phe Leu Ser Leu Leu Glu Ala Ala Asp Leu Lys Glu Leu Leu510 515 520 525aca caa cct gga gac tgg aca tta ttt gtg cca acc aat gat gct ttt 1634Thr Gln Pro Gly Asp Trp Thr Leu Phe Val Pro Thr Asn Asp Ala Phe 530 535 540aag gga atg act agt gaa gaa aaa gaa att ctg ata cgg gac aaa aat 1682Lys Gly Met Thr Ser Glu Glu Lys Glu Ile Leu Ile Arg Asp Lys Asn 545 550 555gct ctt caa aac atc att ctt tat cac ctg aca cca gga gtt ttc att 1730Ala Leu Gln Asn Ile Ile Leu Tyr His Leu Thr Pro Gly Val Phe Ile 560 565 570gga aaa gga ttt gaa cct ggt gtt act aac att tta aag acc aca caa 1778Gly Lys Gly Phe Glu Pro Gly Val Thr Asn Ile Leu Lys Thr Thr Gln 575 580 585gga agc aaa atc ttt ctg aaa gaa gta aat gat aca ctt ctg gtg aat 1826Gly Ser Lys Ile Phe Leu Lys Glu Val Asn Asp Thr Leu Leu Val Asn590 595 600 605gaa ttg aaa tca aaa gaa tct gac atc atg aca aca aat ggt gta att 1874Glu Leu Lys Ser Lys Glu Ser Asp Ile Met Thr Thr Asn Gly Val Ile 610 615 620cat gtt gta gat aaa ctc ctc tat cca gca gac aca cct gtt gga aat 1922His Val Val Asp Lys Leu Leu Tyr Pro Ala Asp Thr Pro Val Gly Asn 625 630 635gat caa ctg ctg gaa ata ctt aat aaa tta atc aaa tac atc caa att 1970Asp Gln Leu Leu Glu Ile Leu Asn Lys Leu Ile Lys Tyr Ile Gln Ile 640 645 650aag ttt gtt cgt ggt agc acc ttc aaa gaa atc ccc gtg act gtc tat 2018Lys Phe Val Arg Gly Ser Thr Phe Lys Glu Ile Pro Val Thr Val Tyr 655 660 665aga ccc aca cta aca aaa gtc aaa att gaa ggt gaa cct gaa ttc aga 2066Arg Pro Thr Leu Thr Lys Val Lys Ile Glu Gly Glu Pro Glu Phe Arg670 675 680 685ctg att aaa gaa ggt gaa aca ata act gaa gtg atc cat gga gag cca 2114Leu Ile Lys Glu Gly Glu Thr Ile Thr Glu Val Ile His Gly Glu Pro 690 695 700att att aaa aaa tac acc aaa atc att gat gga gtg cct gtg gaa ata 2162Ile Ile Lys Lys Tyr Thr Lys Ile Ile Asp Gly Val Pro Val Glu Ile 705 710 715act gaa aaa gag aca cga gaa gaa cga atc att aca ggt cct gaa ata 2210Thr Glu Lys Glu Thr Arg Glu Glu Arg Ile Ile Thr Gly Pro Glu Ile 720 725 730aaa tac act agg att tct act gga ggt gga gaa aca gaa gaa act ctg 2258Lys Tyr Thr Arg Ile Ser Thr Gly Gly Gly Glu Thr Glu Glu Thr Leu 735 740 745aag aaa ttg tta caa gaa gag gtc acc aag gtc acc aaa ttc att gaa 2306Lys Lys Leu Leu Gln Glu Glu Val Thr Lys Val Thr Lys Phe Ile Glu750 755 760 765ggt ggt gat ggt cat tta ttt gaa gat gaa gaa att aaa aga ctg ctt 2354Gly Gly Asp Gly His Leu Phe Glu Asp Glu Glu Ile Lys Arg Leu Leu 770 775 780cag gga gac aca ccc gtg agg aag ttg caa gcc aac aaa aaa gtt caa 2402Gln Gly Asp Thr Pro Val Arg Lys Leu Gln Ala Asn Lys Lys Val Gln 785 790 795gga tct aga aga cga tta agg gaa ggt cgt tct cag tga aaatccaaaa 2451Gly Ser Arg Arg Arg Leu Arg Glu Gly Arg Ser Gln * 800 805accagaaaaa aatgtttata caaccctaag tcaataacct gaccttagaa aattgtgaga 2511gccaagttga cttcaggaac tgaaacatca gcacaaagaa gcaatcatca aataattctg 2571aacacaaatt taatattttt ttttctgaat gagaaacatg agggaaattg tggagttagc 2631ctcctgtggt aaaggaattg aagaaaatat aacaccttac accctttttc atcttgacat 2691taaaagttct ggctaacttt ggaatccatt agagaaaaat ccttgtcacc agattcatta 2751caattcaaat cgaagagttg tgaactgtta tcccattgaa aagaccgagc cttgtatgta 2811tgttatggat acataaaatg cacgcaagcc attatctctc catgggaagc taagttataa 2871aaataggtgc ttggtgtaca aaacttttta tatcaaaagg ctttgcacat ttctatatga 2931gtgggtttac tggtaaatta tgttattttt tacaactaat tttgtactct cagaatgttt 2991gtcatatgct tcttgcaatg catatttttt aatctcaaac gtttcaataa aaccattttt 3051cagatataaa gagaattact tcaaattgag taattcagaa aaactcaaga tttaagttaa 3111aaagtggttt ggacttggga a 313240809PRThuman 40Met Ile Pro Phe Leu Pro Met Phe Ser Leu Leu Leu Leu Leu Ile Val1 5 10 15Asn Pro Ile Asn Ala Asn Asn His Tyr Asp Lys Ile Leu Ala His Ser 20 25 30Arg Ile Arg Gly Arg Asp Gln Gly Pro Asn Val Cys Ala Leu Gln Gln 35 40 45Ile Leu Gly Thr Lys Lys Lys Tyr Phe Ser Thr Cys Lys Asn Trp Tyr 50 55 60Lys Lys Ser Ile Cys Gly Gln Lys Thr Thr Val Leu Tyr Glu Cys Cys65 70 75 80Pro Gly Tyr Met Arg Met Glu Gly Met Lys Gly Cys Pro Ala Val Leu 85 90 95Pro Ile Asp His Val Tyr Gly Thr Leu Gly Ile Val Gly Ala Thr Thr 100 105 110Thr Gln Arg Tyr Ser Asp Ala Ser Lys Leu Arg Glu Glu Ile Glu Gly 115 120 125Lys Gly Ser Phe Thr Tyr Phe Ala Pro Ser Asn Glu Ala Trp Asp Asn 130 135 140Leu Asp Ser Asp Ile Arg Arg Gly Leu Glu Ser Asn Val Asn Val Glu145 150 155 160Leu Leu Asn Ala Leu His Ser His Met Ile Asn Lys Arg Met Leu Thr 165 170 175Lys Asp Leu Lys Asn Gly Met Ile Ile Pro Ser Met Tyr Asn Asn Leu 180 185 190Gly Leu Phe Ile Asn His Tyr Pro Asn Gly Val Val Thr Val Asn Cys 195 200 205Ala Arg Ile Ile His Gly Asn Gln Ile Ala Thr Asn Gly Val Val His 210 215 220Val Ile Asp Arg Val Leu Thr Gln Ile Gly Thr Ser Ile Gln Asp Phe225 230 235 240Ile Glu Ala Glu Asp Asp Leu Ser Ser Phe Arg Ala Ala Ala Ile Thr 245 250 255Ser Asp Ile Leu Glu Ala Leu Gly Arg Asp Gly His Phe Thr Leu Phe 260 265 270Ala Pro Thr Asn Glu Ala Phe Glu Lys Leu Pro Arg Gly Val Leu Glu 275 280 285Arg Ile Met Gly Asp Lys Val Ala Ser Glu Ala Leu Met Lys Tyr His 290 295 300Ile Leu Asn Thr Leu Gln Cys Ser Glu Ser Ile Met Gly Gly Ala Val305 310 315 320Phe Glu Thr Leu Glu Gly Asn Thr Ile Glu Ile Gly Cys Asp Gly Asp 325 330 335Ser Ile Thr Val Asn Gly Ile Lys Met Val Asn Lys Lys Asp Ile Val 340 345 350Thr Asn Asn Gly Val Ile His Leu Ile Asp Gln Val Leu Ile Pro Asp 355 360 365Ser Ala Lys Gln Val Ile Glu Leu Ala Gly Lys Gln Gln Thr Thr Phe 370 375 380Thr Asp Leu Val Ala Gln Leu Gly Leu Ala Ser Ala Leu Arg Pro Asp385 390 395 400Gly Glu Tyr Thr Leu Leu Ala Pro Val Asn Asn Ala Phe Ser Asp Asp 405 410 415Thr Leu Ser Met Asp Gln Arg Leu Leu Lys Leu Ile Leu Gln Asn His 420 425 430Ile Leu Lys Val Lys Val Gly Leu Asn Glu Leu Tyr Asn Gly Gln Ile 435 440 445Leu Glu Thr Ile Gly Gly Lys Gln Leu Arg Val Phe Val Tyr Arg Thr 450 455 460Ala Val Cys Ile Glu Asn Ser Cys Met Glu Lys Gly Ser Lys Gln Gly465 470 475 480Arg Asn Gly Ala Ile His Ile Phe Arg Glu Ile Ile Lys Pro Ala Glu 485 490 495Lys Ser Leu His Glu Lys Leu Lys Gln Asp Lys Arg Phe Ser Thr Phe 500 505 510Leu Ser Leu Leu Glu Ala Ala Asp Leu Lys Glu Leu Leu Thr Gln Pro 515 520 525Gly Asp Trp Thr Leu Phe Val Pro Thr Asn Asp Ala Phe Lys Gly Met 530 535 540Thr Ser Glu Glu Lys Glu Ile Leu Ile Arg Asp Lys Asn Ala Leu Gln545 550 555 560Asn Ile Ile Leu Tyr His Leu Thr Pro Gly Val Phe Ile Gly Lys Gly 565 570 575Phe Glu Pro Gly Val Thr Asn Ile Leu Lys Thr Thr Gln Gly Ser Lys 580 585 590Ile Phe Leu Lys Glu Val Asn Asp Thr Leu Leu Val Asn Glu Leu Lys 595 600 605Ser Lys Glu Ser Asp Ile Met Thr Thr Asn Gly Val Ile His Val Val 610 615 620Asp Lys Leu Leu Tyr Pro Ala Asp Thr Pro Val Gly Asn Asp Gln Leu625 630 635 640Leu Glu Ile Leu Asn Lys Leu Ile Lys Tyr Ile Gln Ile Lys Phe Val 645 650 655Arg Gly Ser Thr Phe Lys Glu Ile Pro Val Thr Val Tyr Arg Pro Thr 660 665 670Leu Thr Lys Val Lys Ile Glu Gly Glu Pro Glu Phe Arg Leu Ile Lys 675 680 685Glu Gly Glu Thr Ile Thr Glu Val Ile His Gly Glu Pro Ile Ile Lys 690 695 700Lys Tyr Thr Lys Ile Ile Asp Gly Val Pro Val Glu Ile Thr Glu Lys705 710 715 720Glu Thr Arg Glu Glu Arg Ile Ile Thr Gly Pro Glu Ile Lys Tyr Thr 725 730 735Arg Ile Ser Thr Gly Gly Gly Glu Thr Glu Glu Thr Leu Lys Lys Leu 740 745 750Leu Gln Glu Glu Val Thr Lys Val Thr Lys Phe Ile Glu Gly Gly Asp 755 760 765Gly His Leu Phe Glu Asp Glu Glu Ile Lys Arg Leu Leu Gln Gly Asp 770 775 780Thr Pro Val Arg Lys Leu Gln Ala Asn Lys Lys Val Gln Gly Ser Arg785 790 795 800Arg Arg Leu Arg Glu Gly Arg Ser Gln 805413048DNAhumanCDS(12)...(2357) 41agagactcaa g atg att ccc ttt tta ccc atg ttt tct cta cta ttg ctg 50 Met Ile Pro Phe Leu Pro Met Phe Ser Leu Leu Leu Leu 1 5 10ctt att gtt aac cct ata aac gcc aac aat cat tat gac aag atc ttg 98Leu Ile Val Asn Pro Ile Asn Ala Asn Asn His Tyr Asp Lys Ile Leu 15 20 25gct cat agt cgt atc agg ggt cgg gac caa ggc cca aat gtc tgt gcc 146Ala His Ser Arg Ile Arg Gly Arg Asp Gln Gly Pro Asn Val Cys Ala30 35 40 45ctt caa cag att ttg ggc acc aaa aag aaa tac ttc agc act tgt aag 194Leu Gln Gln Ile Leu Gly Thr Lys Lys Lys Tyr Phe Ser Thr Cys Lys 50 55 60aac tgg tat aaa aag tcc atc tgt gga cag aaa acg act gtg tta tat 242Asn Trp Tyr Lys Lys Ser Ile Cys Gly Gln Lys Thr Thr Val Leu Tyr 65 70 75gaa tgt tgc cct ggt tat atg aga atg gaa gga atg aaa ggc tgc cca 290Glu Cys Cys Pro Gly Tyr Met Arg Met Glu Gly Met Lys Gly Cys Pro 80 85 90gca gtt ttg ccc att gac cat gtt tat ggc act ctg ggc atc gtg gga 338Ala Val Leu Pro Ile Asp His Val Tyr Gly Thr Leu Gly Ile Val Gly 95

100 105gcc acc aca acg cag cgc tat tct gac gcc tca aaa ctg agg gag gag 386Ala Thr Thr Thr Gln Arg Tyr Ser Asp Ala Ser Lys Leu Arg Glu Glu110 115 120 125atc gag gga aag gga tcc ttc act tac ttt gca ccg agt aat gag gct 434Ile Glu Gly Lys Gly Ser Phe Thr Tyr Phe Ala Pro Ser Asn Glu Ala 130 135 140tgg gac aac ttg gat tct gat atc cgt aga ggt ttg gag agc aac gtg 482Trp Asp Asn Leu Asp Ser Asp Ile Arg Arg Gly Leu Glu Ser Asn Val 145 150 155aat gtt gaa tta ctg aat gct tta cat agt cac atg att aat aag aga 530Asn Val Glu Leu Leu Asn Ala Leu His Ser His Met Ile Asn Lys Arg 160 165 170atg ttg acc aag gac tta aaa aat ggc atg att att cct tca atg tat 578Met Leu Thr Lys Asp Leu Lys Asn Gly Met Ile Ile Pro Ser Met Tyr 175 180 185aac aat ttg ggg ctt ttc att aac cat tat cct aat ggg gtt gtc act 626Asn Asn Leu Gly Leu Phe Ile Asn His Tyr Pro Asn Gly Val Val Thr190 195 200 205gtt aat tgt gct cga atc atc cat ggg aac cag att gca aca aat ggt 674Val Asn Cys Ala Arg Ile Ile His Gly Asn Gln Ile Ala Thr Asn Gly 210 215 220gtt gtc cat gtc att gac cgt gtg ctt aca caa att ggt acc tca att 722Val Val His Val Ile Asp Arg Val Leu Thr Gln Ile Gly Thr Ser Ile 225 230 235caa gac ttc att gaa gca gaa gat gac ctt tca tct ttt aga gca gct 770Gln Asp Phe Ile Glu Ala Glu Asp Asp Leu Ser Ser Phe Arg Ala Ala 240 245 250gcc atc aca tcg gac ata ttg gag gcc ctt gga aga gac ggt cac ttc 818Ala Ile Thr Ser Asp Ile Leu Glu Ala Leu Gly Arg Asp Gly His Phe 255 260 265aca ctc ttt gct ccc acc aat gag gct ttt gag aaa ctt cca cga ggt 866Thr Leu Phe Ala Pro Thr Asn Glu Ala Phe Glu Lys Leu Pro Arg Gly270 275 280 285gtc cta gaa agg atc atg gga gac aaa gtg gct tcc gaa gct ctt atg 914Val Leu Glu Arg Ile Met Gly Asp Lys Val Ala Ser Glu Ala Leu Met 290 295 300aag tac cac atc tta aat act ctc cag tgt tct gag tct att atg gga 962Lys Tyr His Ile Leu Asn Thr Leu Gln Cys Ser Glu Ser Ile Met Gly 305 310 315gga gca gtc ttt gag acg ctg gaa gga aat aca att gag ata gga tgt 1010Gly Ala Val Phe Glu Thr Leu Glu Gly Asn Thr Ile Glu Ile Gly Cys 320 325 330gac ggt gac agt ata aca gta aat gga atc aaa atg gtg aac aaa aag 1058Asp Gly Asp Ser Ile Thr Val Asn Gly Ile Lys Met Val Asn Lys Lys 335 340 345gat att gtg aca aat aat ggt gtg atc cat ttg att gat cag gtc cta 1106Asp Ile Val Thr Asn Asn Gly Val Ile His Leu Ile Asp Gln Val Leu350 355 360 365att cct gat tct gcc aaa caa gtt att gag ctg gct gga aaa cag caa 1154Ile Pro Asp Ser Ala Lys Gln Val Ile Glu Leu Ala Gly Lys Gln Gln 370 375 380acc acc ttc acg gat ctt gtg gcc caa tta ggc ttg gca tct gct ctg 1202Thr Thr Phe Thr Asp Leu Val Ala Gln Leu Gly Leu Ala Ser Ala Leu 385 390 395agg cca gat gga gaa tac act ttg ctg gca cct gtg aat aat gca ttt 1250Arg Pro Asp Gly Glu Tyr Thr Leu Leu Ala Pro Val Asn Asn Ala Phe 400 405 410tct gat gat act ctc agc atg gat cag cgc ctc ctt aaa tta att ctg 1298Ser Asp Asp Thr Leu Ser Met Asp Gln Arg Leu Leu Lys Leu Ile Leu 415 420 425cag aat cac ata ttg aaa gta aaa gtt ggc ctt aat gag ctt tac aac 1346Gln Asn His Ile Leu Lys Val Lys Val Gly Leu Asn Glu Leu Tyr Asn430 435 440 445ggg caa ata ctg gaa acc atc gga ggc aaa cag ctc aga gtc ttc gta 1394Gly Gln Ile Leu Glu Thr Ile Gly Gly Lys Gln Leu Arg Val Phe Val 450 455 460tat cgt aca gct gtc tgc att gaa aat tca tgc atg gag aaa ggg agt 1442Tyr Arg Thr Ala Val Cys Ile Glu Asn Ser Cys Met Glu Lys Gly Ser 465 470 475aag caa ggg aga aac ggt gcg att cac ata ttc cgc gag atc atc aag 1490Lys Gln Gly Arg Asn Gly Ala Ile His Ile Phe Arg Glu Ile Ile Lys 480 485 490cca gca gag aaa tcc ctc cat gaa aag tta aaa caa gat aag cgc ttt 1538Pro Ala Glu Lys Ser Leu His Glu Lys Leu Lys Gln Asp Lys Arg Phe 495 500 505agc acc ttc ctc agc cta ctt gaa gct gca gac ttg aaa gag ctc ctg 1586Ser Thr Phe Leu Ser Leu Leu Glu Ala Ala Asp Leu Lys Glu Leu Leu510 515 520 525aca caa cct gga gac tgg aca tta ttt gtg cca acc aat gat gct ttt 1634Thr Gln Pro Gly Asp Trp Thr Leu Phe Val Pro Thr Asn Asp Ala Phe 530 535 540aag gga atg act agt gaa gaa aaa gaa att ctg ata cgg gac aaa aat 1682Lys Gly Met Thr Ser Glu Glu Lys Glu Ile Leu Ile Arg Asp Lys Asn 545 550 555gct ctt caa aac atc att ctt tat cac ctg aca cca gga gtt ttc att 1730Ala Leu Gln Asn Ile Ile Leu Tyr His Leu Thr Pro Gly Val Phe Ile 560 565 570gga aaa gga ttt gaa cct ggt gtt act aac att tta aag acc aca caa 1778Gly Lys Gly Phe Glu Pro Gly Val Thr Asn Ile Leu Lys Thr Thr Gln 575 580 585gga agc aaa atc ttt ctg aaa gaa gta aat gat aca ctt ctg gtg aat 1826Gly Ser Lys Ile Phe Leu Lys Glu Val Asn Asp Thr Leu Leu Val Asn 590 595 600 605gaa ttg aaa tca aaa gaa tct gac atc atg aca aca aat ggt gta att 1874Glu Leu Lys Ser Lys Glu Ser Asp Ile Met Thr Thr Asn Gly Val Ile 610 615 620cat gtt gta gat aaa ctc ctc tat cca gca gac aca cct gtt gga aat 1922His Val Val Asp Lys Leu Leu Tyr Pro Ala Asp Thr Pro Val Gly Asn 625 630 635gat caa ctg ctg gaa ata ctt aat aaa tta atc aaa tac atc caa att 1970Asp Gln Leu Leu Glu Ile Leu Asn Lys Leu Ile Lys Tyr Ile Gln Ile 640 645 650aag ttt gtt cgt ggt agc acc ttc aaa gaa atc ccc gtg act gtc tat 2018Lys Phe Val Arg Gly Ser Thr Phe Lys Glu Ile Pro Val Thr Val Tyr 655 660 665aga ccc aca cta aca aaa gtc aaa att gaa ggt gaa cct gaa ttc aga 2066Arg Pro Thr Leu Thr Lys Val Lys Ile Glu Gly Glu Pro Glu Phe Arg670 675 680 685ctg att aaa gaa ggt gaa aca ata act gaa gtg atc cat gga gag cca 2114Leu Ile Lys Glu Gly Glu Thr Ile Thr Glu Val Ile His Gly Glu Pro 690 695 700att att aaa aaa tac acc aaa atc att gat gga gtg cct gtg gaa ata 2162Ile Ile Lys Lys Tyr Thr Lys Ile Ile Asp Gly Val Pro Val Glu Ile 705 710 715act gaa aaa gag aca cga gaa gaa cga atc att aca ggt cct gaa ata 2210Thr Glu Lys Glu Thr Arg Glu Glu Arg Ile Ile Thr Gly Pro Glu Ile 720 725 730aaa tac act agg att tct act gga ggt gga gaa aca gaa gaa act ctg 2258Lys Tyr Thr Arg Ile Ser Thr Gly Gly Gly Glu Thr Glu Glu Thr Leu 735 740 745aag aaa ttg tta caa gaa gac aca ccc gtg agg aag ttg caa gcc aac 2306Lys Lys Leu Leu Gln Glu Asp Thr Pro Val Arg Lys Leu Gln Ala Asn750 755 760 765aaa aaa gtt caa ggt tct aga aga cga tta agg gaa ggt cgt tct cag 2354Lys Lys Val Gln Gly Ser Arg Arg Arg Leu Arg Glu Gly Arg Ser Gln 770 775 780tga aaatccaaaa accagaaaaa aatgtttata caaccctaag tcaataacct 2407*gaccttagaa aattgtgaga gccaagttga cttcaggaac tgaaacatca gcacaaagaa 2467gcaatcatca aataattctg aacacaaatt taatattttt ttttctgaat gagaaacatg 2527agggaaattg tggagttagc ctcctgtggt aaaggaattg aagaaaatat aacaccttac 2587accctttttc atcttgacat taaaagttct ggctaacttt ggaatccatt agagaaaaat 2647ccttgtcacc agattcatta caattcaaat cgaagagttg tgaactgtta tcccattgaa 2707aagaccgagc cttgtatgta tgttatggat acataaaatg cacgcaagcc attatctctc 2767catgggaagc taagttataa aaataggtgc ttggtgtaca aaacttttta tatcaaaagg 2827ctttgcacat ttctatatga gtgggtttac tggtaaatta tgttattttt tacaactaat 2887tttgtactct cagaatgttt gtcatatgct tcttgcaatg catatttttt aatctcaaac 2947gtttcaataa aaccattttt cagatataaa gagaattact tcaaattgag taattcagaa 3007aaactcaaga tttaagttaa aaagtggttt ggacttggga a 304842781PRThuman 42Met Ile Pro Phe Leu Pro Met Phe Ser Leu Leu Leu Leu Leu Ile Val1 5 10 15Asn Pro Ile Asn Ala Asn Asn His Tyr Asp Lys Ile Leu Ala His Ser 20 25 30Arg Ile Arg Gly Arg Asp Gln Gly Pro Asn Val Cys Ala Leu Gln Gln 35 40 45Ile Leu Gly Thr Lys Lys Lys Tyr Phe Ser Thr Cys Lys Asn Trp Tyr 50 55 60Lys Lys Ser Ile Cys Gly Gln Lys Thr Thr Val Leu Tyr Glu Cys Cys65 70 75 80Pro Gly Tyr Met Arg Met Glu Gly Met Lys Gly Cys Pro Ala Val Leu 85 90 95Pro Ile Asp His Val Tyr Gly Thr Leu Gly Ile Val Gly Ala Thr Thr 100 105 110Thr Gln Arg Tyr Ser Asp Ala Ser Lys Leu Arg Glu Glu Ile Glu Gly 115 120 125Lys Gly Ser Phe Thr Tyr Phe Ala Pro Ser Asn Glu Ala Trp Asp Asn 130 135 140Leu Asp Ser Asp Ile Arg Arg Gly Leu Glu Ser Asn Val Asn Val Glu145 150 155 160Leu Leu Asn Ala Leu His Ser His Met Ile Asn Lys Arg Met Leu Thr 165 170 175Lys Asp Leu Lys Asn Gly Met Ile Ile Pro Ser Met Tyr Asn Asn Leu 180 185 190Gly Leu Phe Ile Asn His Tyr Pro Asn Gly Val Val Thr Val Asn Cys 195 200 205Ala Arg Ile Ile His Gly Asn Gln Ile Ala Thr Asn Gly Val Val His 210 215 220Val Ile Asp Arg Val Leu Thr Gln Ile Gly Thr Ser Ile Gln Asp Phe225 230 235 240Ile Glu Ala Glu Asp Asp Leu Ser Ser Phe Arg Ala Ala Ala Ile Thr 245 250 255Ser Asp Ile Leu Glu Ala Leu Gly Arg Asp Gly His Phe Thr Leu Phe 260 265 270Ala Pro Thr Asn Glu Ala Phe Glu Lys Leu Pro Arg Gly Val Leu Glu 275 280 285Arg Ile Met Gly Asp Lys Val Ala Ser Glu Ala Leu Met Lys Tyr His 290 295 300Ile Leu Asn Thr Leu Gln Cys Ser Glu Ser Ile Met Gly Gly Ala Val305 310 315 320Phe Glu Thr Leu Glu Gly Asn Thr Ile Glu Ile Gly Cys Asp Gly Asp 325 330 335Ser Ile Thr Val Asn Gly Ile Lys Met Val Asn Lys Lys Asp Ile Val 340 345 350Thr Asn Asn Gly Val Ile His Leu Ile Asp Gln Val Leu Ile Pro Asp 355 360 365Ser Ala Lys Gln Val Ile Glu Leu Ala Gly Lys Gln Gln Thr Thr Phe 370 375 380Thr Asp Leu Val Ala Gln Leu Gly Leu Ala Ser Ala Leu Arg Pro Asp385 390 395 400Gly Glu Tyr Thr Leu Leu Ala Pro Val Asn Asn Ala Phe Ser Asp Asp 405 410 415Thr Leu Ser Met Asp Gln Arg Leu Leu Lys Leu Ile Leu Gln Asn His 420 425 430Ile Leu Lys Val Lys Val Gly Leu Asn Glu Leu Tyr Asn Gly Gln Ile 435 440 445Leu Glu Thr Ile Gly Gly Lys Gln Leu Arg Val Phe Val Tyr Arg Thr 450 455 460Ala Val Cys Ile Glu Asn Ser Cys Met Glu Lys Gly Ser Lys Gln Gly465 470 475 480Arg Asn Gly Ala Ile His Ile Phe Arg Glu Ile Ile Lys Pro Ala Glu 485 490 495Lys Ser Leu His Glu Lys Leu Lys Gln Asp Lys Arg Phe Ser Thr Phe 500 505 510Leu Ser Leu Leu Glu Ala Ala Asp Leu Lys Glu Leu Leu Thr Gln Pro 515 520 525Gly Asp Trp Thr Leu Phe Val Pro Thr Asn Asp Ala Phe Lys Gly Met 530 535 540Thr Ser Glu Glu Lys Glu Ile Leu Ile Arg Asp Lys Asn Ala Leu Gln545 550 555 560Asn Ile Ile Leu Tyr His Leu Thr Pro Gly Val Phe Ile Gly Lys Gly 565 570 575Phe Glu Pro Gly Val Thr Asn Ile Leu Lys Thr Thr Gln Gly Ser Lys 580 585 590Ile Phe Leu Lys Glu Val Asn Asp Thr Leu Leu Val Asn Glu Leu Lys 595 600 605Ser Lys Glu Ser Asp Ile Met Thr Thr Asn Gly Val Ile His Val Val 610 615 620Asp Lys Leu Leu Tyr Pro Ala Asp Thr Pro Val Gly Asn Asp Gln Leu625 630 635 640Leu Glu Ile Leu Asn Lys Leu Ile Lys Tyr Ile Gln Ile Lys Phe Val 645 650 655Arg Gly Ser Thr Phe Lys Glu Ile Pro Val Thr Val Tyr Arg Pro Thr 660 665 670Leu Thr Lys Val Lys Ile Glu Gly Glu Pro Glu Phe Arg Leu Ile Lys 675 680 685Glu Gly Glu Thr Ile Thr Glu Val Ile His Gly Glu Pro Ile Ile Lys 690 695 700Lys Tyr Thr Lys Ile Ile Asp Gly Val Pro Val Glu Ile Thr Glu Lys705 710 715 720Glu Thr Arg Glu Glu Arg Ile Ile Thr Gly Pro Glu Ile Lys Tyr Thr 725 730 735Arg Ile Ser Thr Gly Gly Gly Glu Thr Glu Glu Thr Leu Lys Lys Leu 740 745 750Leu Gln Glu Asp Thr Pro Val Arg Lys Leu Gln Ala Asn Lys Lys Val 755 760 765Gln Gly Ser Arg Arg Arg Leu Arg Glu Gly Arg Ser Gln 770 775 780433042DNAhumanCDS(12)...(2351) 43agagactcaa g atg att ccc ttt tta ccc atg ttt tct cta cta ttg ctg 50 Met Ile Pro Phe Leu Pro Met Phe Ser Leu Leu Leu Leu 1 5 10ctt att gtt aac cct ata aac gcc aac aat cat tat gac aag atc ttg 98Leu Ile Val Asn Pro Ile Asn Ala Asn Asn His Tyr Asp Lys Ile Leu 15 20 25gct cat agt cgt atc agg ggt cgg gac caa ggc cca aat gtc tgt gcc 146Ala His Ser Arg Ile Arg Gly Arg Asp Gln Gly Pro Asn Val Cys Ala30 35 40 45ctt caa cag att ttg ggc acc aaa aag aaa tac ttc agc act tgt aag 194Leu Gln Gln Ile Leu Gly Thr Lys Lys Lys Tyr Phe Ser Thr Cys Lys 50 55 60aac tgg tat aaa aag tcc atc tgt gga cag aaa acg act gtg tta tat 242Asn Trp Tyr Lys Lys Ser Ile Cys Gly Gln Lys Thr Thr Val Leu Tyr 65 70 75gaa tgt tgc cct ggt tat atg aga atg gaa gga atg aaa ggc tgc cca 290Glu Cys Cys Pro Gly Tyr Met Arg Met Glu Gly Met Lys Gly Cys Pro 80 85 90gca gtt ttg ccc att gac cat gtt tat ggc act ctg ggc atc gtg gga 338Ala Val Leu Pro Ile Asp His Val Tyr Gly Thr Leu Gly Ile Val Gly 95 100 105gcc acc aca acg cag cgc tat tct gac gcc tca aaa ctg agg gag gag 386Ala Thr Thr Thr Gln Arg Tyr Ser Asp Ala Ser Lys Leu Arg Glu Glu110 115 120 125atc gag gga aag gga tcc ttc act tac ttt gca ccg agt aat gag gct 434Ile Glu Gly Lys Gly Ser Phe Thr Tyr Phe Ala Pro Ser Asn Glu Ala 130 135 140tgg gac aac ttg gat tct gat atc cgt aga ggt ttg gag agc aac gtg 482Trp Asp Asn Leu Asp Ser Asp Ile Arg Arg Gly Leu Glu Ser Asn Val 145 150 155aat gtt gaa tta ctg aat gct tta cat agt cac atg att aat aag aga 530Asn Val Glu Leu Leu Asn Ala Leu His Ser His Met Ile Asn Lys Arg 160 165 170atg ttg acc aag gac tta aaa aat ggc atg att att cct tca atg tat 578Met Leu Thr Lys Asp Leu Lys Asn Gly Met Ile Ile Pro Ser Met Tyr 175 180 185aac aat ttg ggg ctt ttc att aac cat tat cct aat ggg gtt gtc act 626Asn Asn Leu Gly Leu Phe Ile Asn His Tyr Pro Asn Gly Val Val Thr190 195 200 205gtt aat tgt gct cga atc atc cat ggg aac cag att gca aca aat ggt 674Val Asn Cys Ala Arg Ile Ile His Gly Asn Gln Ile Ala Thr Asn Gly 210 215 220gtt gtc cat gtc att gac cgt gtg ctt aca caa att ggt acc tca att 722Val Val His Val Ile Asp Arg Val Leu Thr Gln Ile Gly Thr Ser Ile 225 230 235caa gac ttc att gaa gca gaa gat gac ctt tca tct ttt aga gca gct 770Gln Asp Phe Ile Glu Ala Glu Asp Asp Leu Ser Ser Phe Arg Ala Ala 240 245 250gcc atc aca tcg gac ata ttg gag gcc ctt gga aga gac ggt cac ttc 818Ala Ile Thr Ser Asp Ile Leu Glu Ala Leu Gly Arg Asp Gly His Phe 255 260 265aca ctc ttt gct ccc acc aat gag gct ttt gag aaa ctt cca cga ggt 866Thr Leu Phe Ala Pro Thr Asn Glu Ala Phe Glu Lys Leu Pro Arg Gly270 275 280 285gtc cta gaa agg atc atg gga gac aaa gtg gct tcc gaa gct ctt atg 914Val Leu Glu Arg Ile Met Gly Asp Lys Val Ala Ser Glu Ala Leu Met 290

295 300aag tac cac atc tta aat act ctc cag tgt tct gag tct att atg gga 962Lys Tyr His Ile Leu Asn Thr Leu Gln Cys Ser Glu Ser Ile Met Gly 305 310 315gga gca gtc ttt gag acg ctg gaa gga aat aca att gag ata gga tgt 1010Gly Ala Val Phe Glu Thr Leu Glu Gly Asn Thr Ile Glu Ile Gly Cys 320 325 330gac ggt gac agt ata aca gta aat gga atc aaa atg gtg aac aaa aag 1058Asp Gly Asp Ser Ile Thr Val Asn Gly Ile Lys Met Val Asn Lys Lys 335 340 345gat att gtg aca aat aat ggt gtg atc cat ttg att gat cag gtc cta 1106Asp Ile Val Thr Asn Asn Gly Val Ile His Leu Ile Asp Gln Val Leu350 355 360 365att cct gat tct gcc aaa caa gtt att gag ctg gct gga aaa cag caa 1154Ile Pro Asp Ser Ala Lys Gln Val Ile Glu Leu Ala Gly Lys Gln Gln 370 375 380acc acc ttc acg gat ctt gtg gcc caa tta ggc ttg gca tct gct ctg 1202Thr Thr Phe Thr Asp Leu Val Ala Gln Leu Gly Leu Ala Ser Ala Leu 385 390 395agg cca gat gga gaa tac act ttg ctg gca cct gtg aat aat gca ttt 1250Arg Pro Asp Gly Glu Tyr Thr Leu Leu Ala Pro Val Asn Asn Ala Phe 400 405 410tct gat gat act ctc agc atg gat cag cgc ctc ctt aaa tta att ctg 1298Ser Asp Asp Thr Leu Ser Met Asp Gln Arg Leu Leu Lys Leu Ile Leu 415 420 425cag aat cac ata ttg aaa gta aaa gtt ggc ctt aat gag ctt tac aac 1346Gln Asn His Ile Leu Lys Val Lys Val Gly Leu Asn Glu Leu Tyr Asn430 435 440 445ggg caa ata ctg gaa acc atc gga ggc aaa cag ctc aga gtc ttc gta 1394Gly Gln Ile Leu Glu Thr Ile Gly Gly Lys Gln Leu Arg Val Phe Val 450 455 460 tat cgt aca gct gtc tgc att gaa aat tca tgc atg gag aaa ggg agt 1442Tyr Arg Thr Ala Val Cys Ile Glu Asn Ser Cys Met Glu Lys Gly Ser 465 470 475aag caa ggg aga aac ggt gcg att cac ata ttc cgc gag atc atc aag 1490Lys Gln Gly Arg Asn Gly Ala Ile His Ile Phe Arg Glu Ile Ile Lys 480 485 490cca gca gag aaa tcc ctc cat gaa aag tta aaa caa gat aag cgc ttt 1538Pro Ala Glu Lys Ser Leu His Glu Lys Leu Lys Gln Asp Lys Arg Phe 495 500 505agc acc ttc ctc agc cta ctt gaa gct gca gac ttg aaa gag ctc ctg 1586Ser Thr Phe Leu Ser Leu Leu Glu Ala Ala Asp Leu Lys Glu Leu Leu510 515 520 525aca caa cct gga gac tgg aca tta ttt gtg cca acc aat gat gct ttt 1634Thr Gln Pro Gly Asp Trp Thr Leu Phe Val Pro Thr Asn Asp Ala Phe 530 535 540aag gga atg act agt gaa gaa aaa gaa att ctg ata cgg gac aaa aat 1682Lys Gly Met Thr Ser Glu Glu Lys Glu Ile Leu Ile Arg Asp Lys Asn 545 550 555gct ctt caa aac atc att ctt tat cac ctg aca cca gga gtt ttc att 1730Ala Leu Gln Asn Ile Ile Leu Tyr His Leu Thr Pro Gly Val Phe Ile 560 565 570gga aaa gga ttt gaa cct ggt gtt act aac att tta aag acc aca caa 1778Gly Lys Gly Phe Glu Pro Gly Val Thr Asn Ile Leu Lys Thr Thr Gln 575 580 585gga agc aaa atc ttt ctg aaa gaa gta aat gat aca ctt ctg gtg aat 1826Gly Ser Lys Ile Phe Leu Lys Glu Val Asn Asp Thr Leu Leu Val Asn590 595 600 605gaa ttg aaa tca aaa gaa tct gac atc atg aca aca aat ggt gta att 1874Glu Leu Lys Ser Lys Glu Ser Asp Ile Met Thr Thr Asn Gly Val Ile 610 615 620cat gtt gta gat aaa ctc ctc tat cca gca gac aca cct gtt gga aat 1922His Val Val Asp Lys Leu Leu Tyr Pro Ala Asp Thr Pro Val Gly Asn 625 630 635gat caa ctg ctg gaa ata ctt aat aaa tta atc aaa tac atc caa att 1970Asp Gln Leu Leu Glu Ile Leu Asn Lys Leu Ile Lys Tyr Ile Gln Ile 640 645 650aag ttt gtt cgt ggt agc acc ttc aaa gaa atc ccc gtg act gtc tat 2018Lys Phe Val Arg Gly Ser Thr Phe Lys Glu Ile Pro Val Thr Val Tyr 655 660 665aag cca att att aaa aaa tac acc aaa atc att gat gga gtg cct gtg 2066Lys Pro Ile Ile Lys Lys Tyr Thr Lys Ile Ile Asp Gly Val Pro Val670 675 680 685gaa ata act gaa aaa gag aca cga gaa gaa cga atc att aca ggt cct 2114Glu Ile Thr Glu Lys Glu Thr Arg Glu Glu Arg Ile Ile Thr Gly Pro 690 695 700gaa ata aaa tac act agg att tct act gga ggt gga gaa aca gaa gaa 2162Glu Ile Lys Tyr Thr Arg Ile Ser Thr Gly Gly Gly Glu Thr Glu Glu 705 710 715act ctg aag aaa ttg tta caa gaa gag gtc acc aag gtc acc aaa ttc 2210Thr Leu Lys Lys Leu Leu Gln Glu Glu Val Thr Lys Val Thr Lys Phe 720 725 730att gaa ggt ggt gat ggt cat tta ttt gaa gat gaa gaa att aaa aga 2258Ile Glu Gly Gly Asp Gly His Leu Phe Glu Asp Glu Glu Ile Lys Arg 735 740 745ctg ctt cag gga gac aca ccc gtg agg aag ttg caa gcc aac aaa aaa 2306Leu Leu Gln Gly Asp Thr Pro Val Arg Lys Leu Gln Ala Asn Lys Lys750 755 760 765gtt caa ggt tct aga aga cga tta agg gaa ggt cgt tct cag tga 2351Val Gln Gly Ser Arg Arg Arg Leu Arg Glu Gly Arg Ser Gln * 770 775aaatccaaaa accagaaaaa aatgtttata caaccctaag tcaataacct gaccttagaa 2411aattgtgaga gccaagttga cttcaggaac tgaaacatca gcacaaagaa gcaatcatca 2471aataattctg aacacaaatt taatattttt ttttctgaat gagaaacatg agggaaattg 2531tggagttagc ctcctgtggt aaaggaattg aagaaaatat aacaccttac accctttttc 2591atcttgacat taaaagttct ggctaacttt ggaatccatt agagaaaaat ccttgtcacc 2651agattcatta caattcaaat cgaagagttg tgaactgtta tcccattgaa aagaccgagc 2711cttgtatgta tgttatggat acataaaatg cacgcaagcc attatctctc catgggaagc 2771taagttataa aaataggtgc ttggtgtaca aaacttttta tatcaaaagg ctttgcacat 2831ttctatatga gtgggtttac tggtaaatta tgttattttt tacaactaat tttgtactct 2891cagaatgttt gtcatatgct tcttgcaatg catatttttt aatctcaaac gtttcaataa 2951aaccattttt cagatataaa gagaattact tcaaattgag taattcagaa aaactcaaga 3011tttaagttaa aaagtggttt ggacttggga a 304244779PRThuman 44Met Ile Pro Phe Leu Pro Met Phe Ser Leu Leu Leu Leu Leu Ile Val1 5 10 15Asn Pro Ile Asn Ala Asn Asn His Tyr Asp Lys Ile Leu Ala His Ser 20 25 30Arg Ile Arg Gly Arg Asp Gln Gly Pro Asn Val Cys Ala Leu Gln Gln 35 40 45Ile Leu Gly Thr Lys Lys Lys Tyr Phe Ser Thr Cys Lys Asn Trp Tyr 50 55 60Lys Lys Ser Ile Cys Gly Gln Lys Thr Thr Val Leu Tyr Glu Cys Cys65 70 75 80Pro Gly Tyr Met Arg Met Glu Gly Met Lys Gly Cys Pro Ala Val Leu 85 90 95Pro Ile Asp His Val Tyr Gly Thr Leu Gly Ile Val Gly Ala Thr Thr 100 105 110Thr Gln Arg Tyr Ser Asp Ala Ser Lys Leu Arg Glu Glu Ile Glu Gly 115 120 125Lys Gly Ser Phe Thr Tyr Phe Ala Pro Ser Asn Glu Ala Trp Asp Asn 130 135 140Leu Asp Ser Asp Ile Arg Arg Gly Leu Glu Ser Asn Val Asn Val Glu145 150 155 160Leu Leu Asn Ala Leu His Ser His Met Ile Asn Lys Arg Met Leu Thr 165 170 175Lys Asp Leu Lys Asn Gly Met Ile Ile Pro Ser Met Tyr Asn Asn Leu 180 185 190Gly Leu Phe Ile Asn His Tyr Pro Asn Gly Val Val Thr Val Asn Cys 195 200 205Ala Arg Ile Ile His Gly Asn Gln Ile Ala Thr Asn Gly Val Val His 210 215 220Val Ile Asp Arg Val Leu Thr Gln Ile Gly Thr Ser Ile Gln Asp Phe225 230 235 240Ile Glu Ala Glu Asp Asp Leu Ser Ser Phe Arg Ala Ala Ala Ile Thr 245 250 255Ser Asp Ile Leu Glu Ala Leu Gly Arg Asp Gly His Phe Thr Leu Phe 260 265 270Ala Pro Thr Asn Glu Ala Phe Glu Lys Leu Pro Arg Gly Val Leu Glu 275 280 285Arg Ile Met Gly Asp Lys Val Ala Ser Glu Ala Leu Met Lys Tyr His 290 295 300Ile Leu Asn Thr Leu Gln Cys Ser Glu Ser Ile Met Gly Gly Ala Val305 310 315 320Phe Glu Thr Leu Glu Gly Asn Thr Ile Glu Ile Gly Cys Asp Gly Asp 325 330 335Ser Ile Thr Val Asn Gly Ile Lys Met Val Asn Lys Lys Asp Ile Val 340 345 350Thr Asn Asn Gly Val Ile His Leu Ile Asp Gln Val Leu Ile Pro Asp 355 360 365Ser Ala Lys Gln Val Ile Glu Leu Ala Gly Lys Gln Gln Thr Thr Phe 370 375 380Thr Asp Leu Val Ala Gln Leu Gly Leu Ala Ser Ala Leu Arg Pro Asp385 390 395 400Gly Glu Tyr Thr Leu Leu Ala Pro Val Asn Asn Ala Phe Ser Asp Asp 405 410 415Thr Leu Ser Met Asp Gln Arg Leu Leu Lys Leu Ile Leu Gln Asn His 420 425 430Ile Leu Lys Val Lys Val Gly Leu Asn Glu Leu Tyr Asn Gly Gln Ile 435 440 445Leu Glu Thr Ile Gly Gly Lys Gln Leu Arg Val Phe Val Tyr Arg Thr 450 455 460Ala Val Cys Ile Glu Asn Ser Cys Met Glu Lys Gly Ser Lys Gln Gly465 470 475 480Arg Asn Gly Ala Ile His Ile Phe Arg Glu Ile Ile Lys Pro Ala Glu 485 490 495Lys Ser Leu His Glu Lys Leu Lys Gln Asp Lys Arg Phe Ser Thr Phe 500 505 510Leu Ser Leu Leu Glu Ala Ala Asp Leu Lys Glu Leu Leu Thr Gln Pro 515 520 525Gly Asp Trp Thr Leu Phe Val Pro Thr Asn Asp Ala Phe Lys Gly Met 530 535 540Thr Ser Glu Glu Lys Glu Ile Leu Ile Arg Asp Lys Asn Ala Leu Gln545 550 555 560Asn Ile Ile Leu Tyr His Leu Thr Pro Gly Val Phe Ile Gly Lys Gly 565 570 575Phe Glu Pro Gly Val Thr Asn Ile Leu Lys Thr Thr Gln Gly Ser Lys 580 585 590Ile Phe Leu Lys Glu Val Asn Asp Thr Leu Leu Val Asn Glu Leu Lys 595 600 605Ser Lys Glu Ser Asp Ile Met Thr Thr Asn Gly Val Ile His Val Val 610 615 620Asp Lys Leu Leu Tyr Pro Ala Asp Thr Pro Val Gly Asn Asp Gln Leu625 630 635 640Leu Glu Ile Leu Asn Lys Leu Ile Lys Tyr Ile Gln Ile Lys Phe Val 645 650 655Arg Gly Ser Thr Phe Lys Glu Ile Pro Val Thr Val Tyr Lys Pro Ile 660 665 670Ile Lys Lys Tyr Thr Lys Ile Ile Asp Gly Val Pro Val Glu Ile Thr 675 680 685Glu Lys Glu Thr Arg Glu Glu Arg Ile Ile Thr Gly Pro Glu Ile Lys 690 695 700Tyr Thr Arg Ile Ser Thr Gly Gly Gly Glu Thr Glu Glu Thr Leu Lys705 710 715 720Lys Leu Leu Gln Glu Glu Val Thr Lys Val Thr Lys Phe Ile Glu Gly 725 730 735Gly Asp Gly His Leu Phe Glu Asp Glu Glu Ile Lys Arg Leu Leu Gln 740 745 750Gly Asp Thr Pro Val Arg Lys Leu Gln Ala Asn Lys Lys Val Gln Gly 755 760 765Ser Arg Arg Arg Leu Arg Glu Gly Arg Ser Gln 770 775452958DNAhumanCDS(12)...(2267) 45agagactcaa g atg att ccc ttt tta ccc atg ttt tct cta cta ttg ctg 50 Met Ile Pro Phe Leu Pro Met Phe Ser Leu Leu Leu Leu 1 5 10ctt att gtt aac cct ata aac gcc aac aat cat tat gac aag atc ttg 98Leu Ile Val Asn Pro Ile Asn Ala Asn Asn His Tyr Asp Lys Ile Leu 15 20 25gct cat agt cgt atc agg ggt cgg gac caa ggc cca aat gtc tgt gcc 146Ala His Ser Arg Ile Arg Gly Arg Asp Gln Gly Pro Asn Val Cys Ala30 35 40 45ctt caa cag att ttg ggc acc aaa aag aaa tac ttc agc act tgt aag 194Leu Gln Gln Ile Leu Gly Thr Lys Lys Lys Tyr Phe Ser Thr Cys Lys 50 55 60aac tgg tat aaa aag tcc atc tgt gga cag aaa acg act gtg tta tat 242Asn Trp Tyr Lys Lys Ser Ile Cys Gly Gln Lys Thr Thr Val Leu Tyr 65 70 75gaa tgt tgc cct ggt tat atg aga atg gaa gga atg aaa ggc tgc cca 290Glu Cys Cys Pro Gly Tyr Met Arg Met Glu Gly Met Lys Gly Cys Pro 80 85 90gca gtt ttg ccc att gac cat gtt tat ggc act ctg ggc atc gtg gga 338Ala Val Leu Pro Ile Asp His Val Tyr Gly Thr Leu Gly Ile Val Gly 95 100 105gcc acc aca acg cag cgc tat tct gac gcc tca aaa ctg agg gag gag 386Ala Thr Thr Thr Gln Arg Tyr Ser Asp Ala Ser Lys Leu Arg Glu Glu110 115 120 125atc gag gga aag gga tcc ttc act tac ttt gca ccg agt aat gag gct 434Ile Glu Gly Lys Gly Ser Phe Thr Tyr Phe Ala Pro Ser Asn Glu Ala 130 135 140tgg gac aac ttg gat tct gat atc cgt aga ggt ttg gag agc aac gtg 482Trp Asp Asn Leu Asp Ser Asp Ile Arg Arg Gly Leu Glu Ser Asn Val 145 150 155aat gtt gaa tta ctg aat gct tta cat agt cac atg att aat aag aga 530Asn Val Glu Leu Leu Asn Ala Leu His Ser His Met Ile Asn Lys Arg 160 165 170atg ttg acc aag gac tta aaa aat ggc atg att att cct tca atg tat 578Met Leu Thr Lys Asp Leu Lys Asn Gly Met Ile Ile Pro Ser Met Tyr 175 180 185aac aat ttg ggg ctt ttc att aac cat tat cct aat ggg gtt gtc act 626Asn Asn Leu Gly Leu Phe Ile Asn His Tyr Pro Asn Gly Val Val Thr190 195 200 205gtt aat tgt gct cga atc atc cat ggg aac cag att gca aca aat ggt 674Val Asn Cys Ala Arg Ile Ile His Gly Asn Gln Ile Ala Thr Asn Gly 210 215 220gtt gtc cat gtc att gac cgt gtg ctt aca caa att ggt acc tca att 722Val Val His Val Ile Asp Arg Val Leu Thr Gln Ile Gly Thr Ser Ile 225 230 235caa gac ttc att gaa gca gaa gat gac ctt tca tct ttt aga gca gct 770Gln Asp Phe Ile Glu Ala Glu Asp Asp Leu Ser Ser Phe Arg Ala Ala 240 245 250gcc atc aca tcg gac ata ttg gag gcc ctt gga aga gac ggt cac ttc 818Ala Ile Thr Ser Asp Ile Leu Glu Ala Leu Gly Arg Asp Gly His Phe 255 260 265aca ctc ttt gct ccc acc aat gag gct ttt gag aaa ctt cca cga ggt 866Thr Leu Phe Ala Pro Thr Asn Glu Ala Phe Glu Lys Leu Pro Arg Gly270 275 280 285gtc cta gaa agg atc atg gga gac aaa gtg gct tcc gaa gct ctt atg 914Val Leu Glu Arg Ile Met Gly Asp Lys Val Ala Ser Glu Ala Leu Met 290 295 300aag tac cac atc tta aat act ctc cag tgt tct gag tct att atg gga 962Lys Tyr His Ile Leu Asn Thr Leu Gln Cys Ser Glu Ser Ile Met Gly 305 310 315gga gca gtc ttt gag acg ctg gaa gga aat aca att gag ata gga tgt 1010Gly Ala Val Phe Glu Thr Leu Glu Gly Asn Thr Ile Glu Ile Gly Cys 320 325 330gac ggt gac agt ata aca gta aat gga atc aaa atg gtg aac aaa aag 1058Asp Gly Asp Ser Ile Thr Val Asn Gly Ile Lys Met Val Asn Lys Lys 335 340 345gat att gtg aca aat aat ggt gtg atc cat ttg att gat cag gtc cta 1106Asp Ile Val Thr Asn Asn Gly Val Ile His Leu Ile Asp Gln Val Leu350 355 360 365att cct gat tct gcc aaa caa gtt att gag ctg gct gga aaa cag caa 1154Ile Pro Asp Ser Ala Lys Gln Val Ile Glu Leu Ala Gly Lys Gln Gln 370 375 380acc acc ttc acg gat ctt gtg gcc caa tta ggc ttg gca tct gct ctg 1202Thr Thr Phe Thr Asp Leu Val Ala Gln Leu Gly Leu Ala Ser Ala Leu 385 390 395agg cca gat gga gaa tac act ttg ctg gca cct gtg aat aat gca ttt 1250Arg Pro Asp Gly Glu Tyr Thr Leu Leu Ala Pro Val Asn Asn Ala Phe 400 405 410tct gat gat act ctc agc atg gat cag cgc ctc ctt aaa tta att ctg 1298Ser Asp Asp Thr Leu Ser Met Asp Gln Arg Leu Leu Lys Leu Ile Leu 415 420 425cag aat cac ata ttg aaa gta aaa gtt ggc ctt aat gag ctt tac aac 1346Gln Asn His Ile Leu Lys Val Lys Val Gly Leu Asn Glu Leu Tyr Asn430 435 440 445ggg caa ata ctg gaa acc atc gga ggc aaa cag ctc aga gtc ttc gta 1394Gly Gln Ile Leu Glu Thr Ile Gly Gly Lys Gln Leu Arg Val Phe Val 450 455 460tat cgt aca gct gtc tgc att gaa aat tca tgc atg gag aaa ggg agt 1442Tyr Arg Thr Ala Val Cys Ile Glu Asn Ser Cys Met Glu Lys Gly Ser 465 470 475aag caa ggg aga aac ggt gcg att cac ata ttc cgc gag atc atc aag 1490Lys Gln Gly Arg Asn Gly Ala Ile His Ile Phe Arg Glu Ile Ile Lys 480 485 490cca gca gag aaa tcc ctc cat gaa aag tta aaa caa gat aag

cgc ttt 1538Pro Ala Glu Lys Ser Leu His Glu Lys Leu Lys Gln Asp Lys Arg Phe 495 500 505agc acc ttc ctc agc cta ctt gaa gct gca gac ttg aaa gag ctc ctg 1586Ser Thr Phe Leu Ser Leu Leu Glu Ala Ala Asp Leu Lys Glu Leu Leu510 515 520 525aca caa cct gga gac tgg aca tta ttt gtg cca acc aat gat gct ttt 1634Thr Gln Pro Gly Asp Trp Thr Leu Phe Val Pro Thr Asn Asp Ala Phe 530 535 540aag gga atg act agt gaa gaa aaa gaa att ctg ata cgg gac aaa aat 1682Lys Gly Met Thr Ser Glu Glu Lys Glu Ile Leu Ile Arg Asp Lys Asn 545 550 555gct ctt caa aac atc att ctt tat cac ctg aca cca gga gtt ttc att 1730Ala Leu Gln Asn Ile Ile Leu Tyr His Leu Thr Pro Gly Val Phe Ile 560 565 570gga aaa gga ttt gaa cct ggt gtt act aac att tta aag acc aca caa 1778Gly Lys Gly Phe Glu Pro Gly Val Thr Asn Ile Leu Lys Thr Thr Gln 575 580 585gga agc aaa atc ttt ctg aaa gaa gta aat gat aca ctt ctg gtg aat 1826Gly Ser Lys Ile Phe Leu Lys Glu Val Asn Asp Thr Leu Leu Val Asn590 595 600 605gaa ttg aaa tca aaa gaa tct gac atc atg aca aca aat ggt gta att 1874Glu Leu Lys Ser Lys Glu Ser Asp Ile Met Thr Thr Asn Gly Val Ile 610 615 620cat gtt gta gat aaa ctc ctc tat cca gca gac aca cct gtt gga aat 1922His Val Val Asp Lys Leu Leu Tyr Pro Ala Asp Thr Pro Val Gly Asn 625 630 635gat caa ctg ctg gaa ata ctt aat aaa tta atc aaa tac atc caa att 1970Asp Gln Leu Leu Glu Ile Leu Asn Lys Leu Ile Lys Tyr Ile Gln Ile 640 645 650aag ttt gtt cgt ggt agc acc ttc aaa gaa atc ccc gtg act gtc tat 2018Lys Phe Val Arg Gly Ser Thr Phe Lys Glu Ile Pro Val Thr Val Tyr 655 660 665aag cca att att aaa aaa tac acc aaa atc att gat gga gtg cct gtg 2066Lys Pro Ile Ile Lys Lys Tyr Thr Lys Ile Ile Asp Gly Val Pro Val670 675 680 685gaa ata act gaa aaa gag aca cga gaa gaa cga atc att aca ggt cct 2114Glu Ile Thr Glu Lys Glu Thr Arg Glu Glu Arg Ile Ile Thr Gly Pro 690 695 700gaa ata aaa tac act agg att tct act gga ggt gga gaa aca gaa gaa 2162Glu Ile Lys Tyr Thr Arg Ile Ser Thr Gly Gly Gly Glu Thr Glu Glu 705 710 715act ctg aag aaa ttg tta caa gaa gac aca ccc gtg agg aag ttg caa 2210Thr Leu Lys Lys Leu Leu Gln Glu Asp Thr Pro Val Arg Lys Leu Gln 720 725 730gcc aac aaa aaa gtt caa ggt tct aga aga cga tta agg gaa ggt cgt 2258Ala Asn Lys Lys Val Gln Gly Ser Arg Arg Arg Leu Arg Glu Gly Arg 735 740 745tct cag tga aaatccaaaa accagaaaaa aatgtttata caaccctaag 2307Ser Gln *750tcaataacct gaccttagaa aattgtgaga gccaagttga cttcaggaac tgaaacatca 2367gcacaaagaa gcaatcatca aataattctg aacacaaatt taatattttt ttttctgaat 2427gagaaacatg agggaaattg tggagttagc ctcctgtggt aaaggaattg aagaaaatat 2487aacaccttac accctttttc atcttgacat taaaagttct ggctaacttt ggaatccatt 2547agagaaaaat ccttgtcacc agattcatta caattcaaat cgaagagttg tgaactgtta 2607tcccattgaa aagaccgagc cttgtatgta tgttatggat acataaaatg cacgcaagcc 2667attatctctc catgggaagc taagttataa aaataggtgc ttggtgtaca aaacttttta 2727tatcaaaagg ctttgcacat ttctatatga gtgggtttac tggtaaatta tgttattttt 2787tacaactaat tttgtactct cagaatgttt gtcatatgct tcttgcaatg catatttttt 2847aatctcaaac gtttcaataa aaccattttt cagatataaa gagaattact tcaaattgag 2907taattcagaa aaactcaaga tttaagttaa aaagtggttt ggacttggga a 295846751PRThuman 46Met Ile Pro Phe Leu Pro Met Phe Ser Leu Leu Leu Leu Leu Ile Val1 5 10 15Asn Pro Ile Asn Ala Asn Asn His Tyr Asp Lys Ile Leu Ala His Ser 20 25 30Arg Ile Arg Gly Arg Asp Gln Gly Pro Asn Val Cys Ala Leu Gln Gln 35 40 45Ile Leu Gly Thr Lys Lys Lys Tyr Phe Ser Thr Cys Lys Asn Trp Tyr 50 55 60Lys Lys Ser Ile Cys Gly Gln Lys Thr Thr Val Leu Tyr Glu Cys Cys65 70 75 80Pro Gly Tyr Met Arg Met Glu Gly Met Lys Gly Cys Pro Ala Val Leu 85 90 95Pro Ile Asp His Val Tyr Gly Thr Leu Gly Ile Val Gly Ala Thr Thr 100 105 110Thr Gln Arg Tyr Ser Asp Ala Ser Lys Leu Arg Glu Glu Ile Glu Gly 115 120 125Lys Gly Ser Phe Thr Tyr Phe Ala Pro Ser Asn Glu Ala Trp Asp Asn 130 135 140Leu Asp Ser Asp Ile Arg Arg Gly Leu Glu Ser Asn Val Asn Val Glu145 150 155 160Leu Leu Asn Ala Leu His Ser His Met Ile Asn Lys Arg Met Leu Thr 165 170 175Lys Asp Leu Lys Asn Gly Met Ile Ile Pro Ser Met Tyr Asn Asn Leu 180 185 190Gly Leu Phe Ile Asn His Tyr Pro Asn Gly Val Val Thr Val Asn Cys 195 200 205Ala Arg Ile Ile His Gly Asn Gln Ile Ala Thr Asn Gly Val Val His 210 215 220Val Ile Asp Arg Val Leu Thr Gln Ile Gly Thr Ser Ile Gln Asp Phe225 230 235 240Ile Glu Ala Glu Asp Asp Leu Ser Ser Phe Arg Ala Ala Ala Ile Thr 245 250 255Ser Asp Ile Leu Glu Ala Leu Gly Arg Asp Gly His Phe Thr Leu Phe 260 265 270Ala Pro Thr Asn Glu Ala Phe Glu Lys Leu Pro Arg Gly Val Leu Glu 275 280 285Arg Ile Met Gly Asp Lys Val Ala Ser Glu Ala Leu Met Lys Tyr His 290 295 300Ile Leu Asn Thr Leu Gln Cys Ser Glu Ser Ile Met Gly Gly Ala Val305 310 315 320Phe Glu Thr Leu Glu Gly Asn Thr Ile Glu Ile Gly Cys Asp Gly Asp 325 330 335Ser Ile Thr Val Asn Gly Ile Lys Met Val Asn Lys Lys Asp Ile Val 340 345 350Thr Asn Asn Gly Val Ile His Leu Ile Asp Gln Val Leu Ile Pro Asp 355 360 365Ser Ala Lys Gln Val Ile Glu Leu Ala Gly Lys Gln Gln Thr Thr Phe 370 375 380Thr Asp Leu Val Ala Gln Leu Gly Leu Ala Ser Ala Leu Arg Pro Asp385 390 395 400Gly Glu Tyr Thr Leu Leu Ala Pro Val Asn Asn Ala Phe Ser Asp Asp 405 410 415Thr Leu Ser Met Asp Gln Arg Leu Leu Lys Leu Ile Leu Gln Asn His 420 425 430Ile Leu Lys Val Lys Val Gly Leu Asn Glu Leu Tyr Asn Gly Gln Ile 435 440 445Leu Glu Thr Ile Gly Gly Lys Gln Leu Arg Val Phe Val Tyr Arg Thr 450 455 460Ala Val Cys Ile Glu Asn Ser Cys Met Glu Lys Gly Ser Lys Gln Gly465 470 475 480Arg Asn Gly Ala Ile His Ile Phe Arg Glu Ile Ile Lys Pro Ala Glu 485 490 495Lys Ser Leu His Glu Lys Leu Lys Gln Asp Lys Arg Phe Ser Thr Phe 500 505 510Leu Ser Leu Leu Glu Ala Ala Asp Leu Lys Glu Leu Leu Thr Gln Pro 515 520 525Gly Asp Trp Thr Leu Phe Val Pro Thr Asn Asp Ala Phe Lys Gly Met 530 535 540Thr Ser Glu Glu Lys Glu Ile Leu Ile Arg Asp Lys Asn Ala Leu Gln545 550 555 560Asn Ile Ile Leu Tyr His Leu Thr Pro Gly Val Phe Ile Gly Lys Gly 565 570 575Phe Glu Pro Gly Val Thr Asn Ile Leu Lys Thr Thr Gln Gly Ser Lys 580 585 590Ile Phe Leu Lys Glu Val Asn Asp Thr Leu Leu Val Asn Glu Leu Lys 595 600 605Ser Lys Glu Ser Asp Ile Met Thr Thr Asn Gly Val Ile His Val Val 610 615 620Asp Lys Leu Leu Tyr Pro Ala Asp Thr Pro Val Gly Asn Asp Gln Leu625 630 635 640Leu Glu Ile Leu Asn Lys Leu Ile Lys Tyr Ile Gln Ile Lys Phe Val 645 650 655Arg Gly Ser Thr Phe Lys Glu Ile Pro Val Thr Val Tyr Lys Pro Ile 660 665 670Ile Lys Lys Tyr Thr Lys Ile Ile Asp Gly Val Pro Val Glu Ile Thr 675 680 685Glu Lys Glu Thr Arg Glu Glu Arg Ile Ile Thr Gly Pro Glu Ile Lys 690 695 700Tyr Thr Arg Ile Ser Thr Gly Gly Gly Glu Thr Glu Glu Thr Leu Lys705 710 715 720Lys Leu Leu Gln Glu Asp Thr Pro Val Arg Lys Leu Gln Ala Asn Lys 725 730 735Lys Val Gln Gly Ser Arg Arg Arg Leu Arg Glu Gly Arg Ser Gln 740 745 750472952DNAhumanCDS(12)...(2261) 47agagactcaa g atg att ccc ttt tta ccc atg ttt tct cta cta ttg ctg 50 Met Ile Pro Phe Leu Pro Met Phe Ser Leu Leu Leu Leu 1 5 10ctt att gtt aac cct ata aac gcc aac aat cat tat gac aag atc ttg 98Leu Ile Val Asn Pro Ile Asn Ala Asn Asn His Tyr Asp Lys Ile Leu 15 20 25gct cat agt cgt atc agg ggt cgg gac caa ggc cca aat gtc tgt gcc 146Ala His Ser Arg Ile Arg Gly Arg Asp Gln Gly Pro Asn Val Cys Ala30 35 40 45 ctt caa cag att ttg ggc acc aaa aag aaa tac ttc agc act tgt aag 194Leu Gln Gln Ile Leu Gly Thr Lys Lys Lys Tyr Phe Ser Thr Cys Lys 50 55 60aac tgg tat aaa aag tcc atc tgt gga cag aaa acg act gtg tta tat 242Asn Trp Tyr Lys Lys Ser Ile Cys Gly Gln Lys Thr Thr Val Leu Tyr 65 70 75gaa tgt tgc cct ggt tat atg aga atg gaa gga atg aaa ggc tgc cca 290Glu Cys Cys Pro Gly Tyr Met Arg Met Glu Gly Met Lys Gly Cys Pro 80 85 90gca gtt ttg ccc att gac cat gtt tat ggc act ctg ggc atc gtg gga 338Ala Val Leu Pro Ile Asp His Val Tyr Gly Thr Leu Gly Ile Val Gly 95 100 105gcc acc aca acg cag cgc tat tct gac gcc tca aaa ctg agg gag gag 386Ala Thr Thr Thr Gln Arg Tyr Ser Asp Ala Ser Lys Leu Arg Glu Glu110 115 120 125atc gag gga aag gga tcc ttc act tac ttt gca ccg agt aat gag gct 434Ile Glu Gly Lys Gly Ser Phe Thr Tyr Phe Ala Pro Ser Asn Glu Ala 130 135 140tgg gac aac ttg gat tct gat atc cgt aga ggt ttg gag agc aac gtg 482Trp Asp Asn Leu Asp Ser Asp Ile Arg Arg Gly Leu Glu Ser Asn Val 145 150 155aat gtt gaa tta ctg aat gct tta cat agt cac atg att aat aag aga 530Asn Val Glu Leu Leu Asn Ala Leu His Ser His Met Ile Asn Lys Arg 160 165 170atg ttg acc aag gac tta aaa aat ggc atg att att cct tca atg tat 578Met Leu Thr Lys Asp Leu Lys Asn Gly Met Ile Ile Pro Ser Met Tyr 175 180 185aac aat ttg ggg ctt ttc att aac cat tat cct aat ggg gtt gtc act 626Asn Asn Leu Gly Leu Phe Ile Asn His Tyr Pro Asn Gly Val Val Thr190 195 200 205gtt aat tgt gct cga atc atc cat ggg aac cag att gca aca aat ggt 674Val Asn Cys Ala Arg Ile Ile His Gly Asn Gln Ile Ala Thr Asn Gly 210 215 220gtt gtc cat gtc att gac cgt gtg ctt aca caa att ggt acc tca att 722Val Val His Val Ile Asp Arg Val Leu Thr Gln Ile Gly Thr Ser Ile 225 230 235caa gac ttc att gaa gca gaa gat gac ctt tca tct ttt aga gca gct 770Gln Asp Phe Ile Glu Ala Glu Asp Asp Leu Ser Ser Phe Arg Ala Ala 240 245 250gcc atc aca tcg gac ata ttg gag gcc ctt gga aga gac ggt cac ttc 818Ala Ile Thr Ser Asp Ile Leu Glu Ala Leu Gly Arg Asp Gly His Phe 255 260 265aca ctc ttt gct ccc acc aat gag gct ttt gag aaa ctt cca cga ggt 866Thr Leu Phe Ala Pro Thr Asn Glu Ala Phe Glu Lys Leu Pro Arg Gly270 275 280 285gtc cta gaa agg atc atg gga gac aaa gtg gct tcc gaa gct ctt atg 914Val Leu Glu Arg Ile Met Gly Asp Lys Val Ala Ser Glu Ala Leu Met 290 295 300aag tac cac atc tta aat act ctc cag tgt tct gag tct att atg gga 962Lys Tyr His Ile Leu Asn Thr Leu Gln Cys Ser Glu Ser Ile Met Gly 305 310 315gga gca gtc ttt gag acg ctg gaa gga aat aca att gag ata gga tgt 1010Gly Ala Val Phe Glu Thr Leu Glu Gly Asn Thr Ile Glu Ile Gly Cys 320 325 330gac ggt gac agt ata aca gta aat gga atc aaa atg gtg aac aaa aag 1058Asp Gly Asp Ser Ile Thr Val Asn Gly Ile Lys Met Val Asn Lys Lys 335 340 345gat att gtg aca aat aat ggt gtg atc cat ttg att gat cag gtc cta 1106Asp Ile Val Thr Asn Asn Gly Val Ile His Leu Ile Asp Gln Val Leu350 355 360 365att cct gat tct gcc aaa caa gtt att gag ctg gct gga aaa cag caa 1154Ile Pro Asp Ser Ala Lys Gln Val Ile Glu Leu Ala Gly Lys Gln Gln 370 375 380acc acc ttc acg gat ctt gtg gcc caa tta ggc ttg gca tct gct ctg 1202Thr Thr Phe Thr Asp Leu Val Ala Gln Leu Gly Leu Ala Ser Ala Leu 385 390 395agg cca gat gga gaa tac act ttg ctg gca cct gtg aat aat gca ttt 1250Arg Pro Asp Gly Glu Tyr Thr Leu Leu Ala Pro Val Asn Asn Ala Phe 400 405 410tct gat gat act ctc agc atg gat cag cgc ctc ctt aaa tta att ctg 1298Ser Asp Asp Thr Leu Ser Met Asp Gln Arg Leu Leu Lys Leu Ile Leu 415 420 425cag aat cac ata ttg aaa gta aaa gtt ggc ctt aat gag ctt tac aac 1346Gln Asn His Ile Leu Lys Val Lys Val Gly Leu Asn Glu Leu Tyr Asn430 435 440 445ggg caa ata ctg gaa acc atc gga ggc aaa cag ctc aga gtc ttc gta 1394Gly Gln Ile Leu Glu Thr Ile Gly Gly Lys Gln Leu Arg Val Phe Val 450 455 460tat cgt aca gct gtc tgc att gaa aat tca tgc atg gag aaa ggg agt 1442Tyr Arg Thr Ala Val Cys Ile Glu Asn Ser Cys Met Glu Lys Gly Ser 465 470 475aag caa ggg aga aac ggt gcg att cac ata ttc cgc gag atc atc aag 1490Lys Gln Gly Arg Asn Gly Ala Ile His Ile Phe Arg Glu Ile Ile Lys 480 485 490cca gca gag aaa tcc ctc cat gaa aag tta aaa caa gat aag cgc ttt 1538Pro Ala Glu Lys Ser Leu His Glu Lys Leu Lys Gln Asp Lys Arg Phe 495 500 505agc acc ttc ctc agc cta ctt gaa gct gca gac ttg aaa gag ctc ctg 1586Ser Thr Phe Leu Ser Leu Leu Glu Ala Ala Asp Leu Lys Glu Leu Leu510 515 520 525aca caa cct gga gac tgg aca tta ttt gtg cca acc aat gat gct ttt 1634Thr Gln Pro Gly Asp Trp Thr Leu Phe Val Pro Thr Asn Asp Ala Phe 530 535 540aag gga atg act agt gaa gaa aaa gaa att ctg ata cgg gac aaa aat 1682Lys Gly Met Thr Ser Glu Glu Lys Glu Ile Leu Ile Arg Asp Lys Asn 545 550 555gct ctt caa aac atc att ctt tat cac ctg aca cca gga gtt ttc att 1730Ala Leu Gln Asn Ile Ile Leu Tyr His Leu Thr Pro Gly Val Phe Ile 560 565 570gga aaa gga ttt gaa cct ggt gtt act aac att tta aag acc aca caa 1778Gly Lys Gly Phe Glu Pro Gly Val Thr Asn Ile Leu Lys Thr Thr Gln 575 580 585gga agc aaa atc ttt ctg aaa gaa gta aat gat aca ctt ctg gtg aat 1826Gly Ser Lys Ile Phe Leu Lys Glu Val Asn Asp Thr Leu Leu Val Asn590 595 600 605gaa ttg aaa tca aaa gaa tct gac atc atg aca aca aat ggt gta att 1874Glu Leu Lys Ser Lys Glu Ser Asp Ile Met Thr Thr Asn Gly Val Ile 610 615 620cat gtt gta gat aaa ctc ctc tat cca gca gac aca cct gtt gga aat 1922His Val Val Asp Lys Leu Leu Tyr Pro Ala Asp Thr Pro Val Gly Asn 625 630 635gat caa ctg ctg gaa ata ctt aat aaa tta atc aaa tac atc caa att 1970Asp Gln Leu Leu Glu Ile Leu Asn Lys Leu Ile Lys Tyr Ile Gln Ile 640 645 650aag ttt gtt cgt ggt agc acc ttc aaa gaa atc ccc gtg act gtc tat 2018Lys Phe Val Arg Gly Ser Thr Phe Lys Glu Ile Pro Val Thr Val Tyr 655 660 665agt cct gaa ata aaa tac act agg att tct act gga ggt gga gaa aca 2066Ser Pro Glu Ile Lys Tyr Thr Arg Ile Ser Thr Gly Gly Gly Glu Thr670 675 680 685gaa gaa act ctg aag aaa ttg tta caa gaa gag gtc acc aag gtc acc 2114Glu Glu Thr Leu Lys Lys Leu Leu Gln Glu Glu Val Thr Lys Val Thr 690 695 700aaa ttc att gaa ggt ggt gat ggt cat tta ttt gaa gat gaa gaa att 2162Lys Phe Ile Glu Gly Gly Asp Gly His Leu Phe Glu Asp Glu Glu Ile 705 710 715aaa aga ctg ctt cag gga gac aca ccc gtg agg aag ttg caa gcc aac 2210Lys Arg Leu Leu Gln Gly Asp Thr Pro Val Arg Lys Leu Gln Ala Asn 720 725 730aaa aaa gtt caa ggt tct aga aga cga tta agg gaa ggt cgt tct cag 2258Lys Lys Val Gln Gly Ser Arg

Arg Arg Leu Arg Glu Gly Arg Ser Gln 735 740 745tga aaatccaaaa accagaaaaa aatgtttata caaccctaag tcaataacct 2311*gaccttagaa aattgtgaga gccaagttga cttcaggaac tgaaacatca gcacaaagaa 2371gcaatcatca aataattctg aacacaaatt taatattttt ttttctgaat gagaaacatg 2431agggaaattg tggagttagc ctcctgtggt aaaggaattg aagaaaatat aacaccttac 2491accctttttc atcttgacat taaaagttct ggctaacttt ggaatccatt agagaaaaat 2551ccttgtcacc agattcatta caattcaaat cgaagagttg tgaactgtta tcccattgaa 2611aagaccgagc cttgtatgta tgttatggat acataaaatg cacgcaagcc attatctctc 2671catgggaagc taagttataa aaataggtgc ttggtgtaca aaacttttta tatcaaaagg 2731ctttgcacat ttctatatga gtgggtttac tggtaaatta tgttattttt tacaactaat 2791tttgtactct cagaatgttt gtcatatgct tcttgcaatg catatttttt aatctcaaac 2851gtttcaataa aaccattttt cagatataaa gagaattact tcaaattgag taattcagaa 2911aaactcaaga tttaagttaa aaagtggttt ggacttggga a 295248749PRThuman 48Met Ile Pro Phe Leu Pro Met Phe Ser Leu Leu Leu Leu Leu Ile Val1 5 10 15Asn Pro Ile Asn Ala Asn Asn His Tyr Asp Lys Ile Leu Ala His Ser 20 25 30Arg Ile Arg Gly Arg Asp Gln Gly Pro Asn Val Cys Ala Leu Gln Gln 35 40 45Ile Leu Gly Thr Lys Lys Lys Tyr Phe Ser Thr Cys Lys Asn Trp Tyr 50 55 60Lys Lys Ser Ile Cys Gly Gln Lys Thr Thr Val Leu Tyr Glu Cys Cys65 70 75 80Pro Gly Tyr Met Arg Met Glu Gly Met Lys Gly Cys Pro Ala Val Leu 85 90 95Pro Ile Asp His Val Tyr Gly Thr Leu Gly Ile Val Gly Ala Thr Thr 100 105 110Thr Gln Arg Tyr Ser Asp Ala Ser Lys Leu Arg Glu Glu Ile Glu Gly 115 120 125Lys Gly Ser Phe Thr Tyr Phe Ala Pro Ser Asn Glu Ala Trp Asp Asn 130 135 140Leu Asp Ser Asp Ile Arg Arg Gly Leu Glu Ser Asn Val Asn Val Glu145 150 155 160Leu Leu Asn Ala Leu His Ser His Met Ile Asn Lys Arg Met Leu Thr 165 170 175Lys Asp Leu Lys Asn Gly Met Ile Ile Pro Ser Met Tyr Asn Asn Leu 180 185 190Gly Leu Phe Ile Asn His Tyr Pro Asn Gly Val Val Thr Val Asn Cys 195 200 205Ala Arg Ile Ile His Gly Asn Gln Ile Ala Thr Asn Gly Val Val His 210 215 220Val Ile Asp Arg Val Leu Thr Gln Ile Gly Thr Ser Ile Gln Asp Phe225 230 235 240Ile Glu Ala Glu Asp Asp Leu Ser Ser Phe Arg Ala Ala Ala Ile Thr 245 250 255Ser Asp Ile Leu Glu Ala Leu Gly Arg Asp Gly His Phe Thr Leu Phe 260 265 270Ala Pro Thr Asn Glu Ala Phe Glu Lys Leu Pro Arg Gly Val Leu Glu 275 280 285Arg Ile Met Gly Asp Lys Val Ala Ser Glu Ala Leu Met Lys Tyr His 290 295 300Ile Leu Asn Thr Leu Gln Cys Ser Glu Ser Ile Met Gly Gly Ala Val305 310 315 320Phe Glu Thr Leu Glu Gly Asn Thr Ile Glu Ile Gly Cys Asp Gly Asp 325 330 335Ser Ile Thr Val Asn Gly Ile Lys Met Val Asn Lys Lys Asp Ile Val 340 345 350Thr Asn Asn Gly Val Ile His Leu Ile Asp Gln Val Leu Ile Pro Asp 355 360 365Ser Ala Lys Gln Val Ile Glu Leu Ala Gly Lys Gln Gln Thr Thr Phe 370 375 380Thr Asp Leu Val Ala Gln Leu Gly Leu Ala Ser Ala Leu Arg Pro Asp385 390 395 400Gly Glu Tyr Thr Leu Leu Ala Pro Val Asn Asn Ala Phe Ser Asp Asp 405 410 415Thr Leu Ser Met Asp Gln Arg Leu Leu Lys Leu Ile Leu Gln Asn His 420 425 430Ile Leu Lys Val Lys Val Gly Leu Asn Glu Leu Tyr Asn Gly Gln Ile 435 440 445Leu Glu Thr Ile Gly Gly Lys Gln Leu Arg Val Phe Val Tyr Arg Thr 450 455 460Ala Val Cys Ile Glu Asn Ser Cys Met Glu Lys Gly Ser Lys Gln Gly465 470 475 480Arg Asn Gly Ala Ile His Ile Phe Arg Glu Ile Ile Lys Pro Ala Glu 485 490 495Lys Ser Leu His Glu Lys Leu Lys Gln Asp Lys Arg Phe Ser Thr Phe 500 505 510Leu Ser Leu Leu Glu Ala Ala Asp Leu Lys Glu Leu Leu Thr Gln Pro 515 520 525Gly Asp Trp Thr Leu Phe Val Pro Thr Asn Asp Ala Phe Lys Gly Met 530 535 540Thr Ser Glu Glu Lys Glu Ile Leu Ile Arg Asp Lys Asn Ala Leu Gln545 550 555 560Asn Ile Ile Leu Tyr His Leu Thr Pro Gly Val Phe Ile Gly Lys Gly 565 570 575Phe Glu Pro Gly Val Thr Asn Ile Leu Lys Thr Thr Gln Gly Ser Lys 580 585 590Ile Phe Leu Lys Glu Val Asn Asp Thr Leu Leu Val Asn Glu Leu Lys 595 600 605Ser Lys Glu Ser Asp Ile Met Thr Thr Asn Gly Val Ile His Val Val 610 615 620Asp Lys Leu Leu Tyr Pro Ala Asp Thr Pro Val Gly Asn Asp Gln Leu625 630 635 640Leu Glu Ile Leu Asn Lys Leu Ile Lys Tyr Ile Gln Ile Lys Phe Val 645 650 655Arg Gly Ser Thr Phe Lys Glu Ile Pro Val Thr Val Tyr Ser Pro Glu 660 665 670Ile Lys Tyr Thr Arg Ile Ser Thr Gly Gly Gly Glu Thr Glu Glu Thr 675 680 685Leu Lys Lys Leu Leu Gln Glu Glu Val Thr Lys Val Thr Lys Phe Ile 690 695 700Glu Gly Gly Asp Gly His Leu Phe Glu Asp Glu Glu Ile Lys Arg Leu705 710 715 720Leu Gln Gly Asp Thr Pro Val Arg Lys Leu Gln Ala Asn Lys Lys Val 725 730 735Gln Gly Ser Arg Arg Arg Leu Arg Glu Gly Arg Ser Gln 740 745492868DNAhumanCDS(12)...(2177) 49agagactcaa g atg att ccc ttt tta ccc atg ttt tct cta cta ttg ctg 50 Met Ile Pro Phe Leu Pro Met Phe Ser Leu Leu Leu Leu 1 5 10ctt att gtt aac cct ata aac gcc aac aat cat tat gac aag atc ttg 98Leu Ile Val Asn Pro Ile Asn Ala Asn Asn His Tyr Asp Lys Ile Leu 15 20 25gct cat agt cgt atc agg ggt cgg gac caa ggc cca aat gtc tgt gcc 146Ala His Ser Arg Ile Arg Gly Arg Asp Gln Gly Pro Asn Val Cys Ala30 35 40 45ctt caa cag att ttg ggc acc aaa aag aaa tac ttc agc act tgt aag 194Leu Gln Gln Ile Leu Gly Thr Lys Lys Lys Tyr Phe Ser Thr Cys Lys 50 55 60aac tgg tat aaa aag tcc atc tgt gga cag aaa acg act gtg tta tat 242Asn Trp Tyr Lys Lys Ser Ile Cys Gly Gln Lys Thr Thr Val Leu Tyr 65 70 75gaa tgt tgc cct ggt tat atg aga atg gaa gga atg aaa ggc tgc cca 290Glu Cys Cys Pro Gly Tyr Met Arg Met Glu Gly Met Lys Gly Cys Pro 80 85 90gca gtt ttg ccc att gac cat gtt tat ggc act ctg ggc atc gtg gga 338Ala Val Leu Pro Ile Asp His Val Tyr Gly Thr Leu Gly Ile Val Gly 95 100 105gcc acc aca acg cag cgc tat tct gac gcc tca aaa ctg agg gag gag 386Ala Thr Thr Thr Gln Arg Tyr Ser Asp Ala Ser Lys Leu Arg Glu Glu110 115 120 125atc gag gga aag gga tcc ttc act tac ttt gca ccg agt aat gag gct 434Ile Glu Gly Lys Gly Ser Phe Thr Tyr Phe Ala Pro Ser Asn Glu Ala 130 135 140tgg gac aac ttg gat tct gat atc cgt aga ggt ttg gag agc aac gtg 482Trp Asp Asn Leu Asp Ser Asp Ile Arg Arg Gly Leu Glu Ser Asn Val 145 150 155aat gtt gaa tta ctg aat gct tta cat agt cac atg att aat aag aga 530Asn Val Glu Leu Leu Asn Ala Leu His Ser His Met Ile Asn Lys Arg 160 165 170atg ttg acc aag gac tta aaa aat ggc atg att att cct tca atg tat 578Met Leu Thr Lys Asp Leu Lys Asn Gly Met Ile Ile Pro Ser Met Tyr 175 180 185aac aat ttg ggg ctt ttc att aac cat tat cct aat ggg gtt gtc act 626Asn Asn Leu Gly Leu Phe Ile Asn His Tyr Pro Asn Gly Val Val Thr190 195 200 205gtt aat tgt gct cga atc atc cat ggg aac cag att gca aca aat ggt 674Val Asn Cys Ala Arg Ile Ile His Gly Asn Gln Ile Ala Thr Asn Gly 210 215 220gtt gtc cat gtc att gac cgt gtg ctt aca caa att ggt acc tca att 722Val Val His Val Ile Asp Arg Val Leu Thr Gln Ile Gly Thr Ser Ile 225 230 235caa gac ttc att gaa gca gaa gat gac ctt tca tct ttt aga gca gct 770Gln Asp Phe Ile Glu Ala Glu Asp Asp Leu Ser Ser Phe Arg Ala Ala 240 245 250gcc atc aca tcg gac ata ttg gag gcc ctt gga aga gac ggt cac ttc 818Ala Ile Thr Ser Asp Ile Leu Glu Ala Leu Gly Arg Asp Gly His Phe 255 260 265aca ctc ttt gct ccc acc aat gag gct ttt gag aaa ctt cca cga ggt 866Thr Leu Phe Ala Pro Thr Asn Glu Ala Phe Glu Lys Leu Pro Arg Gly270 275 280 285gtc cta gaa agg atc atg gga gac aaa gtg gct tcc gaa gct ctt atg 914Val Leu Glu Arg Ile Met Gly Asp Lys Val Ala Ser Glu Ala Leu Met 290 295 300aag tac cac atc tta aat act ctc cag tgt tct gag tct att atg gga 962Lys Tyr His Ile Leu Asn Thr Leu Gln Cys Ser Glu Ser Ile Met Gly 305 310 315gga gca gtc ttt gag acg ctg gaa gga aat aca att gag ata gga tgt 1010Gly Ala Val Phe Glu Thr Leu Glu Gly Asn Thr Ile Glu Ile Gly Cys 320 325 330gac ggt gac agt ata aca gta aat gga atc aaa atg gtg aac aaa aag 1058Asp Gly Asp Ser Ile Thr Val Asn Gly Ile Lys Met Val Asn Lys Lys 335 340 345gat att gtg aca aat aat ggt gtg atc cat ttg att gat cag gtc cta 1106Asp Ile Val Thr Asn Asn Gly Val Ile His Leu Ile Asp Gln Val Leu 350 355 360 365att cct gat tct gcc aaa caa gtt att gag ctg gct gga aaa cag caa 1154Ile Pro Asp Ser Ala Lys Gln Val Ile Glu Leu Ala Gly Lys Gln Gln 370 375 380acc acc ttc acg gat ctt gtg gcc caa tta ggc ttg gca tct gct ctg 1202Thr Thr Phe Thr Asp Leu Val Ala Gln Leu Gly Leu Ala Ser Ala Leu 385 390 395agg cca gat gga gaa tac act ttg ctg gca cct gtg aat aat gca ttt 1250Arg Pro Asp Gly Glu Tyr Thr Leu Leu Ala Pro Val Asn Asn Ala Phe 400 405 410tct gat gat act ctc agc atg gat cag cgc ctc ctt aaa tta att ctg 1298Ser Asp Asp Thr Leu Ser Met Asp Gln Arg Leu Leu Lys Leu Ile Leu 415 420 425cag aat cac ata ttg aaa gta aaa gtt ggc ctt aat gag ctt tac aac 1346Gln Asn His Ile Leu Lys Val Lys Val Gly Leu Asn Glu Leu Tyr Asn430 435 440 445ggg caa ata ctg gaa acc atc gga ggc aaa cag ctc aga gtc ttc gta 1394Gly Gln Ile Leu Glu Thr Ile Gly Gly Lys Gln Leu Arg Val Phe Val 450 455 460tat cgt aca gct gtc tgc att gaa aat tca tgc atg gag aaa ggg agt 1442Tyr Arg Thr Ala Val Cys Ile Glu Asn Ser Cys Met Glu Lys Gly Ser 465 470 475aag caa ggg aga aac ggt gcg att cac ata ttc cgc gag atc atc aag 1490Lys Gln Gly Arg Asn Gly Ala Ile His Ile Phe Arg Glu Ile Ile Lys 480 485 490cca gca gag aaa tcc ctc cat gaa aag tta aaa caa gat aag cgc ttt 1538Pro Ala Glu Lys Ser Leu His Glu Lys Leu Lys Gln Asp Lys Arg Phe 495 500 505agc acc ttc ctc agc cta ctt gaa gct gca gac ttg aaa gag ctc ctg 1586Ser Thr Phe Leu Ser Leu Leu Glu Ala Ala Asp Leu Lys Glu Leu Leu510 515 520 525aca caa cct gga gac tgg aca tta ttt gtg cca acc aat gat gct ttt 1634Thr Gln Pro Gly Asp Trp Thr Leu Phe Val Pro Thr Asn Asp Ala Phe 530 535 540aag gga atg act agt gaa gaa aaa gaa att ctg ata cgg gac aaa aat 1682Lys Gly Met Thr Ser Glu Glu Lys Glu Ile Leu Ile Arg Asp Lys Asn 545 550 555gct ctt caa aac atc att ctt tat cac ctg aca cca gga gtt ttc att 1730Ala Leu Gln Asn Ile Ile Leu Tyr His Leu Thr Pro Gly Val Phe Ile 560 565 570gga aaa gga ttt gaa cct ggt gtt act aac att tta aag acc aca caa 1778Gly Lys Gly Phe Glu Pro Gly Val Thr Asn Ile Leu Lys Thr Thr Gln 575 580 585gga agc aaa atc ttt ctg aaa gaa gta aat gat aca ctt ctg gtg aat 1826Gly Ser Lys Ile Phe Leu Lys Glu Val Asn Asp Thr Leu Leu Val Asn590 595 600 605gaa ttg aaa tca aaa gaa tct gac atc atg aca aca aat ggt gta att 1874Glu Leu Lys Ser Lys Glu Ser Asp Ile Met Thr Thr Asn Gly Val Ile 610 615 620cat gtt gta gat aaa ctc ctc tat cca gca gac aca cct gtt gga aat 1922His Val Val Asp Lys Leu Leu Tyr Pro Ala Asp Thr Pro Val Gly Asn 625 630 635gat caa ctg ctg gaa ata ctt aat aaa tta atc aaa tac atc caa att 1970Asp Gln Leu Leu Glu Ile Leu Asn Lys Leu Ile Lys Tyr Ile Gln Ile 640 645 650aag ttt gtt cgt ggt agc acc ttc aaa gaa atc ccc gtg act gtc tat 2018Lys Phe Val Arg Gly Ser Thr Phe Lys Glu Ile Pro Val Thr Val Tyr 655 660 665agt cct gaa ata aaa tac act agg att tct act gga ggt gga gaa aca 2066Ser Pro Glu Ile Lys Tyr Thr Arg Ile Ser Thr Gly Gly Gly Glu Thr 670 675 680 685gaa gaa act ctg aag aaa ttg tta caa gaa gac aca ccc gtg agg aag 2114Glu Glu Thr Leu Lys Lys Leu Leu Gln Glu Asp Thr Pro Val Arg Lys 690 695 700ttg caa gcc aac aaa aaa gtt caa ggt tct aga aga cga tta agg gaa 2162Leu Gln Ala Asn Lys Lys Val Gln Gly Ser Arg Arg Arg Leu Arg Glu 705 710 715ggt cgt tct cag tga aaatccaaaa accagaaaaa aatgtttata caaccctaag 2217Gly Arg Ser Gln * 720tcaataacct gaccttagaa aattgtgaga gccaagttga cttcaggaac tgaaacatca 2277gcacaaagaa gcaatcatca aataattctg aacacaaatt taatattttt ttttctgaat 2337gagaaacatg agggaaattg tggagttagc ctcctgtggt aaaggaattg aagaaaatat 2397aacaccttac accctttttc atcttgacat taaaagttct ggctaacttt ggaatccatt 2457agagaaaaat ccttgtcacc agattcatta caattcaaat cgaagagttg tgaactgtta 2517tcccattgaa aagaccgagc cttgtatgta tgttatggat acataaaatg cacgcaagcc 2577attatctctc catgggaagc taagttataa aaataggtgc ttggtgtaca aaacttttta 2637tatcaaaagg ctttgcacat ttctatatga gtgggtttac tggtaaatta tgttattttt 2697tacaactaat tttgtactct cagaatgttt gtcatatgct tcttgcaatg catatttttt 2757aatctcaaac gtttcaataa aaccattttt cagatataaa gagaattact tcaaattgag 2817taattcagaa aaactcaaga tttaagttaa aaagtggttt ggacttggga a 286850721PRThuman 50Met Ile Pro Phe Leu Pro Met Phe Ser Leu Leu Leu Leu Leu Ile Val1 5 10 15Asn Pro Ile Asn Ala Asn Asn His Tyr Asp Lys Ile Leu Ala His Ser 20 25 30Arg Ile Arg Gly Arg Asp Gln Gly Pro Asn Val Cys Ala Leu Gln Gln 35 40 45Ile Leu Gly Thr Lys Lys Lys Tyr Phe Ser Thr Cys Lys Asn Trp Tyr 50 55 60Lys Lys Ser Ile Cys Gly Gln Lys Thr Thr Val Leu Tyr Glu Cys Cys65 70 75 80Pro Gly Tyr Met Arg Met Glu Gly Met Lys Gly Cys Pro Ala Val Leu 85 90 95Pro Ile Asp His Val Tyr Gly Thr Leu Gly Ile Val Gly Ala Thr Thr 100 105 110Thr Gln Arg Tyr Ser Asp Ala Ser Lys Leu Arg Glu Glu Ile Glu Gly 115 120 125Lys Gly Ser Phe Thr Tyr Phe Ala Pro Ser Asn Glu Ala Trp Asp Asn 130 135 140Leu Asp Ser Asp Ile Arg Arg Gly Leu Glu Ser Asn Val Asn Val Glu145 150 155 160Leu Leu Asn Ala Leu His Ser His Met Ile Asn Lys Arg Met Leu Thr 165 170 175Lys Asp Leu Lys Asn Gly Met Ile Ile Pro Ser Met Tyr Asn Asn Leu 180 185 190Gly Leu Phe Ile Asn His Tyr Pro Asn Gly Val Val Thr Val Asn Cys 195 200 205Ala Arg Ile Ile His Gly Asn Gln Ile Ala Thr Asn Gly Val Val His 210 215 220Val Ile Asp Arg Val Leu Thr Gln Ile Gly Thr Ser Ile Gln Asp Phe225 230 235 240Ile Glu Ala Glu Asp Asp Leu Ser Ser Phe Arg Ala Ala Ala Ile Thr 245 250 255Ser Asp Ile Leu Glu Ala Leu Gly Arg Asp Gly His Phe Thr Leu Phe 260 265 270Ala Pro Thr Asn Glu Ala Phe Glu Lys Leu Pro Arg Gly Val Leu Glu 275 280 285Arg Ile Met Gly Asp Lys Val Ala Ser Glu Ala Leu Met Lys Tyr His 290 295 300Ile Leu Asn Thr Leu Gln Cys Ser Glu Ser Ile Met Gly Gly Ala Val305

310 315 320Phe Glu Thr Leu Glu Gly Asn Thr Ile Glu Ile Gly Cys Asp Gly Asp 325 330 335Ser Ile Thr Val Asn Gly Ile Lys Met Val Asn Lys Lys Asp Ile Val 340 345 350Thr Asn Asn Gly Val Ile His Leu Ile Asp Gln Val Leu Ile Pro Asp 355 360 365Ser Ala Lys Gln Val Ile Glu Leu Ala Gly Lys Gln Gln Thr Thr Phe 370 375 380Thr Asp Leu Val Ala Gln Leu Gly Leu Ala Ser Ala Leu Arg Pro Asp385 390 395 400Gly Glu Tyr Thr Leu Leu Ala Pro Val Asn Asn Ala Phe Ser Asp Asp 405 410 415Thr Leu Ser Met Asp Gln Arg Leu Leu Lys Leu Ile Leu Gln Asn His 420 425 430Ile Leu Lys Val Lys Val Gly Leu Asn Glu Leu Tyr Asn Gly Gln Ile 435 440 445Leu Glu Thr Ile Gly Gly Lys Gln Leu Arg Val Phe Val Tyr Arg Thr 450 455 460Ala Val Cys Ile Glu Asn Ser Cys Met Glu Lys Gly Ser Lys Gln Gly465 470 475 480Arg Asn Gly Ala Ile His Ile Phe Arg Glu Ile Ile Lys Pro Ala Glu 485 490 495Lys Ser Leu His Glu Lys Leu Lys Gln Asp Lys Arg Phe Ser Thr Phe 500 505 510Leu Ser Leu Leu Glu Ala Ala Asp Leu Lys Glu Leu Leu Thr Gln Pro 515 520 525Gly Asp Trp Thr Leu Phe Val Pro Thr Asn Asp Ala Phe Lys Gly Met 530 535 540Thr Ser Glu Glu Lys Glu Ile Leu Ile Arg Asp Lys Asn Ala Leu Gln545 550 555 560Asn Ile Ile Leu Tyr His Leu Thr Pro Gly Val Phe Ile Gly Lys Gly 565 570 575Phe Glu Pro Gly Val Thr Asn Ile Leu Lys Thr Thr Gln Gly Ser Lys 580 585 590Ile Phe Leu Lys Glu Val Asn Asp Thr Leu Leu Val Asn Glu Leu Lys 595 600 605Ser Lys Glu Ser Asp Ile Met Thr Thr Asn Gly Val Ile His Val Val 610 615 620Asp Lys Leu Leu Tyr Pro Ala Asp Thr Pro Val Gly Asn Asp Gln Leu625 630 635 640Leu Glu Ile Leu Asn Lys Leu Ile Lys Tyr Ile Gln Ile Lys Phe Val 645 650 655Arg Gly Ser Thr Phe Lys Glu Ile Pro Val Thr Val Tyr Ser Pro Glu 660 665 670Ile Lys Tyr Thr Arg Ile Ser Thr Gly Gly Gly Glu Thr Glu Glu Thr 675 680 685Leu Lys Lys Leu Leu Gln Glu Asp Thr Pro Val Arg Lys Leu Gln Ala 690 695 700Asn Lys Lys Val Gln Gly Ser Arg Arg Arg Leu Arg Glu Gly Arg Ser705 710 715 720Gln51576DNAhumanCDS(37)...(477) 51cttctctggg acacattgcc ttctgttttc tccagc atg cgc ttg ctc cag ctc 54 Met Arg Leu Leu Gln Leu 1 5ctg ttc agg gcc agc cct gcc acc ctg ctc ctg gtt ctc tgc ctg cag 102Leu Phe Arg Ala Ser Pro Ala Thr Leu Leu Leu Val Leu Cys Leu Gln 10 15 20ttg ggg gcc aac aaa gct cag gac aac act cgg aag atc ata ata aag 150Leu Gly Ala Asn Lys Ala Gln Asp Asn Thr Arg Lys Ile Ile Ile Lys 25 30 35aat ttt gac att ccc aag tca gta cgt cca aat gac gaa gtc act gca 198Asn Phe Asp Ile Pro Lys Ser Val Arg Pro Asn Asp Glu Val Thr Ala 40 45 50gtg ctt gca gtt caa aca gaa ttg aaa gaa tgc atg gtg gtt aaa act 246Val Leu Ala Val Gln Thr Glu Leu Lys Glu Cys Met Val Val Lys Thr55 60 65 70tac ctc att agc agc atc cct cta caa ggt gca ttt aac tat aag tat 294Tyr Leu Ile Ser Ser Ile Pro Leu Gln Gly Ala Phe Asn Tyr Lys Tyr 75 80 85act gcc tgc cta tgt gac gac aat cca aaa acc ttc tac tgg gac ttt 342Thr Ala Cys Leu Cys Asp Asp Asn Pro Lys Thr Phe Tyr Trp Asp Phe 90 95 100tac acc aac aga act gtg caa att gca gcc gtc gtt gat gtt att cgg 390Tyr Thr Asn Arg Thr Val Gln Ile Ala Ala Val Val Asp Val Ile Arg 105 110 115gaa tta ggc atc tgc cct gat gat gct gct gta atc ccc atc aaa aac 438Glu Leu Gly Ile Cys Pro Asp Asp Ala Ala Val Ile Pro Ile Lys Asn 120 125 130aac cgg ttt tat act att gaa atc cta aag gta gaa taa tggaagccct 487Asn Arg Phe Tyr Thr Ile Glu Ile Leu Lys Val Glu *135 140 145gtctgtttgc cacacccagg tgatttcctc taaagaaact tggctggaat ttctgctgtg 547gtctataaaa taaacttctt aacatgctt 57652146PRThuman 52Met Arg Leu Leu Gln Leu Leu Phe Arg Ala Ser Pro Ala Thr Leu Leu1 5 10 15Leu Val Leu Cys Leu Gln Leu Gly Ala Asn Lys Ala Gln Asp Asn Thr 20 25 30Arg Lys Ile Ile Ile Lys Asn Phe Asp Ile Pro Lys Ser Val Arg Pro 35 40 45Asn Asp Glu Val Thr Ala Val Leu Ala Val Gln Thr Glu Leu Lys Glu 50 55 60Cys Met Val Val Lys Thr Tyr Leu Ile Ser Ser Ile Pro Leu Gln Gly65 70 75 80Ala Phe Asn Tyr Lys Tyr Thr Ala Cys Leu Cys Asp Asp Asn Pro Lys 85 90 95Thr Phe Tyr Trp Asp Phe Tyr Thr Asn Arg Thr Val Gln Ile Ala Ala 100 105 110Val Val Asp Val Ile Arg Glu Leu Gly Ile Cys Pro Asp Asp Ala Ala 115 120 125Val Ile Pro Ile Lys Asn Asn Arg Phe Tyr Thr Ile Glu Ile Leu Lys 130 135 140Val Glu145533734DNAhumanCDS(81)...(3077) 53ggcgtccgcg cacacctccc cgcgccgccg ccgccaccgc ccgcactccg ccgcctctgc 60ccgcaaccgc tgagccatcc atg ggg gtc gcg ggc cgc aac cgt ccc ggg gcg 113 Met Gly Val Ala Gly Arg Asn Arg Pro Gly Ala 1 5 10gcc tgg gcg gtg ctg ctg ctg ctg ctg ctg cta cca ctg ctg ctg ctg 161Ala Trp Ala Val Leu Leu Leu Leu Leu Leu Leu Pro Leu Leu Leu Leu 15 20 25gtg ggg gcc gtc ccg ccg ggt cgg ggc cgt gcc gcg ggg ccg cag gag 209Val Gly Ala Val Pro Pro Gly Arg Gly Arg Ala Ala Gly Pro Gln Glu 30 35 40gat gta gat gag tgt gcc caa ggg cta gat gac tgc cat gcc gac gcc 257Asp Val Asp Glu Cys Ala Gln Gly Leu Asp Asp Cys His Ala Asp Ala 45 50 55ctg tgt cag aac aca ccc acc tcc tac aag tgc tcc tgc aag cct ggc 305Leu Cys Gln Asn Thr Pro Thr Ser Tyr Lys Cys Ser Cys Lys Pro Gly60 65 70 75tac caa ggg gaa ggc agg cag tgt gag gac atc gat gaa tgt gga aat 353Tyr Gln Gly Glu Gly Arg Gln Cys Glu Asp Ile Asp Glu Cys Gly Asn 80 85 90gag ctc aat gga ggc tgt gtc cat gac tgt ttg aat att cca ggc aat 401Glu Leu Asn Gly Gly Cys Val His Asp Cys Leu Asn Ile Pro Gly Asn 95 100 105tat cgt tgc act tgt ttt gat ggc ttc atg ttg gct cat gac ggt cat 449Tyr Arg Cys Thr Cys Phe Asp Gly Phe Met Leu Ala His Asp Gly His 110 115 120aat tgt ctt gat gtg gac gag tgc ctg gag aac aat ggc ggc tgc cag 497Asn Cys Leu Asp Val Asp Glu Cys Leu Glu Asn Asn Gly Gly Cys Gln 125 130 135cat acc tgt gtc aac gtc atg ggg agc tat gag tgc tgc tgc aag gag 545His Thr Cys Val Asn Val Met Gly Ser Tyr Glu Cys Cys Cys Lys Glu140 145 150 155ggg ttt ttc ctg agt gac aat cag cac acc tgc att cac cgc tcg gaa 593Gly Phe Phe Leu Ser Asp Asn Gln His Thr Cys Ile His Arg Ser Glu 160 165 170gag ggc ctg agc tgc atg aat aag gat cac ggc tgt agt cac atc tgc 641Glu Gly Leu Ser Cys Met Asn Lys Asp His Gly Cys Ser His Ile Cys 175 180 185aag gag gcc cca agg ggc agc gtc gcc tgt gag tgc agg cct ggt ttt 689Lys Glu Ala Pro Arg Gly Ser Val Ala Cys Glu Cys Arg Pro Gly Phe 190 195 200gag ctg gcc aag aac cag aga gac tgc atc ttg acc tgt aac cat ggg 737Glu Leu Ala Lys Asn Gln Arg Asp Cys Ile Leu Thr Cys Asn His Gly 205 210 215aac ggt ggg tgc cag cac tcc tgt gac gat aca gcc gat ggc cca gag 785Asn Gly Gly Cys Gln His Ser Cys Asp Asp Thr Ala Asp Gly Pro Glu220 225 230 235tgc agc tgc cat cca cag tac aag atg cac aca gat ggg agg agc tgc 833Cys Ser Cys His Pro Gln Tyr Lys Met His Thr Asp Gly Arg Ser Cys 240 245 250ctt gag cga gag gac act gtc ctg gag gtg aca gag agc aac acc aca 881Leu Glu Arg Glu Asp Thr Val Leu Glu Val Thr Glu Ser Asn Thr Thr 255 260 265tca gtg gtg gat ggg gat aaa cgg gtg aaa cgg cgg ctg ctc atg gaa 929Ser Val Val Asp Gly Asp Lys Arg Val Lys Arg Arg Leu Leu Met Glu 270 275 280acg tgt gct gtc aac aat gga ggc tgt gac cgc acc tgt aag gat act 977Thr Cys Ala Val Asn Asn Gly Gly Cys Asp Arg Thr Cys Lys Asp Thr 285 290 295tcg aca ggt gtc cac tgc agt tgt cct gtt gga ttc act ctc cag ttg 1025Ser Thr Gly Val His Cys Ser Cys Pro Val Gly Phe Thr Leu Gln Leu300 305 310 315gat ggg aag aca tgt aaa gat att gat gag tgc cag acc cgc aat gga 1073Asp Gly Lys Thr Cys Lys Asp Ile Asp Glu Cys Gln Thr Arg Asn Gly 320 325 330ggt tgt gat cat ttc tgc aaa aac atc gtg ggc agt ttt gac tgc ggc 1121Gly Cys Asp His Phe Cys Lys Asn Ile Val Gly Ser Phe Asp Cys Gly 335 340 345tgc aag aaa gga ttt aaa tta tta aca gat gag aag tct tgc caa gat 1169Cys Lys Lys Gly Phe Lys Leu Leu Thr Asp Glu Lys Ser Cys Gln Asp 350 355 360gtg gat gag tgc tct ttg gat agg acc tgt gac cac agc tgc atc aac 1217Val Asp Glu Cys Ser Leu Asp Arg Thr Cys Asp His Ser Cys Ile Asn 365 370 375cac cct ggc aca ttt gct tgt gct tgc aac cga ggg tac acc ctg tat 1265His Pro Gly Thr Phe Ala Cys Ala Cys Asn Arg Gly Tyr Thr Leu Tyr380 385 390 395ggc ttc acc cac tgt gga gac acc aat gag tgc agc atc aac aac gga 1313Gly Phe Thr His Cys Gly Asp Thr Asn Glu Cys Ser Ile Asn Asn Gly 400 405 410ggc tgt cag cag gtc tgt gtg aac aca gtg ggc agc tat gaa tgc cag 1361Gly Cys Gln Gln Val Cys Val Asn Thr Val Gly Ser Tyr Glu Cys Gln 415 420 425tgc cac cct ggg tac aag ctc cac tgg aat aaa aaa gac tgt gtg gaa 1409Cys His Pro Gly Tyr Lys Leu His Trp Asn Lys Lys Asp Cys Val Glu 430 435 440gtg aag ggg ctc ctg ccc aca agt gtg tca ccc cgt gtg tcc ctg cac 1457Val Lys Gly Leu Leu Pro Thr Ser Val Ser Pro Arg Val Ser Leu His 445 450 455tgc ggt aag agt ggt gga gga gac ggg tgc ttc ctc aga tgt cac tct 1505Cys Gly Lys Ser Gly Gly Gly Asp Gly Cys Phe Leu Arg Cys His Ser460 465 470 475ggc att cac ctc tct tca gat gtc acc acc atc agg aca agt gta acc 1553Gly Ile His Leu Ser Ser Asp Val Thr Thr Ile Arg Thr Ser Val Thr 480 485 490ttt aag cta aat gaa ggc aag tgt agt ttg aaa aat gct gag ctg ttt 1601Phe Lys Leu Asn Glu Gly Lys Cys Ser Leu Lys Asn Ala Glu Leu Phe 495 500 505ccc gag ggt ctg cga cca gca cta cca gag aag cac agc tca gta aaa 1649Pro Glu Gly Leu Arg Pro Ala Leu Pro Glu Lys His Ser Ser Val Lys 510 515 520gag agc ttc cgc tac gta aac ctt aca tgc agc tct ggc aag caa gtc 1697Glu Ser Phe Arg Tyr Val Asn Leu Thr Cys Ser Ser Gly Lys Gln Val 525 530 535cca gga gcc cct ggc cga cca agc acc cct aag gaa atg ttt atc act 1745Pro Gly Ala Pro Gly Arg Pro Ser Thr Pro Lys Glu Met Phe Ile Thr540 545 550 555gtt gag ttt gag ctt gaa act aac caa aag gag gtg aca gct tct tgt 1793Val Glu Phe Glu Leu Glu Thr Asn Gln Lys Glu Val Thr Ala Ser Cys 560 565 570gac ctg agc tgc atc gta aag cga acc gag aag cgg ctc cgt aaa gcc 1841Asp Leu Ser Cys Ile Val Lys Arg Thr Glu Lys Arg Leu Arg Lys Ala 575 580 585atc cgc acg ctc aga aag gcc gtc cac agg gag cag ttt cac ctc cag 1889Ile Arg Thr Leu Arg Lys Ala Val His Arg Glu Gln Phe His Leu Gln 590 595 600ctc tca ggc atg aac ctc gac gtg gct aaa aag cct ccc aga aca tct 1937Leu Ser Gly Met Asn Leu Asp Val Ala Lys Lys Pro Pro Arg Thr Ser 605 610 615gaa cgc cag gca gag tcc tgt gga gtg ggc cag ggt cat gca gaa aac 1985Glu Arg Gln Ala Glu Ser Cys Gly Val Gly Gln Gly His Ala Glu Asn620 625 630 635caa tgt gtc agt tgc agg gct ggg acc tat tat gat gga gca cga gaa 2033Gln Cys Val Ser Cys Arg Ala Gly Thr Tyr Tyr Asp Gly Ala Arg Glu 640 645 650cgc tgc att tta tgt cca aat gga acc ttc caa aat gag gaa gga caa 2081Arg Cys Ile Leu Cys Pro Asn Gly Thr Phe Gln Asn Glu Glu Gly Gln 655 660 665atg act tgt gaa cca tgc cca aga cca gga aat tct ggg gcc ctg aag 2129Met Thr Cys Glu Pro Cys Pro Arg Pro Gly Asn Ser Gly Ala Leu Lys 670 675 680acc cca gaa gct tgg aat atg tct gaa tgt gga ggt ctg tgt caa cct 2177Thr Pro Glu Ala Trp Asn Met Ser Glu Cys Gly Gly Leu Cys Gln Pro 685 690 695ggt gaa tat tct gca gat ggc ttt gca cct tgc cag ctc tgt gcc ctg 2225Gly Glu Tyr Ser Ala Asp Gly Phe Ala Pro Cys Gln Leu Cys Ala Leu700 705 710 715ggc acg ttc cag cct gaa gct ggt cga act tcc tgc ttc ccc tgt gga 2273Gly Thr Phe Gln Pro Glu Ala Gly Arg Thr Ser Cys Phe Pro Cys Gly 720 725 730gga ggc ctt gcc acc aaa cat cag gga gct act tcc ttt cag gac tgt 2321Gly Gly Leu Ala Thr Lys His Gln Gly Ala Thr Ser Phe Gln Asp Cys 735 740 745gaa acc aga gtt caa tgt tca cct gga cat ttc tac aac acc acc act 2369Glu Thr Arg Val Gln Cys Ser Pro Gly His Phe Tyr Asn Thr Thr Thr 750 755 760cac cga tgt att cgt tgc cca gtg gga aca tac cag cct gaa ttt gga 2417His Arg Cys Ile Arg Cys Pro Val Gly Thr Tyr Gln Pro Glu Phe Gly 765 770 775aaa aat aat tgt gtt tct tgc cca gga aat act acg act gac ttt gat 2465Lys Asn Asn Cys Val Ser Cys Pro Gly Asn Thr Thr Thr Asp Phe Asp780 785 790 795ggc tcc aca aac ata acc cag tgt aaa aac aga aga tgt gga ggg gag 2513Gly Ser Thr Asn Ile Thr Gln Cys Lys Asn Arg Arg Cys Gly Gly Glu 800 805 810ctg gga gat ttc act ggg tac att gaa tcc cca aac tac cca ggc aat 2561Leu Gly Asp Phe Thr Gly Tyr Ile Glu Ser Pro Asn Tyr Pro Gly Asn 815 820 825tac cca gcc aac acc gag tgt acg tgg acc atc aac cca ccc ccc aag 2609Tyr Pro Ala Asn Thr Glu Cys Thr Trp Thr Ile Asn Pro Pro Pro Lys 830 835 840cgc cgc atc ctg atc gtg gtc cct gag atc ttc ctg ccc ata gag gac 2657Arg Arg Ile Leu Ile Val Val Pro Glu Ile Phe Leu Pro Ile Glu Asp 845 850 855gac tgt ggg gac tat ctg gtg atg cgg aaa acc tct tca tcc aat tct 2705Asp Cys Gly Asp Tyr Leu Val Met Arg Lys Thr Ser Ser Ser Asn Ser860 865 870 875gtg aca aca tat gaa acc tgc cag acc tac gaa cgc ccc atc gcc ttc 2753Val Thr Thr Tyr Glu Thr Cys Gln Thr Tyr Glu Arg Pro Ile Ala Phe 880 885 890acc tcc agg tca aag aag ctg tgg att cag ttc aag tcc aat gaa ggg 2801Thr Ser Arg Ser Lys Lys Leu Trp Ile Gln Phe Lys Ser Asn Glu Gly 895 900 905aac agc gct aga ggg ttc cag gtc cca tac gtg aca tat gat gag gac 2849Asn Ser Ala Arg Gly Phe Gln Val Pro Tyr Val Thr Tyr Asp Glu Asp 910 915 920tac cag gaa ctc att gaa gac ata gtt cga gat ggc agg ctc tat gca 2897Tyr Gln Glu Leu Ile Glu Asp Ile Val Arg Asp Gly Arg Leu Tyr Ala 925 930 935tct gag aac cat cag gaa ata ctt aag gat aag aaa ctt atc aag gct 2945Ser Glu Asn His Gln Glu Ile Leu Lys Asp Lys Lys Leu Ile Lys Ala940 945 950 955ctg ttt gat gtc ctg gcc cat ccc cag aac tat ttc aag tac aca gcc 2993Leu Phe Asp Val Leu Ala His Pro Gln Asn Tyr Phe Lys Tyr Thr Ala 960 965 970cag gag tcc cga gag atg ttt cca aga tcg ttc atc cga ttg cta cgt 3041Gln Glu Ser Arg Glu Met Phe Pro Arg Ser Phe Ile Arg Leu Leu Arg 975 980 985tcc aaa gtg tcc agg ttt ttg aga cct tac aaa tga ctcagcccac 3087Ser Lys Val Ser Arg Phe Leu Arg Pro Tyr Lys * 990 995gtgccactca atacaaatgt tctgctatag ggttggtggg acagagctgt cttccttctg 3147catgtcagca cagtcgggta ttgctgcctc ccgtatcagt gactcattag agttcaattt

3207ttatagataa tacagatatt ttggtaaatt gaacttggtt tttctttccc agcatcgtgg 3267atgtagactg agaatggctt tgagtggcat cagcttctca ctgctgtggg cggatgtctt 3327ggatagatca cgggctggct gagctggact ttggtcagcc taggtgagac tcacctgtcc 3387ttctggggtc ttactcctcc tcaaggagtc tgtagtggaa aggaggccac agaataagct 3447gcttattctg aaacttcagc ttcctctagc ccggccctct ctaagggagc cctctgcact 3507cgtgtgcagg ctctgaccag gcagaacagg caagagggga gggaaggaga cccctgcagg 3567ctccctccac ccaccttgag acctgggagg actcagtttc tccacagcct tctccagcct 3627gtgtgataca agtttgatcc caggaacttg agttctaagc agtgctcgtg aaaaaaaaaa 3687gcagaaagaa ttagaaataa ataaaaacta agcacttctg gagacat 373454998PRThuman 54Met Gly Val Ala Gly Arg Asn Arg Pro Gly Ala Ala Trp Ala Val Leu1 5 10 15Leu Leu Leu Leu Leu Leu Pro Leu Leu Leu Leu Val Gly Ala Val Pro 20 25 30Pro Gly Arg Gly Arg Ala Ala Gly Pro Gln Glu Asp Val Asp Glu Cys 35 40 45Ala Gln Gly Leu Asp Asp Cys His Ala Asp Ala Leu Cys Gln Asn Thr 50 55 60Pro Thr Ser Tyr Lys Cys Ser Cys Lys Pro Gly Tyr Gln Gly Glu Gly65 70 75 80Arg Gln Cys Glu Asp Ile Asp Glu Cys Gly Asn Glu Leu Asn Gly Gly 85 90 95Cys Val His Asp Cys Leu Asn Ile Pro Gly Asn Tyr Arg Cys Thr Cys 100 105 110Phe Asp Gly Phe Met Leu Ala His Asp Gly His Asn Cys Leu Asp Val 115 120 125Asp Glu Cys Leu Glu Asn Asn Gly Gly Cys Gln His Thr Cys Val Asn 130 135 140Val Met Gly Ser Tyr Glu Cys Cys Cys Lys Glu Gly Phe Phe Leu Ser145 150 155 160Asp Asn Gln His Thr Cys Ile His Arg Ser Glu Glu Gly Leu Ser Cys 165 170 175Met Asn Lys Asp His Gly Cys Ser His Ile Cys Lys Glu Ala Pro Arg 180 185 190Gly Ser Val Ala Cys Glu Cys Arg Pro Gly Phe Glu Leu Ala Lys Asn 195 200 205Gln Arg Asp Cys Ile Leu Thr Cys Asn His Gly Asn Gly Gly Cys Gln 210 215 220His Ser Cys Asp Asp Thr Ala Asp Gly Pro Glu Cys Ser Cys His Pro225 230 235 240Gln Tyr Lys Met His Thr Asp Gly Arg Ser Cys Leu Glu Arg Glu Asp 245 250 255Thr Val Leu Glu Val Thr Glu Ser Asn Thr Thr Ser Val Val Asp Gly 260 265 270Asp Lys Arg Val Lys Arg Arg Leu Leu Met Glu Thr Cys Ala Val Asn 275 280 285Asn Gly Gly Cys Asp Arg Thr Cys Lys Asp Thr Ser Thr Gly Val His 290 295 300Cys Ser Cys Pro Val Gly Phe Thr Leu Gln Leu Asp Gly Lys Thr Cys305 310 315 320Lys Asp Ile Asp Glu Cys Gln Thr Arg Asn Gly Gly Cys Asp His Phe 325 330 335Cys Lys Asn Ile Val Gly Ser Phe Asp Cys Gly Cys Lys Lys Gly Phe 340 345 350Lys Leu Leu Thr Asp Glu Lys Ser Cys Gln Asp Val Asp Glu Cys Ser 355 360 365Leu Asp Arg Thr Cys Asp His Ser Cys Ile Asn His Pro Gly Thr Phe 370 375 380Ala Cys Ala Cys Asn Arg Gly Tyr Thr Leu Tyr Gly Phe Thr His Cys385 390 395 400Gly Asp Thr Asn Glu Cys Ser Ile Asn Asn Gly Gly Cys Gln Gln Val 405 410 415Cys Val Asn Thr Val Gly Ser Tyr Glu Cys Gln Cys His Pro Gly Tyr 420 425 430Lys Leu His Trp Asn Lys Lys Asp Cys Val Glu Val Lys Gly Leu Leu 435 440 445Pro Thr Ser Val Ser Pro Arg Val Ser Leu His Cys Gly Lys Ser Gly 450 455 460Gly Gly Asp Gly Cys Phe Leu Arg Cys His Ser Gly Ile His Leu Ser465 470 475 480Ser Asp Val Thr Thr Ile Arg Thr Ser Val Thr Phe Lys Leu Asn Glu 485 490 495Gly Lys Cys Ser Leu Lys Asn Ala Glu Leu Phe Pro Glu Gly Leu Arg 500 505 510Pro Ala Leu Pro Glu Lys His Ser Ser Val Lys Glu Ser Phe Arg Tyr 515 520 525Val Asn Leu Thr Cys Ser Ser Gly Lys Gln Val Pro Gly Ala Pro Gly 530 535 540Arg Pro Ser Thr Pro Lys Glu Met Phe Ile Thr Val Glu Phe Glu Leu545 550 555 560Glu Thr Asn Gln Lys Glu Val Thr Ala Ser Cys Asp Leu Ser Cys Ile 565 570 575Val Lys Arg Thr Glu Lys Arg Leu Arg Lys Ala Ile Arg Thr Leu Arg 580 585 590Lys Ala Val His Arg Glu Gln Phe His Leu Gln Leu Ser Gly Met Asn 595 600 605Leu Asp Val Ala Lys Lys Pro Pro Arg Thr Ser Glu Arg Gln Ala Glu 610 615 620Ser Cys Gly Val Gly Gln Gly His Ala Glu Asn Gln Cys Val Ser Cys625 630 635 640Arg Ala Gly Thr Tyr Tyr Asp Gly Ala Arg Glu Arg Cys Ile Leu Cys 645 650 655Pro Asn Gly Thr Phe Gln Asn Glu Glu Gly Gln Met Thr Cys Glu Pro 660 665 670Cys Pro Arg Pro Gly Asn Ser Gly Ala Leu Lys Thr Pro Glu Ala Trp 675 680 685Asn Met Ser Glu Cys Gly Gly Leu Cys Gln Pro Gly Glu Tyr Ser Ala 690 695 700Asp Gly Phe Ala Pro Cys Gln Leu Cys Ala Leu Gly Thr Phe Gln Pro705 710 715 720Glu Ala Gly Arg Thr Ser Cys Phe Pro Cys Gly Gly Gly Leu Ala Thr 725 730 735Lys His Gln Gly Ala Thr Ser Phe Gln Asp Cys Glu Thr Arg Val Gln 740 745 750Cys Ser Pro Gly His Phe Tyr Asn Thr Thr Thr His Arg Cys Ile Arg 755 760 765Cys Pro Val Gly Thr Tyr Gln Pro Glu Phe Gly Lys Asn Asn Cys Val 770 775 780Ser Cys Pro Gly Asn Thr Thr Thr Asp Phe Asp Gly Ser Thr Asn Ile785 790 795 800Thr Gln Cys Lys Asn Arg Arg Cys Gly Gly Glu Leu Gly Asp Phe Thr 805 810 815Gly Tyr Ile Glu Ser Pro Asn Tyr Pro Gly Asn Tyr Pro Ala Asn Thr 820 825 830Glu Cys Thr Trp Thr Ile Asn Pro Pro Pro Lys Arg Arg Ile Leu Ile 835 840 845Val Val Pro Glu Ile Phe Leu Pro Ile Glu Asp Asp Cys Gly Asp Tyr 850 855 860Leu Val Met Arg Lys Thr Ser Ser Ser Asn Ser Val Thr Thr Tyr Glu865 870 875 880Thr Cys Gln Thr Tyr Glu Arg Pro Ile Ala Phe Thr Ser Arg Ser Lys 885 890 895Lys Leu Trp Ile Gln Phe Lys Ser Asn Glu Gly Asn Ser Ala Arg Gly 900 905 910Phe Gln Val Pro Tyr Val Thr Tyr Asp Glu Asp Tyr Gln Glu Leu Ile 915 920 925Glu Asp Ile Val Arg Asp Gly Arg Leu Tyr Ala Ser Glu Asn His Gln 930 935 940Glu Ile Leu Lys Asp Lys Lys Leu Ile Lys Ala Leu Phe Asp Val Leu945 950 955 960Ala His Pro Gln Asn Tyr Phe Lys Tyr Thr Ala Gln Glu Ser Arg Glu 965 970 975Met Phe Pro Arg Ser Phe Ile Arg Leu Leu Arg Ser Lys Val Ser Arg 980 985 990Phe Leu Arg Pro Tyr Lys 995553494DNAhumanCDS(81)...(2837) 55ggcgtccgcg cacacctccc cgcgccgccg ccgccaccgc ccgcactccg ccgcctctgc 60ccgcaaccgc tgagccatcc atg ggg gtc gcg ggc cgc aac cgt ccc ggg gcg 113 Met Gly Val Ala Gly Arg Asn Arg Pro Gly Ala 1 5 10gcc tgg gcg gtg ctg ctg ctg ctg ctg ctg cta cca ctg ctg ctg ctg 161Ala Trp Ala Val Leu Leu Leu Leu Leu Leu Leu Pro Leu Leu Leu Leu 15 20 25gtg ggg gcc gtc ccg ccg ggt cgg ggc cgt gcc gcg ggg ccg cag gag 209Val Gly Ala Val Pro Pro Gly Arg Gly Arg Ala Ala Gly Pro Gln Glu 30 35 40gat gta gat gag tgt gcc caa ggg cta gat gac tgc cat gcc gac gcc 257Asp Val Asp Glu Cys Ala Gln Gly Leu Asp Asp Cys His Ala Asp Ala 45 50 55ctg tgt cag aac aca ccc acc tcc tac aag tgc tcc tgc aag cct ggc 305Leu Cys Gln Asn Thr Pro Thr Ser Tyr Lys Cys Ser Cys Lys Pro Gly60 65 70 75tac caa ggg gaa ggc agg cag tgt gag gac atc gat gaa tgt gga aat 353Tyr Gln Gly Glu Gly Arg Gln Cys Glu Asp Ile Asp Glu Cys Gly Asn 80 85 90gag ctc aat gga ggc tgt gtc cat gac tgt ttg aat att cca ggc aat 401Glu Leu Asn Gly Gly Cys Val His Asp Cys Leu Asn Ile Pro Gly Asn 95 100 105tat cgt tgc act tgt ttt gat ggc ttc atg ttg gct cat gac ggt cat 449Tyr Arg Cys Thr Cys Phe Asp Gly Phe Met Leu Ala His Asp Gly His 110 115 120aat tgt ctt gat gtg gac gag tgc ctg gag aac aat ggc ggc tgc cag 497Asn Cys Leu Asp Val Asp Glu Cys Leu Glu Asn Asn Gly Gly Cys Gln 125 130 135cat acc tgt gtc aac gtc atg ggg agc tat gag tgc tgc tgc aag gag 545His Thr Cys Val Asn Val Met Gly Ser Tyr Glu Cys Cys Cys Lys Glu140 145 150 155ggg ttt ttc ctg agt gac aat cag cac acc tgc att cac cgc tcg gaa 593Gly Phe Phe Leu Ser Asp Asn Gln His Thr Cys Ile His Arg Ser Glu 160 165 170gag ggc ctg agc tgc atg aat aag gat cac ggc tgt agt cac atc tgc 641Glu Gly Leu Ser Cys Met Asn Lys Asp His Gly Cys Ser His Ile Cys 175 180 185aag gag gcc cca agg ggc agc gtc gcc tgt gag tgc agg cct ggt ttt 689Lys Glu Ala Pro Arg Gly Ser Val Ala Cys Glu Cys Arg Pro Gly Phe 190 195 200gag ctg gcc aag aac cag aga gac tgc atc ttg acc tgt aac cat ggg 737Glu Leu Ala Lys Asn Gln Arg Asp Cys Ile Leu Thr Cys Asn His Gly 205 210 215aac ggt ggg tgc cag cac tcc tgt gac gat aca gcc gat ggc cca gag 785Asn Gly Gly Cys Gln His Ser Cys Asp Asp Thr Ala Asp Gly Pro Glu220 225 230 235tgc agc tgc cat cca cag tac aag atg cac aca gat ggg agg agc tgc 833Cys Ser Cys His Pro Gln Tyr Lys Met His Thr Asp Gly Arg Ser Cys 240 245 250ctt gag cga gag gac act gtc ctg gag gtg aca gag agc aac acc aca 881Leu Glu Arg Glu Asp Thr Val Leu Glu Val Thr Glu Ser Asn Thr Thr 255 260 265tca gtg gtg gat ggg gat aaa cgg gtg aaa cgg cgg ctg ctc atg gaa 929Ser Val Val Asp Gly Asp Lys Arg Val Lys Arg Arg Leu Leu Met Glu 270 275 280acg tgt gct gtc aac aat gga ggc tgt gac cgc acc tgt aag gat act 977Thr Cys Ala Val Asn Asn Gly Gly Cys Asp Arg Thr Cys Lys Asp Thr 285 290 295tcg aca ggt gtc cac tgc agt tgt cct gtt gga ttc act ctc cag ttg 1025Ser Thr Gly Val His Cys Ser Cys Pro Val Gly Phe Thr Leu Gln Leu300 305 310 315gat ggg aag aca tgt aaa gat att gat gag tgc cag acc cgc aat gga 1073Asp Gly Lys Thr Cys Lys Asp Ile Asp Glu Cys Gln Thr Arg Asn Gly 320 325 330ggt tgt gat cat ttc tgc aaa aac atc gtg ggc agt ttt gac tgc ggc 1121Gly Cys Asp His Phe Cys Lys Asn Ile Val Gly Ser Phe Asp Cys Gly 335 340 345tgc aag aaa gga ttt aaa tta tta aca gat gag aag tct tgc caa gat 1169Cys Lys Lys Gly Phe Lys Leu Leu Thr Asp Glu Lys Ser Cys Gln Asp 350 355 360gtg gat gag tgc tct ttg gat agg acc tgt gac cac agc tgc atc aac 1217Val Asp Glu Cys Ser Leu Asp Arg Thr Cys Asp His Ser Cys Ile Asn 365 370 375cac cct ggc aca ttt gct tgt gct tgc aac cga ggg tac acc ctg tat 1265His Pro Gly Thr Phe Ala Cys Ala Cys Asn Arg Gly Tyr Thr Leu Tyr380 385 390 395ggc ttc acc cac tgt gga gat gtc acc acc atc agg aca agt gta acc 1313Gly Phe Thr His Cys Gly Asp Val Thr Thr Ile Arg Thr Ser Val Thr 400 405 410ttt aag cta aat gaa ggc aag tgt agt ttg aaa aat gct gag ctg ttt 1361Phe Lys Leu Asn Glu Gly Lys Cys Ser Leu Lys Asn Ala Glu Leu Phe 415 420 425ccc gag ggt ctg cga cca gca cta cca gag aag cac agc tca gta aaa 1409Pro Glu Gly Leu Arg Pro Ala Leu Pro Glu Lys His Ser Ser Val Lys 430 435 440gag agc ttc cgc tac gta aac ctt aca tgc agc tct ggc aag caa gtc 1457Glu Ser Phe Arg Tyr Val Asn Leu Thr Cys Ser Ser Gly Lys Gln Val 445 450 455cca gga gcc cct ggc cga cca agc acc cct aag gaa atg ttt atc act 1505Pro Gly Ala Pro Gly Arg Pro Ser Thr Pro Lys Glu Met Phe Ile Thr460 465 470 475gtt gag ttt gag ctt gaa act aac caa aag gag gtg aca gct tct tgt 1553Val Glu Phe Glu Leu Glu Thr Asn Gln Lys Glu Val Thr Ala Ser Cys 480 485 490gac ctg agc tgc atc gta aag cga acc gag aag cgg ctc cgt aaa gcc 1601Asp Leu Ser Cys Ile Val Lys Arg Thr Glu Lys Arg Leu Arg Lys Ala 495 500 505atc cgc acg ctc aga aag gcc gtc cac agg gag cag ttt cac ctc cag 1649Ile Arg Thr Leu Arg Lys Ala Val His Arg Glu Gln Phe His Leu Gln 510 515 520ctc tca ggc atg aac ctc gac gtg gct aaa aag cct ccc aga aca tct 1697Leu Ser Gly Met Asn Leu Asp Val Ala Lys Lys Pro Pro Arg Thr Ser 525 530 535gaa cgc cag gca gag tcc tgt gga gtg ggc cag ggt cat gca gaa aac 1745Glu Arg Gln Ala Glu Ser Cys Gly Val Gly Gln Gly His Ala Glu Asn540 545 550 555caa tgt gtc agt tgc agg gct ggg acc tat tat gat gga gca cga gaa 1793Gln Cys Val Ser Cys Arg Ala Gly Thr Tyr Tyr Asp Gly Ala Arg Glu 560 565 570cgc tgc att tta tgt cca aat gga acc ttc caa aat gag gaa gga caa 1841Arg Cys Ile Leu Cys Pro Asn Gly Thr Phe Gln Asn Glu Glu Gly Gln 575 580 585atg act tgt gaa cca tgc cca aga cca gga aat tct ggg gcc ctg aag 1889Met Thr Cys Glu Pro Cys Pro Arg Pro Gly Asn Ser Gly Ala Leu Lys 590 595 600acc cca gaa gct tgg aat atg tct gaa tgt gga ggt ctg tgt caa cct 1937Thr Pro Glu Ala Trp Asn Met Ser Glu Cys Gly Gly Leu Cys Gln Pro 605 610 615ggt gaa tat tct gca gat ggc ttt gca cct tgc cag ctc tgt gcc ctg 1985Gly Glu Tyr Ser Ala Asp Gly Phe Ala Pro Cys Gln Leu Cys Ala Leu620 625 630 635 ggc acg ttc cag cct gaa gct ggt cga act tcc tgc ttc ccc tgt gga 2033Gly Thr Phe Gln Pro Glu Ala Gly Arg Thr Ser Cys Phe Pro Cys Gly 640 645 650gga ggc ctt gcc acc aaa cat cag gga gct act tcc ttt cag gac tgt 2081Gly Gly Leu Ala Thr Lys His Gln Gly Ala Thr Ser Phe Gln Asp Cys 655 660 665gaa acc aga gtt caa tgt tca cct gga cat ttc tac aac acc acc act 2129Glu Thr Arg Val Gln Cys Ser Pro Gly His Phe Tyr Asn Thr Thr Thr 670 675 680cac cga tgt att cgt tgc cca gtg gga aca tac cag cct gaa ttt gga 2177His Arg Cys Ile Arg Cys Pro Val Gly Thr Tyr Gln Pro Glu Phe Gly 685 690 695aaa aat aat tgt gtt tct tgc cca gga aat act acg act gac ttt gat 2225Lys Asn Asn Cys Val Ser Cys Pro Gly Asn Thr Thr Thr Asp Phe Asp700 705 710 715ggc tcc aca aac ata acc cag tgt aaa aac aga aga tgt gga ggg gag 2273Gly Ser Thr Asn Ile Thr Gln Cys Lys Asn Arg Arg Cys Gly Gly Glu 720 725 730ctg gga gat ttc act ggg tac att gaa tcc cca aac tac cca ggc aat 2321Leu Gly Asp Phe Thr Gly Tyr Ile Glu Ser Pro Asn Tyr Pro Gly Asn 735 740 745tac cca gcc aac acc gag tgt acg tgg acc atc aac cca ccc ccc aag 2369Tyr Pro Ala Asn Thr Glu Cys Thr Trp Thr Ile Asn Pro Pro Pro Lys 750 755 760cgc cgc atc ctg atc gtg gtc cct gag atc ttc ctg ccc ata gag gac 2417Arg Arg Ile Leu Ile Val Val Pro Glu Ile Phe Leu Pro Ile Glu Asp 765 770 775gac tgt ggg gac tat ctg gtg atg cgg aaa acc tct tca tcc aat tct 2465Asp Cys Gly Asp Tyr Leu Val Met Arg Lys Thr Ser Ser Ser Asn Ser780 785 790 795gtg aca aca tat gaa acc tgc cag acc tac gaa cgc ccc atc gcc ttc 2513Val Thr Thr Tyr Glu Thr Cys Gln Thr Tyr Glu Arg Pro Ile Ala Phe 800 805 810acc tcc agg tca aag aag ctg tgg att cag ttc aag tcc aat gaa ggg 2561Thr Ser Arg Ser Lys Lys Leu Trp Ile Gln Phe Lys Ser Asn Glu Gly 815 820 825aac agc gct aga ggg ttc cag gtc cca tac gtg aca tat gat gag gac 2609Asn Ser Ala Arg Gly Phe Gln Val Pro Tyr Val Thr Tyr Asp Glu Asp 830 835 840tac cag gaa ctc att gaa gac ata gtt cga gat ggc agg ctc tat gca 2657Tyr Gln Glu Leu Ile Glu Asp

Ile Val Arg Asp Gly Arg Leu Tyr Ala 845 850 855tct gag aac cat cag gaa ata ctt aag gat aag aaa ctt atc aag gct 2705Ser Glu Asn His Gln Glu Ile Leu Lys Asp Lys Lys Leu Ile Lys Ala860 865 870 875ctg ttt gat gtc ctg gcc cat ccc cag aac tat ttc aag tac aca gcc 2753Leu Phe Asp Val Leu Ala His Pro Gln Asn Tyr Phe Lys Tyr Thr Ala 880 885 890cag gag tcc cga gag atg ttt cca aga tcg ttc atc cga ttg cta cgt 2801Gln Glu Ser Arg Glu Met Phe Pro Arg Ser Phe Ile Arg Leu Leu Arg 895 900 905tcc aaa gtg tcc agg ttt ttg aga cct tac aaa tga ctcagcccac 2847Ser Lys Val Ser Arg Phe Leu Arg Pro Tyr Lys * 910 915gtgccactca atacaaatgt tctgctatag ggttggtggg acagagctgt cttccttctg 2907catgtcagca cagtcgggta ttgctgcctc ccgtatcagt gactcattag agttcaattt 2967ttatagataa tacagatatt ttggtaaatt gaacttggtt tttctttccc agcatcgtgg 3027atgtagactg agaatggctt tgagtggcat cagcttctca ctgctgtggg cggatgtctt 3087ggatagatca cgggctggct gagctggact ttggtcagcc taggtgagac tcacctgtcc 3147ttctggggtc ttactcctcc tcaaggagtc tgtagtggaa aggaggccac agaataagct 3207gcttattctg aaacttcagc ttcctctagc ccggccctct ctaagggagc cctctgcact 3267cgtgtgcagg ctctgaccag gcagaacagg caagagggga gggaaggaga cccctgcagg 3327ctccctccac ccaccttgag acctgggagg actcagtttc tccacagcct tctccagcct 3387gtgtgataca agtttgatcc caggaacttg agttctaagc agtgctcgtg aaaaaaaaaa 3447gcagaaagaa ttagaaataa ataaaaacta agcacttctg gagacat 349456918PRThuman 56Met Gly Val Ala Gly Arg Asn Arg Pro Gly Ala Ala Trp Ala Val Leu1 5 10 15Leu Leu Leu Leu Leu Leu Pro Leu Leu Leu Leu Val Gly Ala Val Pro 20 25 30Pro Gly Arg Gly Arg Ala Ala Gly Pro Gln Glu Asp Val Asp Glu Cys 35 40 45Ala Gln Gly Leu Asp Asp Cys His Ala Asp Ala Leu Cys Gln Asn Thr 50 55 60Pro Thr Ser Tyr Lys Cys Ser Cys Lys Pro Gly Tyr Gln Gly Glu Gly65 70 75 80Arg Gln Cys Glu Asp Ile Asp Glu Cys Gly Asn Glu Leu Asn Gly Gly 85 90 95Cys Val His Asp Cys Leu Asn Ile Pro Gly Asn Tyr Arg Cys Thr Cys 100 105 110Phe Asp Gly Phe Met Leu Ala His Asp Gly His Asn Cys Leu Asp Val 115 120 125Asp Glu Cys Leu Glu Asn Asn Gly Gly Cys Gln His Thr Cys Val Asn 130 135 140Val Met Gly Ser Tyr Glu Cys Cys Cys Lys Glu Gly Phe Phe Leu Ser145 150 155 160Asp Asn Gln His Thr Cys Ile His Arg Ser Glu Glu Gly Leu Ser Cys 165 170 175Met Asn Lys Asp His Gly Cys Ser His Ile Cys Lys Glu Ala Pro Arg 180 185 190Gly Ser Val Ala Cys Glu Cys Arg Pro Gly Phe Glu Leu Ala Lys Asn 195 200 205Gln Arg Asp Cys Ile Leu Thr Cys Asn His Gly Asn Gly Gly Cys Gln 210 215 220His Ser Cys Asp Asp Thr Ala Asp Gly Pro Glu Cys Ser Cys His Pro225 230 235 240Gln Tyr Lys Met His Thr Asp Gly Arg Ser Cys Leu Glu Arg Glu Asp 245 250 255Thr Val Leu Glu Val Thr Glu Ser Asn Thr Thr Ser Val Val Asp Gly 260 265 270Asp Lys Arg Val Lys Arg Arg Leu Leu Met Glu Thr Cys Ala Val Asn 275 280 285Asn Gly Gly Cys Asp Arg Thr Cys Lys Asp Thr Ser Thr Gly Val His 290 295 300Cys Ser Cys Pro Val Gly Phe Thr Leu Gln Leu Asp Gly Lys Thr Cys305 310 315 320Lys Asp Ile Asp Glu Cys Gln Thr Arg Asn Gly Gly Cys Asp His Phe 325 330 335Cys Lys Asn Ile Val Gly Ser Phe Asp Cys Gly Cys Lys Lys Gly Phe 340 345 350Lys Leu Leu Thr Asp Glu Lys Ser Cys Gln Asp Val Asp Glu Cys Ser 355 360 365Leu Asp Arg Thr Cys Asp His Ser Cys Ile Asn His Pro Gly Thr Phe 370 375 380Ala Cys Ala Cys Asn Arg Gly Tyr Thr Leu Tyr Gly Phe Thr His Cys385 390 395 400Gly Asp Val Thr Thr Ile Arg Thr Ser Val Thr Phe Lys Leu Asn Glu 405 410 415Gly Lys Cys Ser Leu Lys Asn Ala Glu Leu Phe Pro Glu Gly Leu Arg 420 425 430Pro Ala Leu Pro Glu Lys His Ser Ser Val Lys Glu Ser Phe Arg Tyr 435 440 445Val Asn Leu Thr Cys Ser Ser Gly Lys Gln Val Pro Gly Ala Pro Gly 450 455 460Arg Pro Ser Thr Pro Lys Glu Met Phe Ile Thr Val Glu Phe Glu Leu465 470 475 480Glu Thr Asn Gln Lys Glu Val Thr Ala Ser Cys Asp Leu Ser Cys Ile 485 490 495Val Lys Arg Thr Glu Lys Arg Leu Arg Lys Ala Ile Arg Thr Leu Arg 500 505 510Lys Ala Val His Arg Glu Gln Phe His Leu Gln Leu Ser Gly Met Asn 515 520 525Leu Asp Val Ala Lys Lys Pro Pro Arg Thr Ser Glu Arg Gln Ala Glu 530 535 540Ser Cys Gly Val Gly Gln Gly His Ala Glu Asn Gln Cys Val Ser Cys545 550 555 560Arg Ala Gly Thr Tyr Tyr Asp Gly Ala Arg Glu Arg Cys Ile Leu Cys 565 570 575Pro Asn Gly Thr Phe Gln Asn Glu Glu Gly Gln Met Thr Cys Glu Pro 580 585 590Cys Pro Arg Pro Gly Asn Ser Gly Ala Leu Lys Thr Pro Glu Ala Trp 595 600 605Asn Met Ser Glu Cys Gly Gly Leu Cys Gln Pro Gly Glu Tyr Ser Ala 610 615 620Asp Gly Phe Ala Pro Cys Gln Leu Cys Ala Leu Gly Thr Phe Gln Pro625 630 635 640Glu Ala Gly Arg Thr Ser Cys Phe Pro Cys Gly Gly Gly Leu Ala Thr 645 650 655Lys His Gln Gly Ala Thr Ser Phe Gln Asp Cys Glu Thr Arg Val Gln 660 665 670Cys Ser Pro Gly His Phe Tyr Asn Thr Thr Thr His Arg Cys Ile Arg 675 680 685Cys Pro Val Gly Thr Tyr Gln Pro Glu Phe Gly Lys Asn Asn Cys Val 690 695 700Ser Cys Pro Gly Asn Thr Thr Thr Asp Phe Asp Gly Ser Thr Asn Ile705 710 715 720Thr Gln Cys Lys Asn Arg Arg Cys Gly Gly Glu Leu Gly Asp Phe Thr 725 730 735Gly Tyr Ile Glu Ser Pro Asn Tyr Pro Gly Asn Tyr Pro Ala Asn Thr 740 745 750Glu Cys Thr Trp Thr Ile Asn Pro Pro Pro Lys Arg Arg Ile Leu Ile 755 760 765Val Val Pro Glu Ile Phe Leu Pro Ile Glu Asp Asp Cys Gly Asp Tyr 770 775 780Leu Val Met Arg Lys Thr Ser Ser Ser Asn Ser Val Thr Thr Tyr Glu785 790 795 800Thr Cys Gln Thr Tyr Glu Arg Pro Ile Ala Phe Thr Ser Arg Ser Lys 805 810 815Lys Leu Trp Ile Gln Phe Lys Ser Asn Glu Gly Asn Ser Ala Arg Gly 820 825 830Phe Gln Val Pro Tyr Val Thr Tyr Asp Glu Asp Tyr Gln Glu Leu Ile 835 840 845Glu Asp Ile Val Arg Asp Gly Arg Leu Tyr Ala Ser Glu Asn His Gln 850 855 860Glu Ile Leu Lys Asp Lys Lys Leu Ile Lys Ala Leu Phe Asp Val Leu865 870 875 880Ala His Pro Gln Asn Tyr Phe Lys Tyr Thr Ala Gln Glu Ser Arg Glu 885 890 895Met Phe Pro Arg Ser Phe Ile Arg Leu Leu Arg Ser Lys Val Ser Arg 900 905 910Phe Leu Arg Pro Tyr Lys 915573356DNAhumanCDS(81)...(2699) 57ggcgtccgcg cacacctccc cgcgccgccg ccgccaccgc ccgcactccg ccgcctctgc 60ccgcaaccgc tgagccatcc atg ggg gtc gcg ggc cgc aac cgt ccc ggg gcg 113 Met Gly Val Ala Gly Arg Asn Arg Pro Gly Ala 1 5 10gcc tgg gcg gtg ctg ctg ctg ctg ctg ctg cta cca ctg ctg ctg ctg 161Ala Trp Ala Val Leu Leu Leu Leu Leu Leu Leu Pro Leu Leu Leu Leu 15 20 25gtg ggg gcc gtc ccg ccg ggt cgg ggc cgt gcc gcg ggg ccg cag gag 209Val Gly Ala Val Pro Pro Gly Arg Gly Arg Ala Ala Gly Pro Gln Glu 30 35 40gat gta gat gag tgt gcc caa ggg cta gat gac tgc cat gcc gac gcc 257Asp Val Asp Glu Cys Ala Gln Gly Leu Asp Asp Cys His Ala Asp Ala 45 50 55ctg tgt cag aac aca ccc acc tcc tac aag tgc tcc tgc aag cct ggc 305Leu Cys Gln Asn Thr Pro Thr Ser Tyr Lys Cys Ser Cys Lys Pro Gly60 65 70 75tac caa ggg gaa ggc agg cag tgt gag gac atc gat gaa tgt gga aat 353Tyr Gln Gly Glu Gly Arg Gln Cys Glu Asp Ile Asp Glu Cys Gly Asn 80 85 90gag ctc aat gga ggc tgt gtc cat gac tgt ttg aat att cca ggc aat 401Glu Leu Asn Gly Gly Cys Val His Asp Cys Leu Asn Ile Pro Gly Asn 95 100 105tat cgt tgc act tgt ttt gat ggc ttc atg ttg gct cat gac ggt cat 449Tyr Arg Cys Thr Cys Phe Asp Gly Phe Met Leu Ala His Asp Gly His 110 115 120aat tgt ctt gat gtg gac gag tgc ctg gag aac aat ggc ggc tgc cag 497Asn Cys Leu Asp Val Asp Glu Cys Leu Glu Asn Asn Gly Gly Cys Gln 125 130 135cat acc tgt gtc aac gtc atg ggg agc tat gag tgc tgc tgc aag gag 545His Thr Cys Val Asn Val Met Gly Ser Tyr Glu Cys Cys Cys Lys Glu140 145 150 155ggg ttt ttc ctg agt gac aat cag cac acc tgc att cac cgc tcg gaa 593Gly Phe Phe Leu Ser Asp Asn Gln His Thr Cys Ile His Arg Ser Glu 160 165 170gag ggc ctg agc tgc atg aat aag gat cac ggc tgt agt cac atc tgc 641Glu Gly Leu Ser Cys Met Asn Lys Asp His Gly Cys Ser His Ile Cys 175 180 185aag gag gcc cca agg ggc agc gtc gcc tgt gag tgc agg cct ggt ttt 689Lys Glu Ala Pro Arg Gly Ser Val Ala Cys Glu Cys Arg Pro Gly Phe 190 195 200gag ctg gcc aag aac cag aga gac tgc atc ttg acc tgt aac cat ggg 737Glu Leu Ala Lys Asn Gln Arg Asp Cys Ile Leu Thr Cys Asn His Gly 205 210 215aac ggt ggg tgc cag cac tcc tgt gac gat aca gcc gat ggc cca gag 785Asn Gly Gly Cys Gln His Ser Cys Asp Asp Thr Ala Asp Gly Pro Glu220 225 230 235tgc agc tgc cat cca cag tac aag atg cac aca gat ggg agg agc tgc 833Cys Ser Cys His Pro Gln Tyr Lys Met His Thr Asp Gly Arg Ser Cys 240 245 250ctt gag cga gag gac act gtc ctg gag gtg aca gag agc aac acc aca 881Leu Glu Arg Glu Asp Thr Val Leu Glu Val Thr Glu Ser Asn Thr Thr 255 260 265tca gtg gtg gat ggg gat aaa cgg gtg aaa cgg cgg ctg ctc atg gaa 929Ser Val Val Asp Gly Asp Lys Arg Val Lys Arg Arg Leu Leu Met Glu 270 275 280acg tgt gct gtc aac aat gga ggc tgt gac cgc acc tgt aag gat act 977Thr Cys Ala Val Asn Asn Gly Gly Cys Asp Arg Thr Cys Lys Asp Thr 285 290 295tcg aca ggt gtc cac tgc agt tgt cct gtt gga ttc act ctc cag ttg 1025Ser Thr Gly Val His Cys Ser Cys Pro Val Gly Phe Thr Leu Gln Leu300 305 310 315gat ggg aag aca tgt aaa gat att gat gag tgc cag acc cgc aat gga 1073Asp Gly Lys Thr Cys Lys Asp Ile Asp Glu Cys Gln Thr Arg Asn Gly 320 325 330ggt tgt gat cat ttc tgc aaa aac atc gtg ggc agt ttt gac tgc ggc 1121Gly Cys Asp His Phe Cys Lys Asn Ile Val Gly Ser Phe Asp Cys Gly 335 340 345tgc aag aaa gga ttt aaa tta tta aca gat gag aag tct tgc caa gat 1169Cys Lys Lys Gly Phe Lys Leu Leu Thr Asp Glu Lys Ser Cys Gln Asp 350 355 360gtg gat gag tgc tct ttg gat agg acc tgt gac cac agc tgc atc aac 1217Val Asp Glu Cys Ser Leu Asp Arg Thr Cys Asp His Ser Cys Ile Asn 365 370 375 cac cct ggc aca ttt gct tgt gct tgc aac cga ggg tac acc ctg tat 1265His Pro Gly Thr Phe Ala Cys Ala Cys Asn Arg Gly Tyr Thr Leu Tyr380 385 390 395ggc ttc acc cac tgt gga gac acc aat gag tgc agc atc aac aac gga 1313Gly Phe Thr His Cys Gly Asp Thr Asn Glu Cys Ser Ile Asn Asn Gly 400 405 410ggc tgt cag cag gtc tgt gtg aac aca gtg ggc agc tat gaa tgc cag 1361Gly Cys Gln Gln Val Cys Val Asn Thr Val Gly Ser Tyr Glu Cys Gln 415 420 425tgc cac cct ggg tac aag ctc cac tgg aat aaa aaa gac tgt gtg gct 1409Cys His Pro Gly Tyr Lys Leu His Trp Asn Lys Lys Asp Cys Val Ala 430 435 440tct tgt gac ctg agc tgc atc gta aag cga acc gag aag cgg ctc cgt 1457Ser Cys Asp Leu Ser Cys Ile Val Lys Arg Thr Glu Lys Arg Leu Arg 445 450 455aaa gcc atc cgc acg ctc aga aag gcc gtc cac agg gag cag ttt cac 1505Lys Ala Ile Arg Thr Leu Arg Lys Ala Val His Arg Glu Gln Phe His460 465 470 475ctc cag ctc tca ggc atg aac ctc gac gtg gct aaa aag cct ccc aga 1553Leu Gln Leu Ser Gly Met Asn Leu Asp Val Ala Lys Lys Pro Pro Arg 480 485 490aca tct gaa cgc cag gca gag tcc tgt gga gtg ggc cag ggt cat gca 1601Thr Ser Glu Arg Gln Ala Glu Ser Cys Gly Val Gly Gln Gly His Ala 495 500 505gaa aac caa tgt gtc agt tgc agg gct ggg acc tat tat gat gga gca 1649Glu Asn Gln Cys Val Ser Cys Arg Ala Gly Thr Tyr Tyr Asp Gly Ala 510 515 520cga gaa cgc tgc att tta tgt cca aat gga acc ttc caa aat gag gaa 1697Arg Glu Arg Cys Ile Leu Cys Pro Asn Gly Thr Phe Gln Asn Glu Glu 525 530 535gga caa atg act tgt gaa cca tgc cca aga cca gga aat tct ggg gcc 1745Gly Gln Met Thr Cys Glu Pro Cys Pro Arg Pro Gly Asn Ser Gly Ala540 545 550 555ctg aag acc cca gaa gct tgg aat atg tct gaa tgt gga ggt ctg tgt 1793Leu Lys Thr Pro Glu Ala Trp Asn Met Ser Glu Cys Gly Gly Leu Cys 560 565 570caa cct ggt gaa tat tct gca gat ggc ttt gca cct tgc cag ctc tgt 1841Gln Pro Gly Glu Tyr Ser Ala Asp Gly Phe Ala Pro Cys Gln Leu Cys 575 580 585gcc ctg ggc acg ttc cag cct gaa gct ggt cga act tcc tgc ttc ccc 1889Ala Leu Gly Thr Phe Gln Pro Glu Ala Gly Arg Thr Ser Cys Phe Pro 590 595 600tgt gga gga ggc ctt gcc acc aaa cat cag gga gct act tcc ttt cag 1937Cys Gly Gly Gly Leu Ala Thr Lys His Gln Gly Ala Thr Ser Phe Gln 605 610 615gac tgt gaa acc aga gtt caa tgt tca cct gga cat ttc tac aac acc 1985Asp Cys Glu Thr Arg Val Gln Cys Ser Pro Gly His Phe Tyr Asn Thr620 625 630 635acc act cac cga tgt att cgt tgc cca gtg gga aca tac cag cct gaa 2033Thr Thr His Arg Cys Ile Arg Cys Pro Val Gly Thr Tyr Gln Pro Glu 640 645 650ttt gga aaa aat aat tgt gtt tct tgc cca gga aat act acg act gac 2081Phe Gly Lys Asn Asn Cys Val Ser Cys Pro Gly Asn Thr Thr Thr Asp 655 660 665ttt gat ggc tcc aca aac ata acc cag tgt aaa aac aga aga tgt gga 2129Phe Asp Gly Ser Thr Asn Ile Thr Gln Cys Lys Asn Arg Arg Cys Gly 670 675 680ggg gag ctg gga gat ttc act ggg tac att gaa tcc cca aac tac cca 2177Gly Glu Leu Gly Asp Phe Thr Gly Tyr Ile Glu Ser Pro Asn Tyr Pro 685 690 695ggc aat tac cca gcc aac acc gag tgt acg tgg acc atc aac cca ccc 2225Gly Asn Tyr Pro Ala Asn Thr Glu Cys Thr Trp Thr Ile Asn Pro Pro700 705 710 715ccc aag cgc cgc atc ctg atc gtg gtc cct gag atc ttc ctg ccc ata 2273Pro Lys Arg Arg Ile Leu Ile Val Val Pro Glu Ile Phe Leu Pro Ile 720 725 730gag gac gac tgt ggg gac tat ctg gtg atg cgg aaa acc tct tca tcc 2321Glu Asp Asp Cys Gly Asp Tyr Leu Val Met Arg Lys Thr Ser Ser Ser 735 740 745aat tct gtg aca aca tat gaa acc tgc cag acc tac gaa cgc ccc atc 2369Asn Ser Val Thr Thr Tyr Glu Thr Cys Gln Thr Tyr Glu Arg Pro Ile 750 755 760gcc ttc acc tcc agg tca aag aag ctg tgg att cag ttc aag tcc aat 2417Ala Phe Thr Ser Arg Ser Lys Lys Leu Trp Ile Gln Phe Lys Ser Asn 765 770 775gaa ggg aac agc gct aga ggg ttc cag gtc cca tac gtg aca tat gat 2465Glu Gly Asn Ser Ala Arg Gly Phe Gln Val Pro Tyr Val Thr Tyr Asp780 785 790 795gag gac tac cag gaa ctc att gaa gac ata gtt cga gat ggc agg ctc 2513Glu Asp Tyr Gln Glu Leu Ile Glu Asp Ile Val Arg Asp Gly Arg Leu 800 805 810tat gca tct gag aac cat cag gaa ata ctt aag gat aag aaa ctt atc 2561Tyr Ala Ser Glu Asn His Gln Glu Ile Leu

Lys Asp Lys Lys Leu Ile 815 820 825aag gct ctg ttt gat gtc ctg gcc cat ccc cag aac tat ttc aag tac 2609Lys Ala Leu Phe Asp Val Leu Ala His Pro Gln Asn Tyr Phe Lys Tyr 830 835 840aca gcc cag gag tcc cga gag atg ttt cca aga tcg ttc atc cga ttg 2657Thr Ala Gln Glu Ser Arg Glu Met Phe Pro Arg Ser Phe Ile Arg Leu 845 850 855cta cgt tcc aaa gtg tcc agg ttt ttg aga cct tac aaa tga 2699Leu Arg Ser Lys Val Ser Arg Phe Leu Arg Pro Tyr Lys *860 865 870ctcagcccac gtgccactca atacaaatgt tctgctatag ggttggtggg acagagctgt 2759cttccttctg catgtcagca cagtcgggta ttgctgcctc ccgtatcagt gactcattag 2819agttcaattt ttatagataa tacagatatt ttggtaaatt gaacttggtt tttctttccc 2879agcatcgtgg atgtagactg agaatggctt tgagtggcat cagcttctca ctgctgtggg 2939cggatgtctt ggatagatca cgggctggct gagctggact ttggtcagcc taggtgagac 2999tcacctgtcc ttctggggtc ttactcctcc tcaaggagtc tgtagtggaa aggaggccac 3059agaataagct gcttattctg aaacttcagc ttcctctagc ccggccctct ctaagggagc 3119cctctgcact cgtgtgcagg ctctgaccag gcagaacagg caagagggga gggaaggaga 3179cccctgcagg ctccctccac ccaccttgag acctgggagg actcagtttc tccacagcct 3239tctccagcct gtgtgataca agtttgatcc caggaacttg agttctaagc agtgctcgtg 3299aaaaaaaaaa gcagaaagaa ttagaaataa ataaaaacta agcacttctg gagacat 335658872PRThuman 58Met Gly Val Ala Gly Arg Asn Arg Pro Gly Ala Ala Trp Ala Val Leu1 5 10 15Leu Leu Leu Leu Leu Leu Pro Leu Leu Leu Leu Val Gly Ala Val Pro 20 25 30Pro Gly Arg Gly Arg Ala Ala Gly Pro Gln Glu Asp Val Asp Glu Cys 35 40 45Ala Gln Gly Leu Asp Asp Cys His Ala Asp Ala Leu Cys Gln Asn Thr 50 55 60Pro Thr Ser Tyr Lys Cys Ser Cys Lys Pro Gly Tyr Gln Gly Glu Gly65 70 75 80Arg Gln Cys Glu Asp Ile Asp Glu Cys Gly Asn Glu Leu Asn Gly Gly 85 90 95Cys Val His Asp Cys Leu Asn Ile Pro Gly Asn Tyr Arg Cys Thr Cys 100 105 110Phe Asp Gly Phe Met Leu Ala His Asp Gly His Asn Cys Leu Asp Val 115 120 125Asp Glu Cys Leu Glu Asn Asn Gly Gly Cys Gln His Thr Cys Val Asn 130 135 140Val Met Gly Ser Tyr Glu Cys Cys Cys Lys Glu Gly Phe Phe Leu Ser145 150 155 160Asp Asn Gln His Thr Cys Ile His Arg Ser Glu Glu Gly Leu Ser Cys 165 170 175Met Asn Lys Asp His Gly Cys Ser His Ile Cys Lys Glu Ala Pro Arg 180 185 190Gly Ser Val Ala Cys Glu Cys Arg Pro Gly Phe Glu Leu Ala Lys Asn 195 200 205Gln Arg Asp Cys Ile Leu Thr Cys Asn His Gly Asn Gly Gly Cys Gln 210 215 220His Ser Cys Asp Asp Thr Ala Asp Gly Pro Glu Cys Ser Cys His Pro225 230 235 240Gln Tyr Lys Met His Thr Asp Gly Arg Ser Cys Leu Glu Arg Glu Asp 245 250 255Thr Val Leu Glu Val Thr Glu Ser Asn Thr Thr Ser Val Val Asp Gly 260 265 270Asp Lys Arg Val Lys Arg Arg Leu Leu Met Glu Thr Cys Ala Val Asn 275 280 285Asn Gly Gly Cys Asp Arg Thr Cys Lys Asp Thr Ser Thr Gly Val His 290 295 300Cys Ser Cys Pro Val Gly Phe Thr Leu Gln Leu Asp Gly Lys Thr Cys305 310 315 320Lys Asp Ile Asp Glu Cys Gln Thr Arg Asn Gly Gly Cys Asp His Phe 325 330 335Cys Lys Asn Ile Val Gly Ser Phe Asp Cys Gly Cys Lys Lys Gly Phe 340 345 350Lys Leu Leu Thr Asp Glu Lys Ser Cys Gln Asp Val Asp Glu Cys Ser 355 360 365Leu Asp Arg Thr Cys Asp His Ser Cys Ile Asn His Pro Gly Thr Phe 370 375 380Ala Cys Ala Cys Asn Arg Gly Tyr Thr Leu Tyr Gly Phe Thr His Cys385 390 395 400Gly Asp Thr Asn Glu Cys Ser Ile Asn Asn Gly Gly Cys Gln Gln Val 405 410 415Cys Val Asn Thr Val Gly Ser Tyr Glu Cys Gln Cys His Pro Gly Tyr 420 425 430Lys Leu His Trp Asn Lys Lys Asp Cys Val Ala Ser Cys Asp Leu Ser 435 440 445Cys Ile Val Lys Arg Thr Glu Lys Arg Leu Arg Lys Ala Ile Arg Thr 450 455 460Leu Arg Lys Ala Val His Arg Glu Gln Phe His Leu Gln Leu Ser Gly465 470 475 480Met Asn Leu Asp Val Ala Lys Lys Pro Pro Arg Thr Ser Glu Arg Gln 485 490 495Ala Glu Ser Cys Gly Val Gly Gln Gly His Ala Glu Asn Gln Cys Val 500 505 510Ser Cys Arg Ala Gly Thr Tyr Tyr Asp Gly Ala Arg Glu Arg Cys Ile 515 520 525Leu Cys Pro Asn Gly Thr Phe Gln Asn Glu Glu Gly Gln Met Thr Cys 530 535 540Glu Pro Cys Pro Arg Pro Gly Asn Ser Gly Ala Leu Lys Thr Pro Glu545 550 555 560Ala Trp Asn Met Ser Glu Cys Gly Gly Leu Cys Gln Pro Gly Glu Tyr 565 570 575Ser Ala Asp Gly Phe Ala Pro Cys Gln Leu Cys Ala Leu Gly Thr Phe 580 585 590Gln Pro Glu Ala Gly Arg Thr Ser Cys Phe Pro Cys Gly Gly Gly Leu 595 600 605Ala Thr Lys His Gln Gly Ala Thr Ser Phe Gln Asp Cys Glu Thr Arg 610 615 620Val Gln Cys Ser Pro Gly His Phe Tyr Asn Thr Thr Thr His Arg Cys625 630 635 640Ile Arg Cys Pro Val Gly Thr Tyr Gln Pro Glu Phe Gly Lys Asn Asn 645 650 655Cys Val Ser Cys Pro Gly Asn Thr Thr Thr Asp Phe Asp Gly Ser Thr 660 665 670Asn Ile Thr Gln Cys Lys Asn Arg Arg Cys Gly Gly Glu Leu Gly Asp 675 680 685Phe Thr Gly Tyr Ile Glu Ser Pro Asn Tyr Pro Gly Asn Tyr Pro Ala 690 695 700Asn Thr Glu Cys Thr Trp Thr Ile Asn Pro Pro Pro Lys Arg Arg Ile705 710 715 720Leu Ile Val Val Pro Glu Ile Phe Leu Pro Ile Glu Asp Asp Cys Gly 725 730 735Asp Tyr Leu Val Met Arg Lys Thr Ser Ser Ser Asn Ser Val Thr Thr 740 745 750Tyr Glu Thr Cys Gln Thr Tyr Glu Arg Pro Ile Ala Phe Thr Ser Arg 755 760 765Ser Lys Lys Leu Trp Ile Gln Phe Lys Ser Asn Glu Gly Asn Ser Ala 770 775 780Arg Gly Phe Gln Val Pro Tyr Val Thr Tyr Asp Glu Asp Tyr Gln Glu785 790 795 800Leu Ile Glu Asp Ile Val Arg Asp Gly Arg Leu Tyr Ala Ser Glu Asn 805 810 815His Gln Glu Ile Leu Lys Asp Lys Lys Leu Ile Lys Ala Leu Phe Asp 820 825 830Val Leu Ala His Pro Gln Asn Tyr Phe Lys Tyr Thr Ala Gln Glu Ser 835 840 845Arg Glu Met Phe Pro Arg Ser Phe Ile Arg Leu Leu Arg Ser Lys Val 850 855 860Ser Arg Phe Leu Arg Pro Tyr Lys865 870593821DNAhumanCDS(81)...(3164) 59ggcgtccgcg cacacctccc cgcgccgccg ccgccaccgc ccgcactccg ccgcctctgc 60ccgcaaccgc tgagccatcc atg ggg gtc gcg ggc cgc aac cgt ccc ggg gcg 113 Met Gly Val Ala Gly Arg Asn Arg Pro Gly Ala 1 5 10gcc tgg gcg gtg ctg ctg ctg ctg ctg ctg cta cca ctg ctg ctg ctg 161Ala Trp Ala Val Leu Leu Leu Leu Leu Leu Leu Pro Leu Leu Leu Leu 15 20 25gtg ggg gcc gtc ccg ccg ggt cgg ggc cgt gcc gcg ggg ccg cag gag 209Val Gly Ala Val Pro Pro Gly Arg Gly Arg Ala Ala Gly Pro Gln Glu 30 35 40gat gta gat gag tgt gcc caa ggg cta gat gac tgc cat gcc gac gcc 257Asp Val Asp Glu Cys Ala Gln Gly Leu Asp Asp Cys His Ala Asp Ala 45 50 55ctg tgt cag aac aca ccc acc tcc tac aag tgc tcc tgc aag cct ggc 305Leu Cys Gln Asn Thr Pro Thr Ser Tyr Lys Cys Ser Cys Lys Pro Gly60 65 70 75tac caa ggg gaa ggc agg cag tgt gag gac atc gat gaa tgt gga aat 353Tyr Gln Gly Glu Gly Arg Gln Cys Glu Asp Ile Asp Glu Cys Gly Asn 80 85 90gag ctc aat gga ggc tgt gtc cat gac tgt ttg aat att cca ggc aat 401Glu Leu Asn Gly Gly Cys Val His Asp Cys Leu Asn Ile Pro Gly Asn 95 100 105tat cgt tgc act tgt ttt gat ggc ttc atg ttg gct cat gac ggt cat 449Tyr Arg Cys Thr Cys Phe Asp Gly Phe Met Leu Ala His Asp Gly His 110 115 120aat tgt ctt gat gtg gac gag tgc ctg gag aac aat ggc ggc tgc cag 497Asn Cys Leu Asp Val Asp Glu Cys Leu Glu Asn Asn Gly Gly Cys Gln 125 130 135cat acc tgt gtc aac gtc atg ggg agc tat gag tgc tgc tgc aag gag 545His Thr Cys Val Asn Val Met Gly Ser Tyr Glu Cys Cys Cys Lys Glu140 145 150 155ggg ttt ttc ctg agt gac aat cag cac acc tgc att cac cgc tcg gaa 593Gly Phe Phe Leu Ser Asp Asn Gln His Thr Cys Ile His Arg Ser Glu 160 165 170gag ggc ctg agc tgc atg aat aag gat cac ggc tgt agt cac atc tgc 641Glu Gly Leu Ser Cys Met Asn Lys Asp His Gly Cys Ser His Ile Cys 175 180 185aag gag gcc cca agg ggc agc gtc gcc tgt gag tgc agg cct ggt ttt 689Lys Glu Ala Pro Arg Gly Ser Val Ala Cys Glu Cys Arg Pro Gly Phe 190 195 200gag ctg gcc aag aac cag aga gac tgc atc ttg acc tgt aac cat ggg 737Glu Leu Ala Lys Asn Gln Arg Asp Cys Ile Leu Thr Cys Asn His Gly 205 210 215aac ggt ggg tgc cag cac tcc tgt gac gat aca gcc gat ggc cca gag 785Asn Gly Gly Cys Gln His Ser Cys Asp Asp Thr Ala Asp Gly Pro Glu220 225 230 235tgc agc tgc cat cca cag tac aag atg cac aca gat ggg agg agc tgc 833Cys Ser Cys His Pro Gln Tyr Lys Met His Thr Asp Gly Arg Ser Cys 240 245 250ctt gag cga gag gac act gtc ctg gag gtg aca gag agc aac acc aca 881Leu Glu Arg Glu Asp Thr Val Leu Glu Val Thr Glu Ser Asn Thr Thr 255 260 265tca gtg gtg gat ggg gat aaa cgg gtg aaa cgg cgg ctg ctc atg gaa 929Ser Val Val Asp Gly Asp Lys Arg Val Lys Arg Arg Leu Leu Met Glu 270 275 280acg tgt gct gtc aac aat gga ggc tgt gac cgc acc tgt aag gat act 977Thr Cys Ala Val Asn Asn Gly Gly Cys Asp Arg Thr Cys Lys Asp Thr 285 290 295tcg aca ggt gtc cac tgc agt tgt cct gtt gga ttc act ctc cag ttg 1025Ser Thr Gly Val His Cys Ser Cys Pro Val Gly Phe Thr Leu Gln Leu300 305 310 315gat ggg aag aca tgt aaa gat att gat gag tgc cag acc cgc aat gga 1073Asp Gly Lys Thr Cys Lys Asp Ile Asp Glu Cys Gln Thr Arg Asn Gly 320 325 330ggt tgt gat cat ttc tgc aaa aac atc gtg ggc agt ttt gac tgc ggc 1121Gly Cys Asp His Phe Cys Lys Asn Ile Val Gly Ser Phe Asp Cys Gly 335 340 345tgc aag aaa gga ttt aaa tta tta aca gat gag aag tct tgc caa gat 1169Cys Lys Lys Gly Phe Lys Leu Leu Thr Asp Glu Lys Ser Cys Gln Asp 350 355 360gtg gat gag tgc tct ttg gat agg acc tgt gac cac agc tgc atc aac 1217Val Asp Glu Cys Ser Leu Asp Arg Thr Cys Asp His Ser Cys Ile Asn 365 370 375cac cct ggc aca ttt gct tgt gct tgc aac cga ggg tac acc ctg tat 1265His Pro Gly Thr Phe Ala Cys Ala Cys Asn Arg Gly Tyr Thr Leu Tyr380 385 390 395ggc ttc acc cac tgt gga gac acc aat gag tgc agc atc aac aac gga 1313Gly Phe Thr His Cys Gly Asp Thr Asn Glu Cys Ser Ile Asn Asn Gly 400 405 410ggc tgt cag cag gtc tgt gtg aac aca gtg ggc agc tat gaa tgc cag 1361Gly Cys Gln Gln Val Cys Val Asn Thr Val Gly Ser Tyr Glu Cys Gln 415 420 425tgc cac cct ggg tac aag ctc cac tgg aat aaa aaa gac tgt gtg gaa 1409Cys His Pro Gly Tyr Lys Leu His Trp Asn Lys Lys Asp Cys Val Glu 430 435 440gtg aag ggg ctc ctg ccc aca agt gtg tca ccc cgt gtg tcc ctg cac 1457Val Lys Gly Leu Leu Pro Thr Ser Val Ser Pro Arg Val Ser Leu His 445 450 455tgc ggt aag agt ggt gga gga gac ggg tgc ttc ctc aga tgt cac tct 1505Cys Gly Lys Ser Gly Gly Gly Asp Gly Cys Phe Leu Arg Cys His Ser460 465 470 475ggc att cac ctc tct tca gga ctg caa ggg gcc tac tct gtc acc tgt 1553Gly Ile His Leu Ser Ser Gly Leu Gln Gly Ala Tyr Ser Val Thr Cys 480 485 490ggc tct tcc tct cct ctc agg aac aaa caa caa aaa tca aat gac tct 1601Gly Ser Ser Ser Pro Leu Arg Asn Lys Gln Gln Lys Ser Asn Asp Ser 495 500 505gct ttt ggg gat gtc acc acc atc agg aca agt gta acc ttt aag cta 1649Ala Phe Gly Asp Val Thr Thr Ile Arg Thr Ser Val Thr Phe Lys Leu 510 515 520aat gaa ggc aag tgt agt ttg aaa aat gct gag ctg ttt ccc gag ggt 1697Asn Glu Gly Lys Cys Ser Leu Lys Asn Ala Glu Leu Phe Pro Glu Gly 525 530 535ctg cga cca gca cta cca gag aag cac agc tca gta aaa gag agc ttc 1745Leu Arg Pro Ala Leu Pro Glu Lys His Ser Ser Val Lys Glu Ser Phe540 545 550 555cgc tac gta aac ctt aca tgc agc tct ggc aag caa gtc cca gga gcc 1793Arg Tyr Val Asn Leu Thr Cys Ser Ser Gly Lys Gln Val Pro Gly Ala 560 565 570cct ggc cga cca agc acc cct aag gaa atg ttt atc act gtt gag ttt 1841Pro Gly Arg Pro Ser Thr Pro Lys Glu Met Phe Ile Thr Val Glu Phe 575 580 585gag ctt gaa act aac caa aag gag gtg aca gct tct tgt gac ctg agc 1889Glu Leu Glu Thr Asn Gln Lys Glu Val Thr Ala Ser Cys Asp Leu Ser 590 595 600tgc atc gta aag cga acc gag aag cgg ctc cgt aaa gcc atc cgc acg 1937Cys Ile Val Lys Arg Thr Glu Lys Arg Leu Arg Lys Ala Ile Arg Thr 605 610 615ctc aga aag gcc gtc cac agg gag cag ttt cac ctc cag ctc tca ggc 1985Leu Arg Lys Ala Val His Arg Glu Gln Phe His Leu Gln Leu Ser Gly620 625 630 635atg aac ctc gac gtg gct aaa aag cct ccc aga aca tct gaa cgc cag 2033Met Asn Leu Asp Val Ala Lys Lys Pro Pro Arg Thr Ser Glu Arg Gln 640 645 650gca gag tcc tgt gga gtg ggc cag ggt cat gca gaa aac caa tgt gtc 2081Ala Glu Ser Cys Gly Val Gly Gln Gly His Ala Glu Asn Gln Cys Val 655 660 665agt tgc agg gct ggg acc tat tat gat gga gca cga gaa cgc tgc att 2129Ser Cys Arg Ala Gly Thr Tyr Tyr Asp Gly Ala Arg Glu Arg Cys Ile 670 675 680tta tgt cca aat gga acc ttc caa aat gag gaa gga caa atg act tgt 2177Leu Cys Pro Asn Gly Thr Phe Gln Asn Glu Glu Gly Gln Met Thr Cys 685 690 695gaa cca tgc cca aga cca gga aat tct ggg gcc ctg aag acc cca gaa 2225Glu Pro Cys Pro Arg Pro Gly Asn Ser Gly Ala Leu Lys Thr Pro Glu700 705 710 715gct tgg aat atg tct gaa tgt gga ggt ctg tgt caa cct ggt gaa tat 2273Ala Trp Asn Met Ser Glu Cys Gly Gly Leu Cys Gln Pro Gly Glu Tyr 720 725 730tct gca gat ggc ttt gca cct tgc cag ctc tgt gcc ctg ggc acg ttc 2321Ser Ala Asp Gly Phe Ala Pro Cys Gln Leu Cys Ala Leu Gly Thr Phe 735 740 745cag cct gaa gct ggt cga act tcc tgc ttc ccc tgt gga gga ggc ctt 2369Gln Pro Glu Ala Gly Arg Thr Ser Cys Phe Pro Cys Gly Gly Gly Leu 750 755 760gcc acc aaa cat cag gga gct act tcc ttt cag gac tgt gaa acc aga 2417Ala Thr Lys His Gln Gly Ala Thr Ser Phe Gln Asp Cys Glu Thr Arg 765 770 775gtt caa tgt tca cct gga cat ttc tac aac acc acc act cac cga tgt 2465Val Gln Cys Ser Pro Gly His Phe Tyr Asn Thr Thr Thr His Arg Cys780 785 790 795att cgt tgc cca gtg gga aca tac cag cct gaa ttt gga aaa aat aat 2513Ile Arg Cys Pro Val Gly Thr Tyr Gln Pro Glu Phe Gly Lys Asn Asn 800 805 810tgt gtt tct tgc cca gga aat act acg act gac ttt gat ggc tcc aca 2561Cys Val Ser Cys Pro Gly Asn Thr Thr Thr Asp Phe Asp Gly Ser Thr 815 820 825aac ata acc cag tgt aaa aac aga aga tgt gga ggg gag ctg gga gat 2609Asn Ile Thr Gln Cys Lys Asn Arg Arg Cys Gly Gly Glu Leu Gly Asp 830 835 840ttc act ggg tac att gaa tcc cca aac tac cca ggc aat tac cca gcc 2657Phe Thr Gly Tyr Ile Glu Ser Pro Asn Tyr Pro Gly Asn Tyr Pro Ala 845 850 855aac acc gag tgt acg tgg acc atc aac cca ccc ccc aag cgc cgc atc

2705Asn Thr Glu Cys Thr Trp Thr Ile Asn Pro Pro Pro Lys Arg Arg Ile860 865 870 875ctg atc gtg gtc cct gag atc ttc ctg ccc ata gag gac gac tgt ggg 2753Leu Ile Val Val Pro Glu Ile Phe Leu Pro Ile Glu Asp Asp Cys Gly 880 885 890gac tat ctg gtg atg cgg aaa acc tct tca tcc aat tct gtg aca aca 2801Asp Tyr Leu Val Met Arg Lys Thr Ser Ser Ser Asn Ser Val Thr Thr 895 900 905 tat gaa acc tgc cag acc tac gaa cgc ccc atc gcc ttc acc tcc agg 2849Tyr Glu Thr Cys Gln Thr Tyr Glu Arg Pro Ile Ala Phe Thr Ser Arg 910 915 920tca aag aag ctg tgg att cag ttc aag tcc aat gaa ggg aac agc gct 2897Ser Lys Lys Leu Trp Ile Gln Phe Lys Ser Asn Glu Gly Asn Ser Ala 925 930 935aga ggg ttc cag gtc cca tac gtg aca tat gat gag gac tac cag gaa 2945Arg Gly Phe Gln Val Pro Tyr Val Thr Tyr Asp Glu Asp Tyr Gln Glu940 945 950 955ctc att gaa gac ata gtt cga gat ggc agg ctc tat gca tct gag aac 2993Leu Ile Glu Asp Ile Val Arg Asp Gly Arg Leu Tyr Ala Ser Glu Asn 960 965 970cat cag gaa ata ctt aag gat aag aaa ctt atc aag gct ctg ttt gat 3041His Gln Glu Ile Leu Lys Asp Lys Lys Leu Ile Lys Ala Leu Phe Asp 975 980 985gtc ctg gcc cat ccc cag aac tat ttc aag tac aca gcc cag gag tcc 3089Val Leu Ala His Pro Gln Asn Tyr Phe Lys Tyr Thr Ala Gln Glu Ser 990 995 1000cga gag atg ttt cca aga tcg ttc atc cga ttg cta cgt tcc aaa gtg 3137Arg Glu Met Phe Pro Arg Ser Phe Ile Arg Leu Leu Arg Ser Lys Val 1005 1010 1015tcc agg ttt ttg aga cct tac aaa tga ctcagcccac gtgccactca 3184Ser Arg Phe Leu Arg Pro Tyr Lys *1020 1025atacaaatgt tctgctatag ggttggtggg acagagctgt cttccttctg catgtcagca 3244cagtcgggta ttgctgcctc ccgtatcagt gactcattag agttcaattt ttatagataa 3304tacagatatt ttggtaaatt gaacttggtt tttctttccc agcatcgtgg atgtagactg 3364agaatggctt tgagtggcat cagcttctca ctgctgtggg cggatgtctt ggatagatca 3424cgggctggct gagctggact ttggtcagcc taggtgagac tcacctgtcc ttctggggtc 3484ttactcctcc tcaaggagtc tgtagtggaa aggaggccac agaataagct gcttattctg 3544aaacttcagc ttcctctagc ccggccctct ctaagggagc cctctgcact cgtgtgcagg 3604ctctgaccag gcagaacagg caagagggga gggaaggaga cccctgcagg ctccctccac 3664ccaccttgag acctgggagg actcagtttc tccacagcct tctccagcct gtgtgataca 3724agtttgatcc caggaacttg agttctaagc agtgctcgtg aaaaaaaaaa gcagaaagaa 3784ttagaaataa ataaaaacta agcacttctg gagacat 3821601027PRThuman 60Met Gly Val Ala Gly Arg Asn Arg Pro Gly Ala Ala Trp Ala Val Leu1 5 10 15Leu Leu Leu Leu Leu Leu Pro Leu Leu Leu Leu Val Gly Ala Val Pro 20 25 30Pro Gly Arg Gly Arg Ala Ala Gly Pro Gln Glu Asp Val Asp Glu Cys 35 40 45Ala Gln Gly Leu Asp Asp Cys His Ala Asp Ala Leu Cys Gln Asn Thr 50 55 60Pro Thr Ser Tyr Lys Cys Ser Cys Lys Pro Gly Tyr Gln Gly Glu Gly65 70 75 80Arg Gln Cys Glu Asp Ile Asp Glu Cys Gly Asn Glu Leu Asn Gly Gly 85 90 95Cys Val His Asp Cys Leu Asn Ile Pro Gly Asn Tyr Arg Cys Thr Cys 100 105 110Phe Asp Gly Phe Met Leu Ala His Asp Gly His Asn Cys Leu Asp Val 115 120 125Asp Glu Cys Leu Glu Asn Asn Gly Gly Cys Gln His Thr Cys Val Asn 130 135 140Val Met Gly Ser Tyr Glu Cys Cys Cys Lys Glu Gly Phe Phe Leu Ser145 150 155 160Asp Asn Gln His Thr Cys Ile His Arg Ser Glu Glu Gly Leu Ser Cys 165 170 175Met Asn Lys Asp His Gly Cys Ser His Ile Cys Lys Glu Ala Pro Arg 180 185 190Gly Ser Val Ala Cys Glu Cys Arg Pro Gly Phe Glu Leu Ala Lys Asn 195 200 205Gln Arg Asp Cys Ile Leu Thr Cys Asn His Gly Asn Gly Gly Cys Gln 210 215 220His Ser Cys Asp Asp Thr Ala Asp Gly Pro Glu Cys Ser Cys His Pro225 230 235 240Gln Tyr Lys Met His Thr Asp Gly Arg Ser Cys Leu Glu Arg Glu Asp 245 250 255Thr Val Leu Glu Val Thr Glu Ser Asn Thr Thr Ser Val Val Asp Gly 260 265 270Asp Lys Arg Val Lys Arg Arg Leu Leu Met Glu Thr Cys Ala Val Asn 275 280 285Asn Gly Gly Cys Asp Arg Thr Cys Lys Asp Thr Ser Thr Gly Val His 290 295 300Cys Ser Cys Pro Val Gly Phe Thr Leu Gln Leu Asp Gly Lys Thr Cys305 310 315 320Lys Asp Ile Asp Glu Cys Gln Thr Arg Asn Gly Gly Cys Asp His Phe 325 330 335Cys Lys Asn Ile Val Gly Ser Phe Asp Cys Gly Cys Lys Lys Gly Phe 340 345 350Lys Leu Leu Thr Asp Glu Lys Ser Cys Gln Asp Val Asp Glu Cys Ser 355 360 365Leu Asp Arg Thr Cys Asp His Ser Cys Ile Asn His Pro Gly Thr Phe 370 375 380Ala Cys Ala Cys Asn Arg Gly Tyr Thr Leu Tyr Gly Phe Thr His Cys385 390 395 400Gly Asp Thr Asn Glu Cys Ser Ile Asn Asn Gly Gly Cys Gln Gln Val 405 410 415Cys Val Asn Thr Val Gly Ser Tyr Glu Cys Gln Cys His Pro Gly Tyr 420 425 430Lys Leu His Trp Asn Lys Lys Asp Cys Val Glu Val Lys Gly Leu Leu 435 440 445Pro Thr Ser Val Ser Pro Arg Val Ser Leu His Cys Gly Lys Ser Gly 450 455 460Gly Gly Asp Gly Cys Phe Leu Arg Cys His Ser Gly Ile His Leu Ser465 470 475 480Ser Gly Leu Gln Gly Ala Tyr Ser Val Thr Cys Gly Ser Ser Ser Pro 485 490 495Leu Arg Asn Lys Gln Gln Lys Ser Asn Asp Ser Ala Phe Gly Asp Val 500 505 510Thr Thr Ile Arg Thr Ser Val Thr Phe Lys Leu Asn Glu Gly Lys Cys 515 520 525Ser Leu Lys Asn Ala Glu Leu Phe Pro Glu Gly Leu Arg Pro Ala Leu 530 535 540Pro Glu Lys His Ser Ser Val Lys Glu Ser Phe Arg Tyr Val Asn Leu545 550 555 560Thr Cys Ser Ser Gly Lys Gln Val Pro Gly Ala Pro Gly Arg Pro Ser 565 570 575Thr Pro Lys Glu Met Phe Ile Thr Val Glu Phe Glu Leu Glu Thr Asn 580 585 590Gln Lys Glu Val Thr Ala Ser Cys Asp Leu Ser Cys Ile Val Lys Arg 595 600 605Thr Glu Lys Arg Leu Arg Lys Ala Ile Arg Thr Leu Arg Lys Ala Val 610 615 620His Arg Glu Gln Phe His Leu Gln Leu Ser Gly Met Asn Leu Asp Val625 630 635 640Ala Lys Lys Pro Pro Arg Thr Ser Glu Arg Gln Ala Glu Ser Cys Gly 645 650 655Val Gly Gln Gly His Ala Glu Asn Gln Cys Val Ser Cys Arg Ala Gly 660 665 670Thr Tyr Tyr Asp Gly Ala Arg Glu Arg Cys Ile Leu Cys Pro Asn Gly 675 680 685Thr Phe Gln Asn Glu Glu Gly Gln Met Thr Cys Glu Pro Cys Pro Arg 690 695 700Pro Gly Asn Ser Gly Ala Leu Lys Thr Pro Glu Ala Trp Asn Met Ser705 710 715 720Glu Cys Gly Gly Leu Cys Gln Pro Gly Glu Tyr Ser Ala Asp Gly Phe 725 730 735Ala Pro Cys Gln Leu Cys Ala Leu Gly Thr Phe Gln Pro Glu Ala Gly 740 745 750Arg Thr Ser Cys Phe Pro Cys Gly Gly Gly Leu Ala Thr Lys His Gln 755 760 765Gly Ala Thr Ser Phe Gln Asp Cys Glu Thr Arg Val Gln Cys Ser Pro 770 775 780Gly His Phe Tyr Asn Thr Thr Thr His Arg Cys Ile Arg Cys Pro Val785 790 795 800Gly Thr Tyr Gln Pro Glu Phe Gly Lys Asn Asn Cys Val Ser Cys Pro 805 810 815Gly Asn Thr Thr Thr Asp Phe Asp Gly Ser Thr Asn Ile Thr Gln Cys 820 825 830Lys Asn Arg Arg Cys Gly Gly Glu Leu Gly Asp Phe Thr Gly Tyr Ile 835 840 845Glu Ser Pro Asn Tyr Pro Gly Asn Tyr Pro Ala Asn Thr Glu Cys Thr 850 855 860Trp Thr Ile Asn Pro Pro Pro Lys Arg Arg Ile Leu Ile Val Val Pro865 870 875 880Glu Ile Phe Leu Pro Ile Glu Asp Asp Cys Gly Asp Tyr Leu Val Met 885 890 895Arg Lys Thr Ser Ser Ser Asn Ser Val Thr Thr Tyr Glu Thr Cys Gln 900 905 910Thr Tyr Glu Arg Pro Ile Ala Phe Thr Ser Arg Ser Lys Lys Leu Trp 915 920 925Ile Gln Phe Lys Ser Asn Glu Gly Asn Ser Ala Arg Gly Phe Gln Val 930 935 940Pro Tyr Val Thr Tyr Asp Glu Asp Tyr Gln Glu Leu Ile Glu Asp Ile945 950 955 960Val Arg Asp Gly Arg Leu Tyr Ala Ser Glu Asn His Gln Glu Ile Leu 965 970 975Lys Asp Lys Lys Leu Ile Lys Ala Leu Phe Asp Val Leu Ala His Pro 980 985 990Gln Asn Tyr Phe Lys Tyr Thr Ala Gln Glu Ser Arg Glu Met Phe Pro 995 1000 1005Arg Ser Phe Ile Arg Leu Leu Arg Ser Lys Val Ser Arg Phe Leu Arg 1010 1015 1020Pro Tyr Lys102561540DNAhumanCDS(41)...(295) 61atccctgact cggggtcgcc tttggagcag agaggaggca atg gcc acc atg gag 55 Met Ala Thr Met Glu 1 5aac aag gtg atc tgc gcc ctg gtc ctg gtg tcc atg ctg gcc ctc ggc 103Asn Lys Val Ile Cys Ala Leu Val Leu Val Ser Met Leu Ala Leu Gly 10 15 20acc ctg gcc gag gcc cag aca gag acg tgt aca gtg gcc ccc cgt gaa 151Thr Leu Ala Glu Ala Gln Thr Glu Thr Cys Thr Val Ala Pro Arg Glu 25 30 35aga cag aat tgt ggt ttt cct ggt gtc acg ccc tcc cag tgt gca aat 199Arg Gln Asn Cys Gly Phe Pro Gly Val Thr Pro Ser Gln Cys Ala Asn 40 45 50aag ggc tgc tgt ttc gac gac acc gtt cgt ggg gtc ccc tgg tgc ttc 247Lys Gly Cys Cys Phe Asp Asp Thr Val Arg Gly Val Pro Trp Cys Phe 55 60 65tat cct aat acc atc gac gtc cct cca gaa gag gag tgt gaa ttt tag 295Tyr Pro Asn Thr Ile Asp Val Pro Pro Glu Glu Glu Cys Glu Phe *70 75 80acacttctgc agggatctgc ctgcatcctg acggggtgcc gtccccagca cggtgattag 355tcccagagct cggctgccac ctccaccgga cacctcagac acgcttctgc agctgtgcct 415cggctcacaa cacagattga ctgctctgac tttgactact caaaattggc ctaaaaatta 475aaagagatcg atattaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 535aaaaa 5406284PRThuman 62Met Ala Thr Met Glu Asn Lys Val Ile Cys Ala Leu Val Leu Val Ser1 5 10 15Met Leu Ala Leu Gly Thr Leu Ala Glu Ala Gln Thr Glu Thr Cys Thr 20 25 30Val Ala Pro Arg Glu Arg Gln Asn Cys Gly Phe Pro Gly Val Thr Pro 35 40 45Ser Gln Cys Ala Asn Lys Gly Cys Cys Phe Asp Asp Thr Val Arg Gly 50 55 60Val Pro Trp Cys Phe Tyr Pro Asn Thr Ile Asp Val Pro Pro Glu Glu65 70 75 80Glu Cys Glu Phe63590DNAhumanCDS(28)...(402) 63acctgcaccc cgcccgggca tagcacc atg cct gct tgt cgc cta ggc ccg cta 54 Met Pro Ala Cys Arg Leu Gly Pro Leu 1 5gcc gcc gcc ctc ctc ctc agc ctg ctg ctg ttc ggc ttc acc cta gtc 102Ala Ala Ala Leu Leu Leu Ser Leu Leu Leu Phe Gly Phe Thr Leu Val10 15 20 25tca ggc aca gga gca gag aag act ggc gtg tgc ccc gag ctc cag gct 150Ser Gly Thr Gly Ala Glu Lys Thr Gly Val Cys Pro Glu Leu Gln Ala 30 35 40gac cag aac tgc acg caa gag tgc gtc tcg gac agc gaa tgc gcc gac 198Asp Gln Asn Cys Thr Gln Glu Cys Val Ser Asp Ser Glu Cys Ala Asp 45 50 55aac ctc aag tgc tgc agc gcg ggc tgt gcc acc ttc tgc tct ctg ccc 246Asn Leu Lys Cys Cys Ser Ala Gly Cys Ala Thr Phe Cys Ser Leu Pro 60 65 70aat gat aag gag ggt tcc tgc ccc cag gtg aac att aac ttt ccc cag 294Asn Asp Lys Glu Gly Ser Cys Pro Gln Val Asn Ile Asn Phe Pro Gln 75 80 85ctc ggc ctc tgt cgg gac cag tgc cag gtg gac agc cag tgt cct ggc 342Leu Gly Leu Cys Arg Asp Gln Cys Gln Val Asp Ser Gln Cys Pro Gly90 95 100 105cag atg aaa tgc tgc cgc aat ggc tgt ggg aag gtg tcc tgt gtc act 390Gln Met Lys Cys Cys Arg Asn Gly Cys Gly Lys Val Ser Cys Val Thr 110 115 120ccc aat ttc tga gctccagcca ccaccaggct gagcagtgag gagagaaagt 442Pro Asn Phe *ttctgcctgg ccctgcatct ggttccagcc cacctgccct cccctttttc gggactctgt 502attccctctt gggctgacca cagcttctcc ctttcccaac caataaagta accactttca 562gcaaaaaaaa aaaaaaaaaa aaaaaaaa 59064124PRThuman 64Met Pro Ala Cys Arg Leu Gly Pro Leu Ala Ala Ala Leu Leu Leu Ser1 5 10 15Leu Leu Leu Phe Gly Phe Thr Leu Val Ser Gly Thr Gly Ala Glu Lys 20 25 30Thr Gly Val Cys Pro Glu Leu Gln Ala Asp Gln Asn Cys Thr Gln Glu 35 40 45Cys Val Ser Asp Ser Glu Cys Ala Asp Asn Leu Lys Cys Cys Ser Ala 50 55 60Gly Cys Ala Thr Phe Cys Ser Leu Pro Asn Asp Lys Glu Gly Ser Cys65 70 75 80Pro Gln Val Asn Ile Asn Phe Pro Gln Leu Gly Leu Cys Arg Asp Gln 85 90 95Cys Gln Val Asp Ser Gln Cys Pro Gly Gln Met Lys Cys Cys Arg Asn 100 105 110Gly Cys Gly Lys Val Ser Cys Val Thr Pro Asn Phe 115 12065450DNAhumanCDS(67)...(288) 65cccaagatgg actcaggcag gcagctctgc tgtatgtgaa gcccagtgag gggcagtggg 60ggggcc atg ctg cag gta caa gtt aat ctc cct gta tcg cct ctg ccc 108 Met Leu Gln Val Gln Val Asn Leu Pro Val Ser Pro Leu Pro 1 5 10act tac cct tac tcc ttt ttc tac cca gat aag gag ggt tcc tgc ccc 156Thr Tyr Pro Tyr Ser Phe Phe Tyr Pro Asp Lys Glu Gly Ser Cys Pro15 20 25 30cag gtg aac att aac ttt ccc cag ctc ggc ctc tgt cgg gac cag tgc 204Gln Val Asn Ile Asn Phe Pro Gln Leu Gly Leu Cys Arg Asp Gln Cys 35 40 45cag gtg gac agc cag tgt cct ggc cag atg aaa tgc tgc cgc aat ggc 252Gln Val Asp Ser Gln Cys Pro Gly Gln Met Lys Cys Cys Arg Asn Gly 50 55 60tgt ggg aag gtg tcc tgt gtc act ccc aat ttc tga ggtccagcca 298Cys Gly Lys Val Ser Cys Val Thr Pro Asn Phe * 65 70ccaccaggct gagcagtgag gagagaaagt ttctgcctgg ccctgcatct ggttccagcc 358cacctgccct cccctttttc gggactctgt attccctctt gggctgacca cagcttctcc 418ctttcccaac caataaagta accactttca gc 4506673PRThuman 66Met Leu Gln Val Gln Val Asn Leu Pro Val Ser Pro Leu Pro Thr Tyr1 5 10 15Pro Tyr Ser Phe Phe Tyr Pro Asp Lys Glu Gly Ser Cys Pro Gln Val 20 25 30Asn Ile Asn Phe Pro Gln Leu Gly Leu Cys Arg Asp Gln Cys Gln Val 35 40 45Asp Ser Gln Cys Pro Gly Gln Met Lys Cys Cys Arg Asn Gly Cys Gly 50 55 60Lys Val Ser Cys Val Thr Pro Asn Phe65 70671595DNAhumanCDS(81)...(1319) 67ggcacgaggc ttataacctg ggatgggcac ccctgccagt cctgctctgc cgcctgccac 60cgctgcccga gcccgacgct atg tcc agc aaa ggc tcc gtg gtt ctg gcc tac 113 Met Ser Ser Lys Gly Ser Val Val Leu Ala Tyr 1 5 10agt ggc ggc ctg gac acc tcg tgc atc ctc gtg tgg ctg aag gaa caa 161Ser Gly Gly Leu Asp Thr Ser Cys Ile Leu Val Trp Leu Lys Glu Gln 15 20 25ggc tat gac gtc att gcc tat ctg gcc aac att ggc cag aag gaa gac 209Gly Tyr Asp Val Ile Ala Tyr Leu Ala Asn Ile Gly Gln Lys Glu Asp 30 35 40ttc gag gaa gcc agg aag aag gca ctg aag ctt ggg gcc aaa aag gtg 257Phe Glu Glu Ala Arg Lys Lys Ala Leu Lys Leu Gly Ala Lys Lys Val 45 50 55ttc att gag gat gtc agc agg gag ttt gtg gag gag ttc atc tgg ccg 305Phe Ile Glu Asp Val Ser Arg Glu Phe Val Glu Glu Phe Ile Trp Pro60 65 70 75gcc atc cag tcc agc gca ctg tat gag gac cgc tac ctc ctg ggc acc 353Ala Ile Gln Ser Ser Ala Leu Tyr Glu Asp Arg Tyr Leu Leu Gly Thr 80

85 90tct ctt gcc agg ccc tgc atc gcc cgc aaa caa gtg gaa atc gcc cag 401Ser Leu Ala Arg Pro Cys Ile Ala Arg Lys Gln Val Glu Ile Ala Gln 95 100 105cgg gag ggg gcc aag tat gtg tcc cac ggc gcc aca gga aag ggg aac 449Arg Glu Gly Ala Lys Tyr Val Ser His Gly Ala Thr Gly Lys Gly Asn 110 115 120gat cag gtc cgg ttt gag ctc agc tgc tac tca ctg gcc ccc cag ata 497Asp Gln Val Arg Phe Glu Leu Ser Cys Tyr Ser Leu Ala Pro Gln Ile 125 130 135aag gtc att gct ccc tgg agg atg cct gaa ttc tac aac cgg ttc aag 545Lys Val Ile Ala Pro Trp Arg Met Pro Glu Phe Tyr Asn Arg Phe Lys140 145 150 155ggc cgc aat gac ctg atg gag tac gca aag caa cac ggg att ccc atc 593Gly Arg Asn Asp Leu Met Glu Tyr Ala Lys Gln His Gly Ile Pro Ile 160 165 170ccg gtc act ccc aag aac ccg tgg agc atg gat gag aac ctc atg cac 641Pro Val Thr Pro Lys Asn Pro Trp Ser Met Asp Glu Asn Leu Met His 175 180 185atc agc tac gag gct gga atc ctg gag aac ccc aag aac caa gcg cct 689Ile Ser Tyr Glu Ala Gly Ile Leu Glu Asn Pro Lys Asn Gln Ala Pro 190 195 200cca ggt ctc tac acg aag acc cag gac cca gcc aaa gcc ccc aac acc 737Pro Gly Leu Tyr Thr Lys Thr Gln Asp Pro Ala Lys Ala Pro Asn Thr 205 210 215cct gac att ctc gag atc gag ttc aaa aaa ggg gtc cct gtg aag gtg 785Pro Asp Ile Leu Glu Ile Glu Phe Lys Lys Gly Val Pro Val Lys Val220 225 230 235acc aac gtc aag gat ggc acc acc cac cag acc tcc ttg gag ctc ttc 833Thr Asn Val Lys Asp Gly Thr Thr His Gln Thr Ser Leu Glu Leu Phe 240 245 250atg tac ctg aac gaa gtc gcg ggc aag cat ggc gtg ggc cgt att gac 881Met Tyr Leu Asn Glu Val Ala Gly Lys His Gly Val Gly Arg Ile Asp 255 260 265atc gtg gag aac cgc ttc att gga atg aag tcc cga ggt atc tac gag 929Ile Val Glu Asn Arg Phe Ile Gly Met Lys Ser Arg Gly Ile Tyr Glu 270 275 280acc cca gca ggc acc atc ctt tac cac gct cat tta gac atc gag gcc 977Thr Pro Ala Gly Thr Ile Leu Tyr His Ala His Leu Asp Ile Glu Ala 285 290 295ttc acc atg gac cgg gaa gtg cgc aaa atc aaa caa ggc ctg ggc ttg 1025Phe Thr Met Asp Arg Glu Val Arg Lys Ile Lys Gln Gly Leu Gly Leu300 305 310 315aaa ttt gct gag ctg gtg tat acc ggt ttc tgg cac agc cct gag tgt 1073Lys Phe Ala Glu Leu Val Tyr Thr Gly Phe Trp His Ser Pro Glu Cys 320 325 330gaa ttt gtc cgc cac tgc atc gcc aag tcc cag gag cga gtg gaa ggg 1121Glu Phe Val Arg His Cys Ile Ala Lys Ser Gln Glu Arg Val Glu Gly 335 340 345aaa gtg cag gtg tcc gtc ctc aag ggc cag gtg tac atc ctc ggc cgg 1169Lys Val Gln Val Ser Val Leu Lys Gly Gln Val Tyr Ile Leu Gly Arg 350 355 360gag tcc cca ctg tct ctc tac aat gag gag ctg gtg agc atg aac gtg 1217Glu Ser Pro Leu Ser Leu Tyr Asn Glu Glu Leu Val Ser Met Asn Val 365 370 375cag ggt gat tat gag cca act gat gcc acc ggg ttc atc aac atc aat 1265Gln Gly Asp Tyr Glu Pro Thr Asp Ala Thr Gly Phe Ile Asn Ile Asn380 385 390 395tcc ctc agg ctg aag gaa tat cat cgt ctc cag agc aag gtc act gcc 1313Ser Leu Arg Leu Lys Glu Tyr His Arg Leu Gln Ser Lys Val Thr Ala 400 405 410aaa tag acccgtgtac aatgaggagc tggggcctcc tcaatttgca gatcccccaa 1369Lys *gtacaggcgc taattgttgt gataatttgt aattgtgact tgttctcccc ggctggcagc 1429gtagtggggc tgccaggccc cagctttgtt ccctggtccc cctgaagcct gcaaacgttg 1489tcatcgaagg gaagggtggg gggcagctgc ggtggggagc tataaaaatg acaattaaaa 1549gagacactag tcttttattt ctaaaaaaaa aaaaaaaaaa aaaaaa 159568412PRThuman 68Met Ser Ser Lys Gly Ser Val Val Leu Ala Tyr Ser Gly Gly Leu Asp1 5 10 15Thr Ser Cys Ile Leu Val Trp Leu Lys Glu Gln Gly Tyr Asp Val Ile 20 25 30Ala Tyr Leu Ala Asn Ile Gly Gln Lys Glu Asp Phe Glu Glu Ala Arg 35 40 45Lys Lys Ala Leu Lys Leu Gly Ala Lys Lys Val Phe Ile Glu Asp Val 50 55 60Ser Arg Glu Phe Val Glu Glu Phe Ile Trp Pro Ala Ile Gln Ser Ser65 70 75 80Ala Leu Tyr Glu Asp Arg Tyr Leu Leu Gly Thr Ser Leu Ala Arg Pro 85 90 95Cys Ile Ala Arg Lys Gln Val Glu Ile Ala Gln Arg Glu Gly Ala Lys 100 105 110Tyr Val Ser His Gly Ala Thr Gly Lys Gly Asn Asp Gln Val Arg Phe 115 120 125Glu Leu Ser Cys Tyr Ser Leu Ala Pro Gln Ile Lys Val Ile Ala Pro 130 135 140Trp Arg Met Pro Glu Phe Tyr Asn Arg Phe Lys Gly Arg Asn Asp Leu145 150 155 160Met Glu Tyr Ala Lys Gln His Gly Ile Pro Ile Pro Val Thr Pro Lys 165 170 175Asn Pro Trp Ser Met Asp Glu Asn Leu Met His Ile Ser Tyr Glu Ala 180 185 190Gly Ile Leu Glu Asn Pro Lys Asn Gln Ala Pro Pro Gly Leu Tyr Thr 195 200 205Lys Thr Gln Asp Pro Ala Lys Ala Pro Asn Thr Pro Asp Ile Leu Glu 210 215 220Ile Glu Phe Lys Lys Gly Val Pro Val Lys Val Thr Asn Val Lys Asp225 230 235 240Gly Thr Thr His Gln Thr Ser Leu Glu Leu Phe Met Tyr Leu Asn Glu 245 250 255Val Ala Gly Lys His Gly Val Gly Arg Ile Asp Ile Val Glu Asn Arg 260 265 270Phe Ile Gly Met Lys Ser Arg Gly Ile Tyr Glu Thr Pro Ala Gly Thr 275 280 285Ile Leu Tyr His Ala His Leu Asp Ile Glu Ala Phe Thr Met Asp Arg 290 295 300Glu Val Arg Lys Ile Lys Gln Gly Leu Gly Leu Lys Phe Ala Glu Leu305 310 315 320Val Tyr Thr Gly Phe Trp His Ser Pro Glu Cys Glu Phe Val Arg His 325 330 335Cys Ile Ala Lys Ser Gln Glu Arg Val Glu Gly Lys Val Gln Val Ser 340 345 350Val Leu Lys Gly Gln Val Tyr Ile Leu Gly Arg Glu Ser Pro Leu Ser 355 360 365Leu Tyr Asn Glu Glu Leu Val Ser Met Asn Val Gln Gly Asp Tyr Glu 370 375 380Pro Thr Asp Ala Thr Gly Phe Ile Asn Ile Asn Ser Leu Arg Leu Lys385 390 395 400Glu Tyr His Arg Leu Gln Ser Lys Val Thr Ala Lys 405 410692682DNAhumanCDS(18)...(980) 69cgagccaggg agaaagg atg gcc ggc ctg gcg gcg cgg ttg gtc ctg cta 50 Met Ala Gly Leu Ala Ala Arg Leu Val Leu Leu 1 5 10gct ggg gca gcg gcg ctg gcg agc ggc tcc cag ggc gac cgt gag ccg 98Ala Gly Ala Ala Ala Leu Ala Ser Gly Ser Gln Gly Asp Arg Glu Pro 15 20 25gtg tac cgc gac tgc gta ctg cag tgc gaa gag cag aac tgc tct ggg 146Val Tyr Arg Asp Cys Val Leu Gln Cys Glu Glu Gln Asn Cys Ser Gly 30 35 40ggc gct ctg aat cac ttc cgc tcc cgc cag cca atc tac atg agt cta 194Gly Ala Leu Asn His Phe Arg Ser Arg Gln Pro Ile Tyr Met Ser Leu 45 50 55gca ggc tgg acc tgt cgg gac gac tgt aag tat gag tgt atg tgg gtc 242Ala Gly Trp Thr Cys Arg Asp Asp Cys Lys Tyr Glu Cys Met Trp Val60 65 70 75acc gtt ggg ctc tac ctc cag gaa ggt cac aaa gtg cct cag ttc cat 290Thr Val Gly Leu Tyr Leu Gln Glu Gly His Lys Val Pro Gln Phe His 80 85 90ggc aag tgg ccc ttc tcc cgg ttc ctg ttc ttt caa gag ccg gca tcg 338Gly Lys Trp Pro Phe Ser Arg Phe Leu Phe Phe Gln Glu Pro Ala Ser 95 100 105gcc gtg gcc tcg ttt ctc aat ggc ctg gcc agc ctg gtg atg ctc tgc 386Ala Val Ala Ser Phe Leu Asn Gly Leu Ala Ser Leu Val Met Leu Cys 110 115 120cgc tac cgc acc ttc gtg cca gcc tcc tcc ccc atg tac cac acc tgt 434Arg Tyr Arg Thr Phe Val Pro Ala Ser Ser Pro Met Tyr His Thr Cys 125 130 135gtg gcc ttc gcc tgg gtg tcc ctc aat gca tgg ttc tgg tcc aca gtt 482Val Ala Phe Ala Trp Val Ser Leu Asn Ala Trp Phe Trp Ser Thr Val140 145 150 155ttc cac acc agg gac act gac ctc aca gag aaa atg gac tac ttc tgt 530Phe His Thr Arg Asp Thr Asp Leu Thr Glu Lys Met Asp Tyr Phe Cys 160 165 170gcc tcc act gtc atc cta cac tca atc tac ctg tgc tgc gtc agg acc 578Ala Ser Thr Val Ile Leu His Ser Ile Tyr Leu Cys Cys Val Arg Thr 175 180 185gtg ggg ctg cag cac cca gct gtg gtc agt gcc ttc cgg gct ctc ctg 626Val Gly Leu Gln His Pro Ala Val Val Ser Ala Phe Arg Ala Leu Leu 190 195 200ctg ctc atg ctg acc gtg cac gtc tcc tac ctg agc ctc atc cgc ttc 674Leu Leu Met Leu Thr Val His Val Ser Tyr Leu Ser Leu Ile Arg Phe 205 210 215gac tat ggc tac aac ctg gtg gcc aac gtg gct att ggc ctg gtc aac 722Asp Tyr Gly Tyr Asn Leu Val Ala Asn Val Ala Ile Gly Leu Val Asn220 225 230 235gtg gtg tgg tgg ctg gcc tgg tgc ctg tgg aac cag cgg cgg ctg cct 770Val Val Trp Trp Leu Ala Trp Cys Leu Trp Asn Gln Arg Arg Leu Pro 240 245 250cac gtg cgc aag tgc gtg gtg gtg gtc ttg ctg ctg cag ggg ctg tcc 818His Val Arg Lys Cys Val Val Val Val Leu Leu Leu Gln Gly Leu Ser 255 260 265ctg ctc gag ctg ctt gac ttc cca ccg ctc ttc tgg gtc ctg gat gcc 866Leu Leu Glu Leu Leu Asp Phe Pro Pro Leu Phe Trp Val Leu Asp Ala 270 275 280cat gcc atc tgg cac atc agc acc atc cct gtc cac gtc ctc ttt ttc 914His Ala Ile Trp His Ile Ser Thr Ile Pro Val His Val Leu Phe Phe 285 290 295agc ttt ctg gaa gat gac agc ctg tac ctg ctg aag gaa tca gag gac 962Ser Phe Leu Glu Asp Asp Ser Leu Tyr Leu Leu Lys Glu Ser Glu Asp300 305 310 315aag ttc aag ctg gac tga agaccttgga gcgagtctgc cccagtgggg 1010Lys Phe Lys Leu Asp * 320atcctgcccc cgccctgctg gcctcccttc tcccctcaac ccttgagatg attttctctt 1070ttcaacttct tgaacttgga catgaaggat gtgggcccag aatcatgtgg ccagcccacc 1130ccctgttggc cctcaccagc cttggagtct gttctaggga aggcctccca gcatctggga 1190ctcgagagtg ggcagcccct ctacctcctg gagctgaact ggggtggaac tgagtgtgct 1250cttagctcta ccgggaggac agctgcctgt ttcctcccca tcagcctcct ccccacatcc 1310ccagctgcct ggctgggtcc tgaagccctc tgtctacctg ggagaccagg gaccacaggc 1370cttagggata cagggggtcc ccttctgtta ccacccccca ccctcctcca ggacaccact 1430aggtggtgct ggatgcttgt tctttggcca gccaaggttc acggcgattc tccccatggg 1490atcttgaggg accaagctgc tgggattggg aaggagtttc accctgacca ttgccctagc 1550caggttccca ggaggcctca ccatactccc tttcagggcc agggctccag caagcccagg 1610gcaaggatcc tgtgctgctg tctggttgag agcctgccac cgtgtgtcgg gagtgtgggc 1670caggctgagt gcataggtga cagggccgtg agcatgggcc tgggtgtgtg tgagctcagg 1730cctaggtgcg cagtgtggag acgggtgttg tcggggaaga ggtgtggctt caaagtgtgt 1790gtgtgcaggg ggtgggtgtg ttagcgtggg ttaggggaac gtgtgtgcgc gtgctggtgg 1850gcatgtgaga tgagtgactg ccggtgaatg tgtccacagt tgagaggttg gagcaggatg 1910agggaatcct gtcaccatca ataatcactt gtggagcgcc agctctgccc aaggcgccac 1970ctgggcggac agccaggagc tctccatggc caggctgcct gtgtgcatgt tccctgtctg 2030gtgccccttt gcccgcctcc tgcaaacctc acagggtccc cacacaacag tgccctccag 2090aagcagcccc tcggaggcag aggaaggaaa atggggatgg ctggggctct ctccatcctc 2150cttttctcct tgccttcgca tggctggcct tcccctccaa aacctccatt cccctgctgc 2210cagccccttt gccatagcct gattttgggg aggaggaagg ggcgatttga gggagaaggg 2270gagaaagctt atggctgggt ctggtttctt cccttcccag agggtcttac tgttccaggg 2330tggccccagg gcaggcaggg gccacactat gcctgcgccc tggtaaaggt gacccctgcc 2390atttaccagc agccctggca tgttcctgcc ccacaggaat agaatggagg gagctccaga 2450aactttccat cccaaaggca gtctccgtgg ttgaagcaga ctggattttt gctctgcccc 2510tgaccccttg tccctctttg agggagggga gctatgctag gactccaacc tcagggactc 2570gggtggcctg cgctagcttc ttttgatact gaaaactttt aaggtgggag ggtggcaagg 2630gatgtgctta ataaatcaat tccaagcctc aaaaaaaaaa aaaaaaaaaa aa 268270320PRThuman 70Met Ala Gly Leu Ala Ala Arg Leu Val Leu Leu Ala Gly Ala Ala Ala1 5 10 15Leu Ala Ser Gly Ser Gln Gly Asp Arg Glu Pro Val Tyr Arg Asp Cys 20 25 30Val Leu Gln Cys Glu Glu Gln Asn Cys Ser Gly Gly Ala Leu Asn His 35 40 45Phe Arg Ser Arg Gln Pro Ile Tyr Met Ser Leu Ala Gly Trp Thr Cys 50 55 60Arg Asp Asp Cys Lys Tyr Glu Cys Met Trp Val Thr Val Gly Leu Tyr65 70 75 80Leu Gln Glu Gly His Lys Val Pro Gln Phe His Gly Lys Trp Pro Phe 85 90 95Ser Arg Phe Leu Phe Phe Gln Glu Pro Ala Ser Ala Val Ala Ser Phe 100 105 110Leu Asn Gly Leu Ala Ser Leu Val Met Leu Cys Arg Tyr Arg Thr Phe 115 120 125Val Pro Ala Ser Ser Pro Met Tyr His Thr Cys Val Ala Phe Ala Trp 130 135 140Val Ser Leu Asn Ala Trp Phe Trp Ser Thr Val Phe His Thr Arg Asp145 150 155 160Thr Asp Leu Thr Glu Lys Met Asp Tyr Phe Cys Ala Ser Thr Val Ile 165 170 175Leu His Ser Ile Tyr Leu Cys Cys Val Arg Thr Val Gly Leu Gln His 180 185 190Pro Ala Val Val Ser Ala Phe Arg Ala Leu Leu Leu Leu Met Leu Thr 195 200 205Val His Val Ser Tyr Leu Ser Leu Ile Arg Phe Asp Tyr Gly Tyr Asn 210 215 220Leu Val Ala Asn Val Ala Ile Gly Leu Val Asn Val Val Trp Trp Leu225 230 235 240Ala Trp Cys Leu Trp Asn Gln Arg Arg Leu Pro His Val Arg Lys Cys 245 250 255Val Val Val Val Leu Leu Leu Gln Gly Leu Ser Leu Leu Glu Leu Leu 260 265 270Asp Phe Pro Pro Leu Phe Trp Val Leu Asp Ala His Ala Ile Trp His 275 280 285Ile Ser Thr Ile Pro Val His Val Leu Phe Phe Ser Phe Leu Glu Asp 290 295 300Asp Ser Leu Tyr Leu Leu Lys Glu Ser Glu Asp Lys Phe Lys Leu Asp305 310 315 320712116DNAhumanCDS(57)...(299) 71cggttctcca agcacccagc atcctgctag acgcgccgcg caccgacgga ggggac atg 59 Met 1ggc aga gca atg gtg gcc agg ctg ggg ctg ggg ctg ctg ctg ctg gca 107Gly Arg Ala Met Val Ala Arg Leu Gly Leu Gly Leu Leu Leu Leu Ala 5 10 15ctg ctc cta ccc acg cag att tat tcc agt gaa aca aca act gga act 155Leu Leu Leu Pro Thr Gln Ile Tyr Ser Ser Glu Thr Thr Thr Gly Thr 20 25 30tca agt aac tcc tcc cag agt act tcc aac tct ggg ttg gcc cca aat 203Ser Ser Asn Ser Ser Gln Ser Thr Ser Asn Ser Gly Leu Ala Pro Asn 35 40 45cca act aat gcc acc acc aag gcg gct ggt ggt gcc ctg cag tca aca 251Pro Thr Asn Ala Thr Thr Lys Ala Ala Gly Gly Ala Leu Gln Ser Thr 50 55 60 65gcc agt ctc ttc gtg gtc tca ctc tct ctt ctg cat ctc tac tct taa 299Ala Ser Leu Phe Val Val Ser Leu Ser Leu Leu His Leu Tyr Ser * 70 75 80gagactcagg ccaagaaacg tcttctaaat ttccccatct tctaaaccca atccaaatgg 359cgtctggaag tccaatgtgg caaggaaaaa caggtcttca tcgaatctac taattccaca 419ccttttattg acacagaaaa tgttgagaat cccaaatttg attgatttga agaacatgtg 479agaggtttga ctagatgatg aatgccaata ttaaatctgc tggagtttca tgtacaagat 539gaaggagagg caacatccaa aatagttaag acatgatttc cttgaatgtg gcttgagaaa 599tatggacact taatactacc ttgaaaataa gaatagaaat aaaggatggg attgtggaat 659ggagattcag ttttcattgg ttcattaatt ctataaggcc ataaaacagg taatataaaa 719agcttccatc gatctattta tatgtacatg agaaggaatc cccaggtgtt actgtaattc 779ctcaacgtat tgtttcgacg gcactaattt aatgccgata tactctagat gaatgtttac 839attgttgagc tattgctgtt ctcttgggaa ctgaactcac tttcctcctg aggctttgga 899tttgacattg catttgacct tttaggtagt aattgacatg tgccagggca atgatgaatg 959agaatctacc ccagatccaa gcatcctgag caactcttga ttatccatat tgagtcaaat 1019ggtaggcatt tcctatcacc tgtttccatt caacaagagc actacattct tttagctaaa 1079cggattccaa agagtagaat tgcattgacc acgactaatt tcaaaatgct ttttattatt 1139attatttttt agacagtctc actttgtcgc ccaggccgga gtgcagtggt gcgatctcag 1199atcagtgtac catttgcctc ccgggctcaa gcgattctcc tgcctcagcc tcccaagtag 1259ctgggattac aggcacctgc caccatgccc ggctaatttt tgtaatttta gtagagacag 1319ggtttcacca tgttgcccag gctggtttag aactcctgac ctcaggtgat ccacccgcct 1379cggcctccca aagtgctggg attacaggct tgagcccccg cgcccagcca tcaaaatgct 1439ttttatttct gcatatgttt gaatactttt tacaatttaa aaaaatgatc tgttttgaag 1499gcaaaattgc aaatcttgaa attaagaagg caaaatgtaa

aggagtcaaa ctataaatca 1559agtatttggg aagtgaagac tggaagctaa tttgcataaa ttcacaaact tttatactct 1619ttctgtatat acattttttt tctttaaaaa acaactatgg atcagaatag caacatttag 1679aacacttttt gttatcagtc aatattttta gatagttaga acctggtcct aagcctaaaa 1739gtgggcttga ttctgcagta aatcttttac aactgcctcg acacacataa acctttttaa 1799aaatagacac tccccgaagt cttttgtttg tatggtcaca cactgatgct tagatgttcc 1859agtaatctaa tatggccaca gtagtcttga tgaccaaagt cctttttttc catctttaga 1919aaactacatg ggaacaaaca gatcgaacag ttttgaagct actgtgtgtg tgaatgaaca 1979ctcttgcttt attccagaat gctgtacatc tattttggat tgtatattgt ggttgtgtat 2039ttacgctttg attcatagta acttcttatg gaattgattt gcattgaacg acaaactgta 2099aataaaaaga aacggtg 21167280PRThuman 72Met Gly Arg Ala Met Val Ala Arg Leu Gly Leu Gly Leu Leu Leu Leu1 5 10 15Ala Leu Leu Leu Pro Thr Gln Ile Tyr Ser Ser Glu Thr Thr Thr Gly 20 25 30Thr Ser Ser Asn Ser Ser Gln Ser Thr Ser Asn Ser Gly Leu Ala Pro 35 40 45Asn Pro Thr Asn Ala Thr Thr Lys Ala Ala Gly Gly Ala Leu Gln Ser 50 55 60Thr Ala Ser Leu Phe Val Val Ser Leu Ser Leu Leu His Leu Tyr Ser65 70 75 80731513DNAhumanCDS(236)...(742) 73attcacttct cacaaggact gggtgaagag ttctgcagcc ttacagagac tggaaaagaa 60gcccaaacca aggcccccag agaggtcccc caggcccctt tgggtccctg agcctcagct 120ggaggtgggg ggtgcctgca gtgcgctggc tcagtctcct tctgaaaagc tggatccagc 180ttgtttgaag cccttgagct gatcttagat ccggcgcagg agaccaacgc ctgcc atg 238 Met 1ctg ttc cgg ctc tca gag cac tcc tca cca gag gag gaa gcc tcc ccc 286Leu Phe Arg Leu Ser Glu His Ser Ser Pro Glu Glu Glu Ala Ser Pro 5 10 15cac cag aga gcc tca gga gag ggg cac cat ctc aag tcg aag aga ccc 334His Gln Arg Ala Ser Gly Glu Gly His His Leu Lys Ser Lys Arg Pro 20 25 30aac ccc tgt gcc tac aca cca cct tcg ctg aaa gct gtg cag cgc att 382Asn Pro Cys Ala Tyr Thr Pro Pro Ser Leu Lys Ala Val Gln Arg Ile 35 40 45gct gag tct cac ctg cag tct atc agc aat ttg aat gag aac cag gcc 430Ala Glu Ser His Leu Gln Ser Ile Ser Asn Leu Asn Glu Asn Gln Ala50 55 60 65tca gag gag gag gat gag ctg ggg gag ctt cgg gag ctg ggt tat cca 478Ser Glu Glu Glu Asp Glu Leu Gly Glu Leu Arg Glu Leu Gly Tyr Pro 70 75 80aga gag gaa gat gag gag gaa gag gag gat gat gaa gaa gag gaa gaa 526Arg Glu Glu Asp Glu Glu Glu Glu Glu Asp Asp Glu Glu Glu Glu Glu 85 90 95gaa gag gac agc cag gct gaa gtc ctg aag gtc atc agg cag tct gct 574Glu Glu Asp Ser Gln Ala Glu Val Leu Lys Val Ile Arg Gln Ser Ala 100 105 110ggg caa aag aca acc tgt ggc cag ggt ctg gaa ggg ccc tgg gag cgc 622Gly Gln Lys Thr Thr Cys Gly Gln Gly Leu Glu Gly Pro Trp Glu Arg 115 120 125cca ccc cct ctg gat gag tcc gag aga gat gga ggc tct gag gac caa 670Pro Pro Pro Leu Asp Glu Ser Glu Arg Asp Gly Gly Ser Glu Asp Gln130 135 140 145gtg gaa gac cca gca cta agt gag cct ggg gag gaa cct cag cgc cct 718Val Glu Asp Pro Ala Leu Ser Glu Pro Gly Glu Glu Pro Gln Arg Pro 150 155 160tcc ccc tct gag cct ggc aca tag gcacccagcc tgcatctccc aggaggaagt 772Ser Pro Ser Glu Pro Gly Thr * 165ggaggggaca tcgctgttcc ccagaaaccc actctatcct caccctgttt tgtgctcttc 832ccctcgcctg ctagggctgc ggcttctgac ttctagaaga ctaaggctgg tctgtgtttg 892cttgtttgcc cacctttggc tgatacccag agaacctggg cacttgctgc ctgatgccca 952cccctgccag tcattcctcc attcacccag cgggaggtgg gatgtgagac agcccacatt 1012ggaaaatcca gaaaaccggg aacagggatt tgcccttcac aattctactc cccagatcct 1072ctcccctgga cacaggagac ccacagggca ggaccctaag atctggggaa aggaggtcct 1132gagaaccttg aggtaccctt agatcctttt ctacccactt tcctatggag gattccaagt 1192caccacttct ctcaccggct tctaccaggg tccaggacta aggcgttttt ctccatagcc 1252tcaacatttt gggaatcttc ccttaatcac ccttgctcct cctgggtgcc tggaagatgg 1312actggcagag acctctttgt tgcgttttgt gctttgatgc caggaatgcc gcctagttta 1372tgtccccggt ggggcacaca gcggggggcg ccaggttttc cttgtccccc agctgctctg 1432cccctttccc cttcttccct gactccaggc ctgaacccct cccgtgctgt aataaatctt 1492tgtaaataac aaaaaaaaaa a 151374168PRThuman 74Met Leu Phe Arg Leu Ser Glu His Ser Ser Pro Glu Glu Glu Ala Ser1 5 10 15Pro His Gln Arg Ala Ser Gly Glu Gly His His Leu Lys Ser Lys Arg 20 25 30Pro Asn Pro Cys Ala Tyr Thr Pro Pro Ser Leu Lys Ala Val Gln Arg 35 40 45Ile Ala Glu Ser His Leu Gln Ser Ile Ser Asn Leu Asn Glu Asn Gln 50 55 60Ala Ser Glu Glu Glu Asp Glu Leu Gly Glu Leu Arg Glu Leu Gly Tyr65 70 75 80Pro Arg Glu Glu Asp Glu Glu Glu Glu Glu Asp Asp Glu Glu Glu Glu 85 90 95Glu Glu Glu Asp Ser Gln Ala Glu Val Leu Lys Val Ile Arg Gln Ser 100 105 110Ala Gly Gln Lys Thr Thr Cys Gly Gln Gly Leu Glu Gly Pro Trp Glu 115 120 125Arg Pro Pro Pro Leu Asp Glu Ser Glu Arg Asp Gly Gly Ser Glu Asp 130 135 140Gln Val Glu Asp Pro Ala Leu Ser Glu Pro Gly Glu Glu Pro Gln Arg145 150 155 160Pro Ser Pro Ser Glu Pro Gly Thr 165751841DNAhumanCDS(468)...(1082) 75agctgggacc ggagggtgag cccggcagag gcagagacac acgcggagag gaggagaggc 60tgagggaggg aggtggagaa ggacgggaga ggcagagaga ggagacacgc agagacactc 120aggaggggag agacaccgag acgcagagac actcaggagg ggagagacac cgagacgcag 180agacacccag gccggggagc gcgagggagc gaggcacaga cctggctcag cgagcgcggg 240gggcgagccc cgagtcccga gagcctgggg gcgcgcccag cccgggcgcc gaccctcctc 300ccgctcccgc gccctcccct cggcgggcac ggtattttta tccgtgcgcg aacagccctc 360ctcctcctct cgccgcacag cccgccgcct gcgcggggga gcccagcaca gaccgccgcc 420gggaccccga gtcgcgcacc ccagccccac cgcccacccc gcgcgcc atg gac ccc 476 Met Asp Pro 1aag gac cgc aag aag atc cag ttc tcg gtg ccc gcg ccc cct agc cag 524Lys Asp Arg Lys Lys Ile Gln Phe Ser Val Pro Ala Pro Pro Ser Gln 5 10 15ctc gac ccc cgc cag gtg gag atg atc cgg cgc agg aga cca acg cct 572Leu Asp Pro Arg Gln Val Glu Met Ile Arg Arg Arg Arg Pro Thr Pro20 25 30 35gcc atg ctg ttc cgg ctc tca gag cac tcc tca cca gag gag gaa gcc 620Ala Met Leu Phe Arg Leu Ser Glu His Ser Ser Pro Glu Glu Glu Ala 40 45 50tcc ccc cac cag aga gcc tca gga gag ggg cac cat ctc aag tcg aag 668Ser Pro His Gln Arg Ala Ser Gly Glu Gly His His Leu Lys Ser Lys 55 60 65aga ccc aac ccc tgt gcc tac aca cca cct tcg ctg aaa gct gtg cag 716Arg Pro Asn Pro Cys Ala Tyr Thr Pro Pro Ser Leu Lys Ala Val Gln 70 75 80cgc att gct gag tct cac ctg cag tct atc agc aat ttg aat gag aac 764Arg Ile Ala Glu Ser His Leu Gln Ser Ile Ser Asn Leu Asn Glu Asn 85 90 95cag gcc tca gag gag gag gat gag ctg ggg gag ctt cgg gag ctg ggt 812Gln Ala Ser Glu Glu Glu Asp Glu Leu Gly Glu Leu Arg Glu Leu Gly100 105 110 115tat cca aga gag gaa gat gag gag gaa gag gag gat gat gaa gaa gag 860Tyr Pro Arg Glu Glu Asp Glu Glu Glu Glu Glu Asp Asp Glu Glu Glu 120 125 130gaa gaa gaa gag gac agc cag gct gaa gtc ctg aag gtc atc agg cag 908Glu Glu Glu Glu Asp Ser Gln Ala Glu Val Leu Lys Val Ile Arg Gln 135 140 145tct gct ggg caa aag aca acc tgt ggc cag ggt ctg gaa ggg ccc tgg 956Ser Ala Gly Gln Lys Thr Thr Cys Gly Gln Gly Leu Glu Gly Pro Trp 150 155 160gag cgc cca ccc cct ctg gat gag tcc gag aga gat gga ggc tct gag 1004Glu Arg Pro Pro Pro Leu Asp Glu Ser Glu Arg Asp Gly Gly Ser Glu 165 170 175gac caa gtg gaa gac cca gca cta agt gag cct ggg gag gaa cct cag 1052Asp Gln Val Glu Asp Pro Ala Leu Ser Glu Pro Gly Glu Glu Pro Gln180 185 190 195cgc cct tcc ccc tct gag cct ggc aca tag gcacccagcc tgcatctccc 1102Arg Pro Ser Pro Ser Glu Pro Gly Thr * 200aggaggaagt ggaggggaca tcgctgttcc ccagaaaccc actctatcct caccctgttt 1162tgtgctcttc ccctcgcctg ctagggctgc ggcttctgac ttctagaaga ctaaggctgg 1222tctgtgtttg cttgtttgcc cacctttggc tgatacccag agaacctggg cacttgctgc 1282ctgatgccca cccctgccag tcattcctcc attcacccag cgggaggtgg gatgtgagac 1342agcccacatt ggaaaatcca gaaaaccggg aacagggatt tgcccttcac aattctactc 1402cccagatcct ctcccctgga cacaggagac ccacagggca ggaccctaag atctggggaa 1462aggaggtcct gagaaccttg aggtaccctt agatcctttt ctacccactt tcctatggag 1522gattccaagt caccacttct ctcaccggct tctaccaggg tccaggacta aggcgttttt 1582ctccatagcc tcaacatttt gggaatcttc ccttaatcac ccttgctcct cctgggtgcc 1642tggaagatgg actggcagag acctctttgt tgcgttttgt gctttgatgc caggaatgcc 1702gcctagttta tgtccccggt ggggcacaca gcggggggcg ccaggttttc cttgtccccc 1762agctgctctg cccctttccc cttcttccct gactccaggc ctgaacccct cccgtgctgt 1822aataaatctt tgtaaataa 184176204PRThuman 76Met Asp Pro Lys Asp Arg Lys Lys Ile Gln Phe Ser Val Pro Ala Pro1 5 10 15Pro Ser Gln Leu Asp Pro Arg Gln Val Glu Met Ile Arg Arg Arg Arg 20 25 30Pro Thr Pro Ala Met Leu Phe Arg Leu Ser Glu His Ser Ser Pro Glu 35 40 45Glu Glu Ala Ser Pro His Gln Arg Ala Ser Gly Glu Gly His His Leu 50 55 60Lys Ser Lys Arg Pro Asn Pro Cys Ala Tyr Thr Pro Pro Ser Leu Lys65 70 75 80Ala Val Gln Arg Ile Ala Glu Ser His Leu Gln Ser Ile Ser Asn Leu 85 90 95Asn Glu Asn Gln Ala Ser Glu Glu Glu Asp Glu Leu Gly Glu Leu Arg 100 105 110Glu Leu Gly Tyr Pro Arg Glu Glu Asp Glu Glu Glu Glu Glu Asp Asp 115 120 125Glu Glu Glu Glu Glu Glu Glu Asp Ser Gln Ala Glu Val Leu Lys Val 130 135 140Ile Arg Gln Ser Ala Gly Gln Lys Thr Thr Cys Gly Gln Gly Leu Glu145 150 155 160Gly Pro Trp Glu Arg Pro Pro Pro Leu Asp Glu Ser Glu Arg Asp Gly 165 170 175Gly Ser Glu Asp Gln Val Glu Asp Pro Ala Leu Ser Glu Pro Gly Glu 180 185 190Glu Pro Gln Arg Pro Ser Pro Ser Glu Pro Gly Thr 195 200773745DNAhumanCDS(124)...(2220) 77agcggcgcct taaatagcat ccagagccgg cgcggggcag ggagtgggct gcagtgacag 60ccggcggcgg agcggccggt ccacggagga gaattcagct tagagaacta tcaacacagg 120aca atg caa gcc cat gag ctg ttc cgg tat ttt cga atg cca gag ctg 168 Met Gln Ala His Glu Leu Phe Arg Tyr Phe Arg Met Pro Glu Leu 1 5 10 15gtt gac ttc cga cag tac gtg cgt act ctt ccg acc aac acg ctt atg 216Val Asp Phe Arg Gln Tyr Val Arg Thr Leu Pro Thr Asn Thr Leu Met 20 25 30ggc ttc gga gct ttt gca gca ctc acc acc ttc tgg tac gcc acg aga 264Gly Phe Gly Ala Phe Ala Ala Leu Thr Thr Phe Trp Tyr Ala Thr Arg 35 40 45ccc aaa ccc ctg aag ccg cca tgc gac ctc tcc atg cag tca gtg gaa 312Pro Lys Pro Leu Lys Pro Pro Cys Asp Leu Ser Met Gln Ser Val Glu 50 55 60gtg gcg ggt agt ggt ggt gca cga aga tcc gca cta ctt gac agc gac 360Val Ala Gly Ser Gly Gly Ala Arg Arg Ser Ala Leu Leu Asp Ser Asp 65 70 75gag ccc ttg gtg tat ttc tat gat gat gtc aca aca tta tac gaa ggt 408Glu Pro Leu Val Tyr Phe Tyr Asp Asp Val Thr Thr Leu Tyr Glu Gly80 85 90 95ttc cag agg gga ata cag gtg tca aat aat ggc cct tgt tta ggc tct 456Phe Gln Arg Gly Ile Gln Val Ser Asn Asn Gly Pro Cys Leu Gly Ser 100 105 110cgg aaa cca gac caa ccc tat gaa tgg ctt tca tat aaa cag gtt gca 504Arg Lys Pro Asp Gln Pro Tyr Glu Trp Leu Ser Tyr Lys Gln Val Ala 115 120 125gaa ttg tcg gag tgc ata ggc tca gca ctg atc cag aag ggc ttc aag 552Glu Leu Ser Glu Cys Ile Gly Ser Ala Leu Ile Gln Lys Gly Phe Lys 130 135 140act gcc cca gat cag ttc att ggc atc ttt gct caa aat aga cct gag 600Thr Ala Pro Asp Gln Phe Ile Gly Ile Phe Ala Gln Asn Arg Pro Glu 145 150 155tgg gtg att att gaa caa gga tgc ttt gct tat tcg atg gtg atc gtt 648Trp Val Ile Ile Glu Gln Gly Cys Phe Ala Tyr Ser Met Val Ile Val160 165 170 175cca ctt tat gat acc ctt gga aat gaa gcc atc acg tac ata gtc aac 696Pro Leu Tyr Asp Thr Leu Gly Asn Glu Ala Ile Thr Tyr Ile Val Asn 180 185 190aaa gct gaa ctc tct ctg gtt ttt gtt gac aag cca gag aag gcc aaa 744Lys Ala Glu Leu Ser Leu Val Phe Val Asp Lys Pro Glu Lys Ala Lys 195 200 205ctc tta tta gag ggt gta gaa aat aag tta ata cca ggc ctt aaa atc 792Leu Leu Leu Glu Gly Val Glu Asn Lys Leu Ile Pro Gly Leu Lys Ile 210 215 220ata gtt gtc atg gat gcc tac ggc agt gaa ctg gtg gaa cga ggc cag 840Ile Val Val Met Asp Ala Tyr Gly Ser Glu Leu Val Glu Arg Gly Gln 225 230 235agg tgt ggg gtg gaa gtc acc agc atg aag gcg atg gag gac ctg gga 888Arg Cys Gly Val Glu Val Thr Ser Met Lys Ala Met Glu Asp Leu Gly240 245 250 255aga gcc aac aga cgg aag ccc aag cct cca gca cct gaa gat ctt gca 936Arg Ala Asn Arg Arg Lys Pro Lys Pro Pro Ala Pro Glu Asp Leu Ala 260 265 270gta att tgt ttc aca agt gga act aca ggc aac ccc aaa gga gca atg 984Val Ile Cys Phe Thr Ser Gly Thr Thr Gly Asn Pro Lys Gly Ala Met 275 280 285gtc act cac cga aac ata gtg agc gat tgt tca gct ttt gtg aaa gca 1032Val Thr His Arg Asn Ile Val Ser Asp Cys Ser Ala Phe Val Lys Ala 290 295 300aca gag aaa gca ctt ccc ttg agt gcc agt gac aca cac att tca tat 1080Thr Glu Lys Ala Leu Pro Leu Ser Ala Ser Asp Thr His Ile Ser Tyr 305 310 315tta cca ctt gct cac att tat gaa cag tta ttg aag tgt gta atg ctg 1128Leu Pro Leu Ala His Ile Tyr Glu Gln Leu Leu Lys Cys Val Met Leu320 325 330 335tgt cat gga gct aaa atc gga ttt ttc caa gga gat atc agg ctg ctc 1176Cys His Gly Ala Lys Ile Gly Phe Phe Gln Gly Asp Ile Arg Leu Leu 340 345 350atg gat gac ctc aag gtg ctt caa ccc act gtc ttc ccc gtg gtt cca 1224Met Asp Asp Leu Lys Val Leu Gln Pro Thr Val Phe Pro Val Val Pro 355 360 365aga ctg ctg aac cgg atg ttt gac cga att ttc gga caa gca aac acc 1272Arg Leu Leu Asn Arg Met Phe Asp Arg Ile Phe Gly Gln Ala Asn Thr 370 375 380acg ctg aag cga tgg ctc ttg gac ttt gcc tcc aag agg aaa gaa gca 1320Thr Leu Lys Arg Trp Leu Leu Asp Phe Ala Ser Lys Arg Lys Glu Ala 385 390 395gag ctt cgc agc ggc atc atc aga aac aac agc ctg tgg gac cgg ctg 1368Glu Leu Arg Ser Gly Ile Ile Arg Asn Asn Ser Leu Trp Asp Arg Leu400 405 410 415atc ttc cac aaa gta cag tcg agc ctg ggc gga aga gtc cgg ctg atg 1416Ile Phe His Lys Val Gln Ser Ser Leu Gly Gly Arg Val Arg Leu Met 420 425 430gtg aca gga gcc gcc ccg gtg tct gcc act gtg ctg acg ttc ctc aga 1464Val Thr Gly Ala Ala Pro Val Ser Ala Thr Val Leu Thr Phe Leu Arg 435 440 445gca gcc ctg ggc tgt cag ttt tat gaa gga tac gga cag aca gag tgc 1512Ala Ala Leu Gly Cys Gln Phe Tyr Glu Gly Tyr Gly Gln Thr Glu Cys 450 455 460act gcc ggg tgc tgc cta acc atg cct gga gac tgg acc gca ggc cat 1560Thr Ala Gly Cys Cys Leu Thr Met Pro Gly Asp Trp Thr Ala Gly His 465 470 475gtt ggg gcc ccg atg ccg tgc aat ttg ata aaa ctt gtt gat gtg gaa 1608Val Gly Ala Pro Met Pro Cys Asn Leu Ile Lys Leu Val Asp Val Glu480 485 490 495gaa atg aat tac atg gct gcc gag ggc gag ggc gag gtg tgt gtg aaa 1656Glu Met Asn Tyr Met Ala Ala Glu Gly Glu Gly Glu Val Cys Val Lys 500 505 510ggg cca aat gta ttt cag ggc tac ttg aag gac cca gcg aaa aca gca 1704Gly Pro Asn Val Phe Gln Gly Tyr Leu Lys Asp Pro Ala Lys Thr Ala 515 520 525gaa gct ttg gac aaa gac ggc tgg tta cac aca ggg gac att gga aaa 1752Glu Ala Leu Asp Lys Asp Gly Trp Leu His Thr Gly Asp Ile Gly Lys 530 535

540tgg tta cca aat ggc acc ttg aaa att atc gac cgg aaa aag cac ata 1800Trp Leu Pro Asn Gly Thr Leu Lys Ile Ile Asp Arg Lys Lys His Ile 545 550 555ttt aag ctg gca caa gga gaa tac ata gcc cct gaa aag att gaa aat 1848Phe Lys Leu Ala Gln Gly Glu Tyr Ile Ala Pro Glu Lys Ile Glu Asn560 565 570 575atc tac atg cga agt gag cct gtt gct cag gtg ttt gtc cac gga gaa 1896Ile Tyr Met Arg Ser Glu Pro Val Ala Gln Val Phe Val His Gly Glu 580 585 590agc ctg cag gca ttt ctc att gca att gtg gta cca gat gtt gag aca 1944Ser Leu Gln Ala Phe Leu Ile Ala Ile Val Val Pro Asp Val Glu Thr 595 600 605tta tgt tcc tgg gcc caa aag aga gga ttt gaa ggg tcg ttt gag gaa 1992Leu Cys Ser Trp Ala Gln Lys Arg Gly Phe Glu Gly Ser Phe Glu Glu 610 615 620ctg tgc aga aat aag gat gtc aaa aaa gct atc ctc gaa gat atg gtg 2040Leu Cys Arg Asn Lys Asp Val Lys Lys Ala Ile Leu Glu Asp Met Val 625 630 635aga ctt ggg aag gat tct ggt ctg aaa cca ttt gaa cag gtc aaa ggc 2088Arg Leu Gly Lys Asp Ser Gly Leu Lys Pro Phe Glu Gln Val Lys Gly640 645 650 655atc aca ttg cac cct gaa tta ttt tct atc gac aat ggc ctt ctg act 2136Ile Thr Leu His Pro Glu Leu Phe Ser Ile Asp Asn Gly Leu Leu Thr 660 665 670cca aca atg aag gcg aaa agg cca gag ctg cgg aac tat ttc agg tcg 2184Pro Thr Met Lys Ala Lys Arg Pro Glu Leu Arg Asn Tyr Phe Arg Ser 675 680 685cag ata gat gac ctc tat tcc act atc aag gtt tag tgtgaagaag 2230Gln Ile Asp Asp Leu Tyr Ser Thr Ile Lys Val * 690 695aaagctcaga ggaaatggca cagttccaca atctcttctc ctgctgatgg ccttcatgtt 2290gttaattttg aatacagcaa gtgtagggaa ggaagcgttc gtgtttgact tgtccattcg 2350gggttcttct cataggaatg ctagaggaaa cagaacaccg ccttacagtc acctcatgtt 2410gcagaccatg tttatggtaa tacacacttt ccaaaatgag ccttaaaaat tgtaaagggg 2470atactataaa tgtgctaagt tatttgagac ttcctcagtt taaaaagtgg gttttaaatc 2530ttctgtctcc ctgcttttct aatcaagggg ttaggacttt gctatctctg agatgtctgc 2590tacttgctgc aaattctgca gctgtctgct gctctaaaga gtacagtgca ctagagggaa 2650gtgttccctt taaaaataag aacaactgtc ctggctggag aatctcacaa gcggaccaga 2710gatcttttta aatccctgct actgtccctt ctcacaggca ttcacagaac ccttctgatt 2770cgtaagggtt acgaaactca tgttcttctc cagtcccctg tggtttctgt tggagcataa 2830ggtttccagt aagcgggagg gcagatccaa ctcagaacca tgcagataag gagcctctgg 2890caaatgggtg ctcatcagaa cgcgtggatt ctctttcatg gcagaatgct cttggactcg 2950gttctccagg cctgattccc cgactccatc ctttttcagg ggttatttaa aaatctgcct 3010tagattctat agtgaagaca agcatttcaa gaaagagtta cctggatcag ccatgctcag 3070ctgtgacgcc tgaataactg tctactttat cttcactgaa ccactcactc tgtgtaaagg 3130ccaacagatt tttaatgtgg ttttcatatc aaaagatcat gttgggatta acttgccttt 3190ttccccaaaa aataaactct caggcaagca tttctttaaa gctattaagg gagtatatac 3250ttgagtactt attgaaatgg acagtaataa gcaaatgttc ttataatgct acctgatttc 3310tatgaaatgt gtttgacaag ccaaaattct aggatgtaga aatctggaaa gttcatttcc 3370tgggattcac ttctccaggg attttttaaa gttaatttgg gaaattaaca gcagttcact 3430ttattgtgag tctttgccac atttgactga attgagctgt catttgtaca tttaaagcag 3490ctgttttggg gtctgtgaga gtacatgtat tatatacaag cacaacaggg cttgcactaa 3550agaattgtca ttgtaataac actacttggt agcctaactt catatatgta ttcttaattg 3610cacaaaaagt caataatttg tcaccttggg gttttgaatg tttgctttaa gtgttggcta 3670tttctatgtt ttataaacca aaacaaaatt tccaaaaaca atgaaggaaa ccaaaataaa 3730tatttctgca tttcg 374578698PRThuman 78Met Gln Ala His Glu Leu Phe Arg Tyr Phe Arg Met Pro Glu Leu Val1 5 10 15Asp Phe Arg Gln Tyr Val Arg Thr Leu Pro Thr Asn Thr Leu Met Gly 20 25 30Phe Gly Ala Phe Ala Ala Leu Thr Thr Phe Trp Tyr Ala Thr Arg Pro 35 40 45Lys Pro Leu Lys Pro Pro Cys Asp Leu Ser Met Gln Ser Val Glu Val 50 55 60Ala Gly Ser Gly Gly Ala Arg Arg Ser Ala Leu Leu Asp Ser Asp Glu65 70 75 80Pro Leu Val Tyr Phe Tyr Asp Asp Val Thr Thr Leu Tyr Glu Gly Phe 85 90 95Gln Arg Gly Ile Gln Val Ser Asn Asn Gly Pro Cys Leu Gly Ser Arg 100 105 110Lys Pro Asp Gln Pro Tyr Glu Trp Leu Ser Tyr Lys Gln Val Ala Glu 115 120 125Leu Ser Glu Cys Ile Gly Ser Ala Leu Ile Gln Lys Gly Phe Lys Thr 130 135 140Ala Pro Asp Gln Phe Ile Gly Ile Phe Ala Gln Asn Arg Pro Glu Trp145 150 155 160Val Ile Ile Glu Gln Gly Cys Phe Ala Tyr Ser Met Val Ile Val Pro 165 170 175Leu Tyr Asp Thr Leu Gly Asn Glu Ala Ile Thr Tyr Ile Val Asn Lys 180 185 190Ala Glu Leu Ser Leu Val Phe Val Asp Lys Pro Glu Lys Ala Lys Leu 195 200 205Leu Leu Glu Gly Val Glu Asn Lys Leu Ile Pro Gly Leu Lys Ile Ile 210 215 220Val Val Met Asp Ala Tyr Gly Ser Glu Leu Val Glu Arg Gly Gln Arg225 230 235 240Cys Gly Val Glu Val Thr Ser Met Lys Ala Met Glu Asp Leu Gly Arg 245 250 255Ala Asn Arg Arg Lys Pro Lys Pro Pro Ala Pro Glu Asp Leu Ala Val 260 265 270Ile Cys Phe Thr Ser Gly Thr Thr Gly Asn Pro Lys Gly Ala Met Val 275 280 285Thr His Arg Asn Ile Val Ser Asp Cys Ser Ala Phe Val Lys Ala Thr 290 295 300Glu Lys Ala Leu Pro Leu Ser Ala Ser Asp Thr His Ile Ser Tyr Leu305 310 315 320Pro Leu Ala His Ile Tyr Glu Gln Leu Leu Lys Cys Val Met Leu Cys 325 330 335His Gly Ala Lys Ile Gly Phe Phe Gln Gly Asp Ile Arg Leu Leu Met 340 345 350Asp Asp Leu Lys Val Leu Gln Pro Thr Val Phe Pro Val Val Pro Arg 355 360 365Leu Leu Asn Arg Met Phe Asp Arg Ile Phe Gly Gln Ala Asn Thr Thr 370 375 380Leu Lys Arg Trp Leu Leu Asp Phe Ala Ser Lys Arg Lys Glu Ala Glu385 390 395 400Leu Arg Ser Gly Ile Ile Arg Asn Asn Ser Leu Trp Asp Arg Leu Ile 405 410 415Phe His Lys Val Gln Ser Ser Leu Gly Gly Arg Val Arg Leu Met Val 420 425 430Thr Gly Ala Ala Pro Val Ser Ala Thr Val Leu Thr Phe Leu Arg Ala 435 440 445Ala Leu Gly Cys Gln Phe Tyr Glu Gly Tyr Gly Gln Thr Glu Cys Thr 450 455 460Ala Gly Cys Cys Leu Thr Met Pro Gly Asp Trp Thr Ala Gly His Val465 470 475 480Gly Ala Pro Met Pro Cys Asn Leu Ile Lys Leu Val Asp Val Glu Glu 485 490 495Met Asn Tyr Met Ala Ala Glu Gly Glu Gly Glu Val Cys Val Lys Gly 500 505 510Pro Asn Val Phe Gln Gly Tyr Leu Lys Asp Pro Ala Lys Thr Ala Glu 515 520 525Ala Leu Asp Lys Asp Gly Trp Leu His Thr Gly Asp Ile Gly Lys Trp 530 535 540Leu Pro Asn Gly Thr Leu Lys Ile Ile Asp Arg Lys Lys His Ile Phe545 550 555 560Lys Leu Ala Gln Gly Glu Tyr Ile Ala Pro Glu Lys Ile Glu Asn Ile 565 570 575Tyr Met Arg Ser Glu Pro Val Ala Gln Val Phe Val His Gly Glu Ser 580 585 590Leu Gln Ala Phe Leu Ile Ala Ile Val Val Pro Asp Val Glu Thr Leu 595 600 605Cys Ser Trp Ala Gln Lys Arg Gly Phe Glu Gly Ser Phe Glu Glu Leu 610 615 620Cys Arg Asn Lys Asp Val Lys Lys Ala Ile Leu Glu Asp Met Val Arg625 630 635 640Leu Gly Lys Asp Ser Gly Leu Lys Pro Phe Glu Gln Val Lys Gly Ile 645 650 655Thr Leu His Pro Glu Leu Phe Ser Ile Asp Asn Gly Leu Leu Thr Pro 660 665 670Thr Met Lys Ala Lys Arg Pro Glu Leu Arg Asn Tyr Phe Arg Ser Gln 675 680 685Ile Asp Asp Leu Tyr Ser Thr Ile Lys Val 690 695793809DNAhumanCDS(188)...(2284) 79agcggatcgt ggctcagccg cggcggtggc gggggcgcaa ccagcgggcc gaggcggcgg 60cgccagcggc gccttaaata gcatccagag ccggcgcggg gcagggagtg ggctgcagtg 120acagccggcg gcggagcggc cggtccacgg aggagaattc agcttagaga actatcaaca 180caggaca atg caa gcc cat gag ctg ttc cgg tat ttt cga atg cca gag 229 Met Gln Ala His Glu Leu Phe Arg Tyr Phe Arg Met Pro Glu 1 5 10ctg gtt gac ttc cga cag tac gtg cgt act ctt ccg acc aac acg ctt 277Leu Val Asp Phe Arg Gln Tyr Val Arg Thr Leu Pro Thr Asn Thr Leu 15 20 25 30atg ggc ttc gga gct ttt gca gca ctc acc acc ttc tgg tac gcc acg 325Met Gly Phe Gly Ala Phe Ala Ala Leu Thr Thr Phe Trp Tyr Ala Thr 35 40 45aga ccc aaa ccc ctg aag ccg cca tgc gac ctc tcc atg cag tca gtg 373Arg Pro Lys Pro Leu Lys Pro Pro Cys Asp Leu Ser Met Gln Ser Val 50 55 60gaa gtg gcg ggt agt ggt ggt gca cga aga tcc gca cta ctt gac agc 421Glu Val Ala Gly Ser Gly Gly Ala Arg Arg Ser Ala Leu Leu Asp Ser 65 70 75gac gag ccc ttg gtg tat ttc tat gat gat gtc aca aca tta tac gaa 469Asp Glu Pro Leu Val Tyr Phe Tyr Asp Asp Val Thr Thr Leu Tyr Glu 80 85 90ggt ttc cag agg gga ata cag gtg tca aat aat ggc cct tgt tta ggc 517Gly Phe Gln Arg Gly Ile Gln Val Ser Asn Asn Gly Pro Cys Leu Gly95 100 105 110tct cgg aaa cca gac caa ccc tat gaa tgg ctt tca tat aaa cag gtt 565Ser Arg Lys Pro Asp Gln Pro Tyr Glu Trp Leu Ser Tyr Lys Gln Val 115 120 125gca gaa ttg tcg gag tgc ata ggc tca gca ctg atc cag aag ggc ttc 613Ala Glu Leu Ser Glu Cys Ile Gly Ser Ala Leu Ile Gln Lys Gly Phe 130 135 140aag act gcc cca gat cag ttc att ggc atc ttt gct caa aat aga cct 661Lys Thr Ala Pro Asp Gln Phe Ile Gly Ile Phe Ala Gln Asn Arg Pro 145 150 155gag tgg gtg att att gaa caa gga tgc ttt gct tat tcg atg gtg atc 709Glu Trp Val Ile Ile Glu Gln Gly Cys Phe Ala Tyr Ser Met Val Ile 160 165 170gtt cca ctt tat gat acc ctt gga aat gaa gcc atc acg tac ata gtc 757Val Pro Leu Tyr Asp Thr Leu Gly Asn Glu Ala Ile Thr Tyr Ile Val175 180 185 190aac aaa gct gaa ctc tct ctg gtt ttt gtt gac aag cca gag aag gcc 805Asn Lys Ala Glu Leu Ser Leu Val Phe Val Asp Lys Pro Glu Lys Ala 195 200 205aaa ctc tta tta gag ggt gta gaa aat aag tta ata cca ggc ctt aaa 853Lys Leu Leu Leu Glu Gly Val Glu Asn Lys Leu Ile Pro Gly Leu Lys 210 215 220atc ata gtt gtc atg gat gcc tac ggc agt gaa ctg gtg gaa cga ggc 901Ile Ile Val Val Met Asp Ala Tyr Gly Ser Glu Leu Val Glu Arg Gly 225 230 235cag agg tgt ggg gtg gaa gtc acc agc atg aag gcg atg gag gac ctg 949Gln Arg Cys Gly Val Glu Val Thr Ser Met Lys Ala Met Glu Asp Leu 240 245 250gga aga gcc aac aga cgg aag ccc aag cct cca gca cct gaa gat ctt 997Gly Arg Ala Asn Arg Arg Lys Pro Lys Pro Pro Ala Pro Glu Asp Leu255 260 265 270gca gta att tgt ttc aca agt gga act aca ggc aac ccc aaa gga gca 1045Ala Val Ile Cys Phe Thr Ser Gly Thr Thr Gly Asn Pro Lys Gly Ala 275 280 285atg gtc act cac cga aac ata gtg agc gat tgt tca gct ttt gtg aaa 1093Met Val Thr His Arg Asn Ile Val Ser Asp Cys Ser Ala Phe Val Lys 290 295 300gca aca gag aat aca gtc aat cct tgc cca gat gat act ttg ata tct 1141Ala Thr Glu Asn Thr Val Asn Pro Cys Pro Asp Asp Thr Leu Ile Ser 305 310 315ttc ttg cct ctc gcc cat atg ttt gag aga gtt gta gag tgt gta atg 1189Phe Leu Pro Leu Ala His Met Phe Glu Arg Val Val Glu Cys Val Met 320 325 330ctg tgt cat gga gct aaa atc gga ttt ttc caa gga gat atc agg ctg 1237Leu Cys His Gly Ala Lys Ile Gly Phe Phe Gln Gly Asp Ile Arg Leu335 340 345 350ctc atg gat gac ctc aag gtg ctt caa ccc act gtc ttc ccc gtg gtt 1285Leu Met Asp Asp Leu Lys Val Leu Gln Pro Thr Val Phe Pro Val Val 355 360 365cca aga ctg ctg aac cgg atg ttt gac cga att ttc gga caa gca aac 1333Pro Arg Leu Leu Asn Arg Met Phe Asp Arg Ile Phe Gly Gln Ala Asn 370 375 380acc acg ctg aag cga tgg ctc ttg gac ttt gcc tcc aag agg aaa gaa 1381Thr Thr Leu Lys Arg Trp Leu Leu Asp Phe Ala Ser Lys Arg Lys Glu 385 390 395gca gag ctt cgc agc ggc atc atc aga aac aac agc ctg tgg gac cgg 1429Ala Glu Leu Arg Ser Gly Ile Ile Arg Asn Asn Ser Leu Trp Asp Arg 400 405 410ctg atc ttc cac aaa gta cag tcg agc ctg ggc gga aga gtc cgg ctg 1477Leu Ile Phe His Lys Val Gln Ser Ser Leu Gly Gly Arg Val Arg Leu415 420 425 430atg gtg aca gga gcc gcc ccg gtg tct gcc act gtg ctg acg ttc ctc 1525Met Val Thr Gly Ala Ala Pro Val Ser Ala Thr Val Leu Thr Phe Leu 435 440 445aga gca gcc ctg ggc tgt cag ttt tat gaa gga tac gga cag aca gag 1573Arg Ala Ala Leu Gly Cys Gln Phe Tyr Glu Gly Tyr Gly Gln Thr Glu 450 455 460tgc act gcc ggg tgc tgc cta acc atg cct gga gac tgg acc gca ggc 1621Cys Thr Ala Gly Cys Cys Leu Thr Met Pro Gly Asp Trp Thr Ala Gly 465 470 475cat gtt ggg gcc ccg atg ccg tgc aat ttg ata aaa ctt gtt gat gtg 1669His Val Gly Ala Pro Met Pro Cys Asn Leu Ile Lys Leu Val Asp Val 480 485 490gaa gaa atg aat tac atg gct gcc gag ggc gag ggc gag gtg tgt gtg 1717Glu Glu Met Asn Tyr Met Ala Ala Glu Gly Glu Gly Glu Val Cys Val495 500 505 510aaa ggg cca aat gta ttt cag ggc tac ttg aag gac cca gcg aaa aca 1765Lys Gly Pro Asn Val Phe Gln Gly Tyr Leu Lys Asp Pro Ala Lys Thr 515 520 525gca gaa gct ttg gac aaa gac ggc tgg tta cac aca ggg gac att gga 1813Ala Glu Ala Leu Asp Lys Asp Gly Trp Leu His Thr Gly Asp Ile Gly 530 535 540aaa tgg tta cca aat ggc acc ttg aaa att atc gac cgg aaa aag cac 1861Lys Trp Leu Pro Asn Gly Thr Leu Lys Ile Ile Asp Arg Lys Lys His 545 550 555ata ttt aag ctg gca caa gga gaa tac ata gcc cct gaa aag att gaa 1909Ile Phe Lys Leu Ala Gln Gly Glu Tyr Ile Ala Pro Glu Lys Ile Glu 560 565 570aat atc tac atg cga agt gag cct gtt gct cag gtg ttt gtc cac gga 1957Asn Ile Tyr Met Arg Ser Glu Pro Val Ala Gln Val Phe Val His Gly575 580 585 590gaa agc ctg cag gca ttt ctc att gca att gtg gta cca gat gtt gag 2005Glu Ser Leu Gln Ala Phe Leu Ile Ala Ile Val Val Pro Asp Val Glu 595 600 605aca tta tgt tcc tgg gcc caa aag aga gga ttt gaa ggg tcg ttt gag 2053Thr Leu Cys Ser Trp Ala Gln Lys Arg Gly Phe Glu Gly Ser Phe Glu 610 615 620gaa ctg tgc aga aat aag gat gtc aaa aaa gct atc ctc gaa gat atg 2101Glu Leu Cys Arg Asn Lys Asp Val Lys Lys Ala Ile Leu Glu Asp Met 625 630 635gtg aga ctt ggg aag gat tct ggt ctg aaa cca ttt gaa cag gtc aaa 2149Val Arg Leu Gly Lys Asp Ser Gly Leu Lys Pro Phe Glu Gln Val Lys 640 645 650ggc atc aca ttg cac cct gaa tta ttt tct atc gac aat ggc ctt ctg 2197Gly Ile Thr Leu His Pro Glu Leu Phe Ser Ile Asp Asn Gly Leu Leu655 660 665 670act cca aca atg aag gcg aaa agg cca gag ctg cgg aac tat ttc agg 2245Thr Pro Thr Met Lys Ala Lys Arg Pro Glu Leu Arg Asn Tyr Phe Arg 675 680 685tcg cag ata gat gac ctc tat tcc act atc aag gtt tag tgtgaagaag 2294Ser Gln Ile Asp Asp Leu Tyr Ser Thr Ile Lys Val * 690 695aaagctcaga ggaaatggca cagttccaca atctcttctc ctgctgatgg ccttcatgtt 2354gttaattttg aatacagcaa gtgtagggaa ggaagcgttc gtgtttgact tgtccattcg 2414gggttcttct cataggaatg ctagaggaaa cagaacaccg ccttacagtc acctcatgtt 2474gcagaccatg tttatggtaa tacacacttt ccaaaatgag ccttaaaaat tgtaaagggg 2534atactataaa tgtgctaagt tatttgagac ttcctcagtt taaaaagtgg gttttaaatc 2594ttctgtctcc ctgcttttct aatcaagggg ttaggacttt gctatctctg agatgtctgc 2654tacttgctgc aaattctgca gctgtctgct gctctaaaga gtacagtgca ctagagggaa 2714gtgttccctt taaaaataag aacaactgtc ctggctggag aatctcacaa gcggaccaga 2774gatcttttta aatccctgct actgtccctt ctcacaggca ttcacagaac ccttctgatt 2834cgtaagggtt acgaaactca tgttcttctc cagtcccctg tggtttctgt tggagcataa 2894ggtttccagt aagcgggagg

gcagatccaa ctcagaacca tgcagataag gagcctctgg 2954caaatgggtg ctcatcagaa cgcgtggatt ctctttcatg gcagaatgct cttggactcg 3014gttctccagg cctgattccc cgactccatc ctttttcagg ggttatttaa aaatctgcct 3074tagattctat agtgaagaca agcatttcaa gaaagagtta cctggatcag ccatgctcag 3134ctgtgacgcc tgaataactg tctactttat cttcactgaa ccactcactc tgtgtaaagg 3194ccaacagatt tttaatgtgg ttttcatatc aaaagatcat gttgggatta acttgccttt 3254ttccccaaaa aataaactct caggcaagca tttctttaaa gctattaagg gagtatatac 3314ttgagtactt attgaaatgg acagtaataa gcaaatgttc ttataatgct acctgatttc 3374tatgaaatgt gtttgacaag ccaaaattct aggatgtaga aatctggaaa gttcatttcc 3434tgggattcac ttctccaggg attttttaaa gttaatttgg gaaattaaca gcagttcact 3494ttattgtgag tctttgccac atttgactga attgagctgt catttgtaca tttaaagcag 3554ctgttttggg gtctgtgaga gtacatgtat tatatacaag cacaacaggg cttgcactaa 3614agaattgtca ttgtaataac actacttggt agcctaactt catatatgta ttcttaattg 3674cacaaaaagt caataatttg tcaccttggg gttttgaatg tttgctttaa gtgttggcta 3734tttctatgtt ttataaacca aaacaaaatt tccaaaaaca atgaaggaaa ccaaaataaa 3794tatttctgca tttcg 380980698PRThuman 80Met Gln Ala His Glu Leu Phe Arg Tyr Phe Arg Met Pro Glu Leu Val1 5 10 15Asp Phe Arg Gln Tyr Val Arg Thr Leu Pro Thr Asn Thr Leu Met Gly 20 25 30Phe Gly Ala Phe Ala Ala Leu Thr Thr Phe Trp Tyr Ala Thr Arg Pro 35 40 45Lys Pro Leu Lys Pro Pro Cys Asp Leu Ser Met Gln Ser Val Glu Val 50 55 60Ala Gly Ser Gly Gly Ala Arg Arg Ser Ala Leu Leu Asp Ser Asp Glu65 70 75 80Pro Leu Val Tyr Phe Tyr Asp Asp Val Thr Thr Leu Tyr Glu Gly Phe 85 90 95Gln Arg Gly Ile Gln Val Ser Asn Asn Gly Pro Cys Leu Gly Ser Arg 100 105 110Lys Pro Asp Gln Pro Tyr Glu Trp Leu Ser Tyr Lys Gln Val Ala Glu 115 120 125Leu Ser Glu Cys Ile Gly Ser Ala Leu Ile Gln Lys Gly Phe Lys Thr 130 135 140Ala Pro Asp Gln Phe Ile Gly Ile Phe Ala Gln Asn Arg Pro Glu Trp145 150 155 160Val Ile Ile Glu Gln Gly Cys Phe Ala Tyr Ser Met Val Ile Val Pro 165 170 175Leu Tyr Asp Thr Leu Gly Asn Glu Ala Ile Thr Tyr Ile Val Asn Lys 180 185 190Ala Glu Leu Ser Leu Val Phe Val Asp Lys Pro Glu Lys Ala Lys Leu 195 200 205Leu Leu Glu Gly Val Glu Asn Lys Leu Ile Pro Gly Leu Lys Ile Ile 210 215 220Val Val Met Asp Ala Tyr Gly Ser Glu Leu Val Glu Arg Gly Gln Arg225 230 235 240Cys Gly Val Glu Val Thr Ser Met Lys Ala Met Glu Asp Leu Gly Arg 245 250 255Ala Asn Arg Arg Lys Pro Lys Pro Pro Ala Pro Glu Asp Leu Ala Val 260 265 270Ile Cys Phe Thr Ser Gly Thr Thr Gly Asn Pro Lys Gly Ala Met Val 275 280 285Thr His Arg Asn Ile Val Ser Asp Cys Ser Ala Phe Val Lys Ala Thr 290 295 300Glu Asn Thr Val Asn Pro Cys Pro Asp Asp Thr Leu Ile Ser Phe Leu305 310 315 320Pro Leu Ala His Met Phe Glu Arg Val Val Glu Cys Val Met Leu Cys 325 330 335His Gly Ala Lys Ile Gly Phe Phe Gln Gly Asp Ile Arg Leu Leu Met 340 345 350Asp Asp Leu Lys Val Leu Gln Pro Thr Val Phe Pro Val Val Pro Arg 355 360 365Leu Leu Asn Arg Met Phe Asp Arg Ile Phe Gly Gln Ala Asn Thr Thr 370 375 380Leu Lys Arg Trp Leu Leu Asp Phe Ala Ser Lys Arg Lys Glu Ala Glu385 390 395 400Leu Arg Ser Gly Ile Ile Arg Asn Asn Ser Leu Trp Asp Arg Leu Ile 405 410 415Phe His Lys Val Gln Ser Ser Leu Gly Gly Arg Val Arg Leu Met Val 420 425 430Thr Gly Ala Ala Pro Val Ser Ala Thr Val Leu Thr Phe Leu Arg Ala 435 440 445Ala Leu Gly Cys Gln Phe Tyr Glu Gly Tyr Gly Gln Thr Glu Cys Thr 450 455 460Ala Gly Cys Cys Leu Thr Met Pro Gly Asp Trp Thr Ala Gly His Val465 470 475 480Gly Ala Pro Met Pro Cys Asn Leu Ile Lys Leu Val Asp Val Glu Glu 485 490 495Met Asn Tyr Met Ala Ala Glu Gly Glu Gly Glu Val Cys Val Lys Gly 500 505 510Pro Asn Val Phe Gln Gly Tyr Leu Lys Asp Pro Ala Lys Thr Ala Glu 515 520 525Ala Leu Asp Lys Asp Gly Trp Leu His Thr Gly Asp Ile Gly Lys Trp 530 535 540Leu Pro Asn Gly Thr Leu Lys Ile Ile Asp Arg Lys Lys His Ile Phe545 550 555 560Lys Leu Ala Gln Gly Glu Tyr Ile Ala Pro Glu Lys Ile Glu Asn Ile 565 570 575Tyr Met Arg Ser Glu Pro Val Ala Gln Val Phe Val His Gly Glu Ser 580 585 590Leu Gln Ala Phe Leu Ile Ala Ile Val Val Pro Asp Val Glu Thr Leu 595 600 605Cys Ser Trp Ala Gln Lys Arg Gly Phe Glu Gly Ser Phe Glu Glu Leu 610 615 620Cys Arg Asn Lys Asp Val Lys Lys Ala Ile Leu Glu Asp Met Val Arg625 630 635 640Leu Gly Lys Asp Ser Gly Leu Lys Pro Phe Glu Gln Val Lys Gly Ile 645 650 655Thr Leu His Pro Glu Leu Phe Ser Ile Asp Asn Gly Leu Leu Thr Pro 660 665 670Thr Met Lys Ala Lys Arg Pro Glu Leu Arg Asn Tyr Phe Arg Ser Gln 675 680 685Ile Asp Asp Leu Tyr Ser Thr Ile Lys Val 690 69581737DNAhumanCDS(30)...(662) 81ggagtttcgc cgccgcagtc ttcgccacc atg ccg ccc tac acc gtg gtc tat 53 Met Pro Pro Tyr Thr Val Val Tyr 1 5ttc cca gtt cga ggc cgc tgc gcg gcc ctg cgc atg ctg ctg gca gat 101Phe Pro Val Arg Gly Arg Cys Ala Ala Leu Arg Met Leu Leu Ala Asp 10 15 20cag ggc cag agc tgg aag gag gag gtg gtg acc gtg gag acg tgg cag 149Gln Gly Gln Ser Trp Lys Glu Glu Val Val Thr Val Glu Thr Trp Gln25 30 35 40gag ggc tca ctc aaa gcc tcc tgc cta tac ggg cag ctc ccc aag ttc 197Glu Gly Ser Leu Lys Ala Ser Cys Leu Tyr Gly Gln Leu Pro Lys Phe 45 50 55cag gac gga gac ctc acc ctg tac cag tcc aat acc atc ctg cgt cac 245Gln Asp Gly Asp Leu Thr Leu Tyr Gln Ser Asn Thr Ile Leu Arg His 60 65 70ctg ggc cgc acc ctt ggg ctc tat ggg aag gac cag cag gag gca gcc 293Leu Gly Arg Thr Leu Gly Leu Tyr Gly Lys Asp Gln Gln Glu Ala Ala 75 80 85ctg gtg gac atg gtg aat gac ggc gtg gag gac ctc cgc tgc aaa tac 341Leu Val Asp Met Val Asn Asp Gly Val Glu Asp Leu Arg Cys Lys Tyr 90 95 100atc tcc ctc atc tac acc aac tat gag gcg ggc aag gat gac tat gtg 389Ile Ser Leu Ile Tyr Thr Asn Tyr Glu Ala Gly Lys Asp Asp Tyr Val105 110 115 120aag gca ctg ccc ggg caa ctg aag cct ttt gag acc ctg ctg tcc cag 437Lys Ala Leu Pro Gly Gln Leu Lys Pro Phe Glu Thr Leu Leu Ser Gln 125 130 135aac cag gga ggc aag acc ttc att gtg gga gac cag atc tcc ttc gct 485Asn Gln Gly Gly Lys Thr Phe Ile Val Gly Asp Gln Ile Ser Phe Ala 140 145 150gac tac aac ctg ctg gac ttg ctg ctg atc cat gag gtc cta gcc cct 533Asp Tyr Asn Leu Leu Asp Leu Leu Leu Ile His Glu Val Leu Ala Pro 155 160 165ggc tgc ctg gat gcg ttc ccc ctg ctc tca gca tat gtg ggg cgc ctc 581Gly Cys Leu Asp Ala Phe Pro Leu Leu Ser Ala Tyr Val Gly Arg Leu 170 175 180agc gcc cgg ccc aag ctc aag gcc ttc ctg gcc tcc cct gag tac gtg 629Ser Ala Arg Pro Lys Leu Lys Ala Phe Leu Ala Ser Pro Glu Tyr Val185 190 195 200aac ctc ccc atc aat ggc aac ggg aaa cag tga gggttggggg gactctgagc 682Asn Leu Pro Ile Asn Gly Asn Gly Lys Gln * 205 210gggaggcaga gtttgccttc ctttctccag gaccaataaa atttctaaga gagct 73782210PRThuman 82Met Pro Pro Tyr Thr Val Val Tyr Phe Pro Val Arg Gly Arg Cys Ala1 5 10 15Ala Leu Arg Met Leu Leu Ala Asp Gln Gly Gln Ser Trp Lys Glu Glu 20 25 30Val Val Thr Val Glu Thr Trp Gln Glu Gly Ser Leu Lys Ala Ser Cys 35 40 45Leu Tyr Gly Gln Leu Pro Lys Phe Gln Asp Gly Asp Leu Thr Leu Tyr 50 55 60Gln Ser Asn Thr Ile Leu Arg His Leu Gly Arg Thr Leu Gly Leu Tyr65 70 75 80Gly Lys Asp Gln Gln Glu Ala Ala Leu Val Asp Met Val Asn Asp Gly 85 90 95Val Glu Asp Leu Arg Cys Lys Tyr Ile Ser Leu Ile Tyr Thr Asn Tyr 100 105 110Glu Ala Gly Lys Asp Asp Tyr Val Lys Ala Leu Pro Gly Gln Leu Lys 115 120 125Pro Phe Glu Thr Leu Leu Ser Gln Asn Gln Gly Gly Lys Thr Phe Ile 130 135 140Val Gly Asp Gln Ile Ser Phe Ala Asp Tyr Asn Leu Leu Asp Leu Leu145 150 155 160Leu Ile His Glu Val Leu Ala Pro Gly Cys Leu Asp Ala Phe Pro Leu 165 170 175Leu Ser Ala Tyr Val Gly Arg Leu Ser Ala Arg Pro Lys Leu Lys Ala 180 185 190Phe Leu Ala Ser Pro Glu Tyr Val Asn Leu Pro Ile Asn Gly Asn Gly 195 200 205Lys Gln 21083704DNAhumanCDS(104)...(568) 83tgcagcggtg gtcggctgtt gggtgtggag tttcccagcg cccctcgggt ccgacccttt 60gagcgttctg ctccggcgcc agcctacctc gctcctcggc gcc atg acc aca acc 115 Met Thr Thr Thr 1acc acc ttc aag gga gtc gac ccc aac agc agg aat agc tcc cga gtt 163Thr Thr Phe Lys Gly Val Asp Pro Asn Ser Arg Asn Ser Ser Arg Val5 10 15 20ttg cgg cct cca ggt ggt gga tcc aat ttt tca tta ggt ttt gat gaa 211Leu Arg Pro Pro Gly Gly Gly Ser Asn Phe Ser Leu Gly Phe Asp Glu 25 30 35cca aca gaa caa cct gtg agg aag aac aaa atg gcc tct aat atc ttt 259Pro Thr Glu Gln Pro Val Arg Lys Asn Lys Met Ala Ser Asn Ile Phe 40 45 50ggg aca cct gaa gaa aat caa gct tct tgg gcc aag tca gca ggt gcc 307Gly Thr Pro Glu Glu Asn Gln Ala Ser Trp Ala Lys Ser Ala Gly Ala 55 60 65aag tct agt ggt ggc agg gaa gac ttg gag tca tct gga ctg cag aga 355Lys Ser Ser Gly Gly Arg Glu Asp Leu Glu Ser Ser Gly Leu Gln Arg 70 75 80agg aac tcc tct gaa gca agc tcc gga gac ttc tta gat ctg aag gga 403Arg Asn Ser Ser Glu Ala Ser Ser Gly Asp Phe Leu Asp Leu Lys Gly85 90 95 100gaa ggt gat att cat gaa aat gtg gac aca gac ttg cca ggc agc ctg 451Glu Gly Asp Ile His Glu Asn Val Asp Thr Asp Leu Pro Gly Ser Leu 105 110 115ggg cag agt gaa gag aag ccc gtg cct gct gcg cct gtg ccc agc ccg 499Gly Gln Ser Glu Glu Lys Pro Val Pro Ala Ala Pro Val Pro Ser Pro 120 125 130gtg gcc ccg gcc cca gtg cca tcc aga aga aat ccc cct ggc ggc aag 547Val Ala Pro Ala Pro Val Pro Ser Arg Arg Asn Pro Pro Gly Gly Lys 135 140 145tcc agc ctc gtc ttg ggt tag ctctgactgt cctgaacgct gtcgttctgt 598Ser Ser Leu Val Leu Gly * 150ctgtttcctc catgcttgag aactgcacaa cttgagcctg actgtacatc ttcttggatt 658tgtttcatta aaaagaagca ctttatgtaa aaaaaaaaaa aaaaaa 70484154PRThuman 84Met Thr Thr Thr Thr Thr Phe Lys Gly Val Asp Pro Asn Ser Arg Asn1 5 10 15Ser Ser Arg Val Leu Arg Pro Pro Gly Gly Gly Ser Asn Phe Ser Leu 20 25 30Gly Phe Asp Glu Pro Thr Glu Gln Pro Val Arg Lys Asn Lys Met Ala 35 40 45Ser Asn Ile Phe Gly Thr Pro Glu Glu Asn Gln Ala Ser Trp Ala Lys 50 55 60Ser Ala Gly Ala Lys Ser Ser Gly Gly Arg Glu Asp Leu Glu Ser Ser65 70 75 80Gly Leu Gln Arg Arg Asn Ser Ser Glu Ala Ser Ser Gly Asp Phe Leu 85 90 95Asp Leu Lys Gly Glu Gly Asp Ile His Glu Asn Val Asp Thr Asp Leu 100 105 110Pro Gly Ser Leu Gly Gln Ser Glu Glu Lys Pro Val Pro Ala Ala Pro 115 120 125Val Pro Ser Pro Val Ala Pro Ala Pro Val Pro Ser Arg Arg Asn Pro 130 135 140Pro Gly Gly Lys Ser Ser Leu Val Leu Gly145 15085748DNAhumanCDS(8)...(355) 85ggccgcg atg agc ggg gag ccg ggg cag acg tcc gta gcg ccc cct ccc 49 Met Ser Gly Glu Pro Gly Gln Thr Ser Val Ala Pro Pro Pro 1 5 10gag gag gtc gag ccg ggc agt ggg gtc cgc atc gtg gtg gag tac tgt 97Glu Glu Val Glu Pro Gly Ser Gly Val Arg Ile Val Val Glu Tyr Cys15 20 25 30gaa ccc tgc ggc ttc gag gcg acc tac ctg gag ctg gcc agt gct gtg 145Glu Pro Cys Gly Phe Glu Ala Thr Tyr Leu Glu Leu Ala Ser Ala Val 35 40 45aag gag cag tat ccg ggc atc gag atc gag tcg cgc ctc ggg ggc aca 193Lys Glu Gln Tyr Pro Gly Ile Glu Ile Glu Ser Arg Leu Gly Gly Thr 50 55 60ggt gcc ttt gag ata gag ata aat gga cag ctg gtg ttc tcc aag ctg 241Gly Ala Phe Glu Ile Glu Ile Asn Gly Gln Leu Val Phe Ser Lys Leu 65 70 75gag aat ggg ggc ttt ccc tat gag aaa gat ctc att gag gcc atc cga 289Glu Asn Gly Gly Phe Pro Tyr Glu Lys Asp Leu Ile Glu Ala Ile Arg 80 85 90aga gcc agt aat gga gaa acc cta gaa aag atc acc aac agc cgt cct 337Arg Ala Ser Asn Gly Glu Thr Leu Glu Lys Ile Thr Asn Ser Arg Pro95 100 105 110ccc tgc gtc atc ctg tga ctgcacagga ctctgggttc ctgctctgtt 385Pro Cys Val Ile Leu * 115ctggggtcca aaccttggtc tccctttggt cctgctggga gctccccctg cctctttccc 445ctacttagct ccttagcaaa gagaccctgg cctccacttt gccctttggg tacaaagaag 505gaatagaaga ttccgtggcc ttgggggcag gagagagaca ctctccatga acacttctcc 565agccacctca tacccccttc ccagggtaag tgcccacgaa agcccagtcc actcttcgcc 625tcggtaatac ctgtctgatg ccacagattt tatttattct cccctaaccc agggcaatgt 685cagctattgg cagtaaagtg gcgctacaaa cactaaaaaa aaaaaaaaaa aaaaaaaaaa 745aaa 74886115PRThuman 86Met Ser Gly Glu Pro Gly Gln Thr Ser Val Ala Pro Pro Pro Glu Glu1 5 10 15Val Glu Pro Gly Ser Gly Val Arg Ile Val Val Glu Tyr Cys Glu Pro 20 25 30Cys Gly Phe Glu Ala Thr Tyr Leu Glu Leu Ala Ser Ala Val Lys Glu 35 40 45Gln Tyr Pro Gly Ile Glu Ile Glu Ser Arg Leu Gly Gly Thr Gly Ala 50 55 60Phe Glu Ile Glu Ile Asn Gly Gln Leu Val Phe Ser Lys Leu Glu Asn65 70 75 80Gly Gly Phe Pro Tyr Glu Lys Asp Leu Ile Glu Ala Ile Arg Arg Ala 85 90 95Ser Asn Gly Glu Thr Leu Glu Lys Ile Thr Asn Ser Arg Pro Pro Cys 100 105 110Val Ile Leu 115873020DNAhumanCDS(111)...(1295) 87tgaagctcgt cagttcacca tccgccctcg gcttccgcgg ggcgctgggc cgccagcctc 60ggcaccgtcc tttcctttct ccctcgcgtt aggcaggtga cagcagggac atg tct 116 Met Ser 1cgg gag atg cag gat gta gac ctc gct gag gtg aag cct ttg gtg gag 164Arg Glu Met Gln Asp Val Asp Leu Ala Glu Val Lys Pro Leu Val Glu 5 10 15aaa ggg gag acc atc acc ggc ctc ctg caa gag ttt gat gtc cag gag 212Lys Gly Glu Thr Ile Thr Gly Leu Leu Gln Glu Phe Asp Val Gln Glu 20 25 30cag gac atc gag act tta cat ggc tct gtt cac gtc acg ctg tgt ggg 260Gln Asp Ile Glu Thr Leu His Gly Ser Val His Val Thr Leu Cys Gly35 40 45 50act ccc aag gga aac cgg cct gtc atc ctc acc tac cat gac atc ggc 308Thr Pro Lys Gly Asn Arg Pro Val Ile Leu Thr Tyr His Asp Ile Gly 55 60 65atg aac cac aaa acc tgc tac aac ccc ctc ttc aac tac gag gac atg 356Met Asn His Lys Thr Cys Tyr Asn Pro Leu Phe Asn Tyr Glu Asp Met 70 75 80cag gag atc acc cag cac ttt gcc gtc tgc cac gtg gac gcc cct ggc 404Gln Glu Ile Thr Gln His Phe Ala Val Cys His Val Asp Ala Pro Gly 85 90 95cag cag gac

ggc gca gcc tcc ttc ccc gca ggg tac atg tac ccc tcc 452Gln Gln Asp Gly Ala Ala Ser Phe Pro Ala Gly Tyr Met Tyr Pro Ser 100 105 110atg gat cag ctg gct gaa atg ctt cct gga gtc ctt caa cag ttt ggg 500Met Asp Gln Leu Ala Glu Met Leu Pro Gly Val Leu Gln Gln Phe Gly115 120 125 130ctg aaa agc att att ggc atg gga aca gga gca ggc gcc tac acc cta 548Leu Lys Ser Ile Ile Gly Met Gly Thr Gly Ala Gly Ala Tyr Thr Leu 135 140 145act cga ttt gct cta aac aac cct gag atg gtg gag ggc ctt gtc ctt 596Thr Arg Phe Ala Leu Asn Asn Pro Glu Met Val Glu Gly Leu Val Leu 150 155 160atc aac gtg aac cct tgt gcg gaa ggc tgg atg gac tgg gcc gcc tcc 644Ile Asn Val Asn Pro Cys Ala Glu Gly Trp Met Asp Trp Ala Ala Ser 165 170 175aag atc tca gga tgg acc caa gct ctg ccg gac atg gtg gtg tcc cac 692Lys Ile Ser Gly Trp Thr Gln Ala Leu Pro Asp Met Val Val Ser His 180 185 190ctt ttt ggg aag gaa gaa atg cag agt aac gtg gaa gtg gtc cac acc 740Leu Phe Gly Lys Glu Glu Met Gln Ser Asn Val Glu Val Val His Thr195 200 205 210tac cgc cag cac att gtg aat gac atg aac ccc ggc aac ctg cac ctg 788Tyr Arg Gln His Ile Val Asn Asp Met Asn Pro Gly Asn Leu His Leu 215 220 225ttc atc aat gcc tac aac agc cgg cgc gac ctg gag att gag cga cca 836Phe Ile Asn Ala Tyr Asn Ser Arg Arg Asp Leu Glu Ile Glu Arg Pro 230 235 240atg ccg gga acc cac aca gtc acc ctg cag tgc cct gct ctg ttg gtg 884Met Pro Gly Thr His Thr Val Thr Leu Gln Cys Pro Ala Leu Leu Val 245 250 255gtt ggg gac agc tcg cct gca gtg gat gcc gtg gtg gag tgc aac tca 932Val Gly Asp Ser Ser Pro Ala Val Asp Ala Val Val Glu Cys Asn Ser 260 265 270aaa ttg gac cca aca aag acc act ctc ctc aag atg gcg gac tgt ggc 980Lys Leu Asp Pro Thr Lys Thr Thr Leu Leu Lys Met Ala Asp Cys Gly275 280 285 290ggc ctc ccg cag atc tcc cag ccg gcc aag ctc gct gag gcc ttc aag 1028Gly Leu Pro Gln Ile Ser Gln Pro Ala Lys Leu Ala Glu Ala Phe Lys 295 300 305tac ttc gtg cag ggc atg gga tac atg ccc tcg gct agc atg acc cgc 1076Tyr Phe Val Gln Gly Met Gly Tyr Met Pro Ser Ala Ser Met Thr Arg 310 315 320ctg atg cgg tcc cgc aca gcc tct ggt tcc agc gtc act tct ctg gat 1124Leu Met Arg Ser Arg Thr Ala Ser Gly Ser Ser Val Thr Ser Leu Asp 325 330 335ggc acc cgc agc cgc tcc cac acc agc gag ggc acc cga agc cgc tcc 1172Gly Thr Arg Ser Arg Ser His Thr Ser Glu Gly Thr Arg Ser Arg Ser 340 345 350cac acc agc gag ggc acc cgc agc cgc tcg cac acc agc gag ggg gcc 1220His Thr Ser Glu Gly Thr Arg Ser Arg Ser His Thr Ser Glu Gly Ala355 360 365 370cac ctg gac atc acc ccc aac tcg ggt gct gct ggg aac agc gcc ggg 1268His Leu Asp Ile Thr Pro Asn Ser Gly Ala Ala Gly Asn Ser Ala Gly 375 380 385ccc aag tcc atg gag gtc tcc tgc tag gcggcctgcc cagctgccgc 1315Pro Lys Ser Met Glu Val Ser Cys * 390ccccggactc tgatctctgt agtggccccc tcctccccgg ccccttttcg ccccctgcct 1375gccatactgc gcctaactcg gtattaatcc aaagcttatt ttgtaagagt gagctctggt 1435ggagacaaat gaggtctatt acgtgggtgc cctctccaaa ggcggggtgg cggtggacca 1495aaggaaggaa gcaagcatct ccgcatcgca tcctcttcca ttaaccagtg gccggttgcc 1555actctcctcc cctccctcag agacaccaaa ctgccaaaaa caagacgcgt agcagcacac 1615acttcacaaa gccaagccta ggccgccctg agcatcctgg ttcaaacggg tgcctggtca 1675gaaggccagc cgcccacttc ccgtttcctc tttaactgag gagaagctga tccagctttc 1735cggaaacaaa atccttttct tcatttgggg aggggggtaa tagtgacatg caggcacctc 1795ttttaaacag gcaaaacagg aagggggaaa aggtgggatt catgtcgagg ctagaggcat 1855ttggaacaac aaatctacgt agttaacttg aagaaaccga tttttaaagt tggtgcatct 1915agaaagcttt gaatgcagaa gcaaacaagc ttgatttttc tagcatcctc ttaatgtgca 1975gcaaaagcag gcaacaaaat ctcctggctt tacagacaaa aatatttcag caaacgttgg 2035gcatcatggt ttttgaaggc tttagttctg ctttctgcct ctcctccaca gccccaacct 2095cccacccctg atacatgagc cagtgattat tcttgttcag ggagaagatc atttagattt 2155gttttgcatt ccttagaatg gagggcaaca ttccacagct gccctggctg tgatgagtgt 2215ccttgcaggg gccggagtag gagcactggg gtgggggcgg aattggggtt actcgatgta 2275agggattcct tgttgttgtg ttgagatcca gtgcagttgt gatttctgtg gatcccagct 2335tggtccagga attttgagag attggcttaa atccagtttt caatcttcga cagctgggct 2395ggaacgtgaa ctcagtagct gaacctgtct gacccggtca cgttcttgga tcctcagaac 2455tctttgctct tgtcggggtg ggggtgggaa ctcacgtggg gagcggtggc tgagaaaatg 2515taaggattct ggaatacata ttccatggac tttccttccc tctcctgctt cctcttttcc 2575tgctccctaa cctttcgccg aatggggcag acaaacactg acgtttctgg gtggccagtg 2635cggctgccag gttcctgtac tactgccttg tacttttcat tttggctcac cgtggatttt 2695ctcataggaa gtttggtcag agtgaattga atattgtaag tcagccactg ggacccgagg 2755atttctggga ccccgcagtt gggaggagga agtagtccag ccttccaggt gggcgtgaga 2815ggcaatgact cgttacctgc cgcccatcac cttggaggcc ttccctggcc ttgagtagaa 2875aagtcgggga tcggggcaag agaggctgag tacggatggg aaactattgt gcacaagtct 2935ttccagagga gtttcttaat gagatatttg tatttatttc cagaccaata aatttgtaac 2995tttgcaaaaa aaaaaaaaaa aaaaa 302088394PRThuman 88Met Ser Arg Glu Met Gln Asp Val Asp Leu Ala Glu Val Lys Pro Leu1 5 10 15Val Glu Lys Gly Glu Thr Ile Thr Gly Leu Leu Gln Glu Phe Asp Val 20 25 30Gln Glu Gln Asp Ile Glu Thr Leu His Gly Ser Val His Val Thr Leu 35 40 45Cys Gly Thr Pro Lys Gly Asn Arg Pro Val Ile Leu Thr Tyr His Asp 50 55 60Ile Gly Met Asn His Lys Thr Cys Tyr Asn Pro Leu Phe Asn Tyr Glu65 70 75 80Asp Met Gln Glu Ile Thr Gln His Phe Ala Val Cys His Val Asp Ala 85 90 95Pro Gly Gln Gln Asp Gly Ala Ala Ser Phe Pro Ala Gly Tyr Met Tyr 100 105 110Pro Ser Met Asp Gln Leu Ala Glu Met Leu Pro Gly Val Leu Gln Gln 115 120 125Phe Gly Leu Lys Ser Ile Ile Gly Met Gly Thr Gly Ala Gly Ala Tyr 130 135 140Thr Leu Thr Arg Phe Ala Leu Asn Asn Pro Glu Met Val Glu Gly Leu145 150 155 160Val Leu Ile Asn Val Asn Pro Cys Ala Glu Gly Trp Met Asp Trp Ala 165 170 175Ala Ser Lys Ile Ser Gly Trp Thr Gln Ala Leu Pro Asp Met Val Val 180 185 190Ser His Leu Phe Gly Lys Glu Glu Met Gln Ser Asn Val Glu Val Val 195 200 205His Thr Tyr Arg Gln His Ile Val Asn Asp Met Asn Pro Gly Asn Leu 210 215 220His Leu Phe Ile Asn Ala Tyr Asn Ser Arg Arg Asp Leu Glu Ile Glu225 230 235 240Arg Pro Met Pro Gly Thr His Thr Val Thr Leu Gln Cys Pro Ala Leu 245 250 255Leu Val Val Gly Asp Ser Ser Pro Ala Val Asp Ala Val Val Glu Cys 260 265 270Asn Ser Lys Leu Asp Pro Thr Lys Thr Thr Leu Leu Lys Met Ala Asp 275 280 285Cys Gly Gly Leu Pro Gln Ile Ser Gln Pro Ala Lys Leu Ala Glu Ala 290 295 300Phe Lys Tyr Phe Val Gln Gly Met Gly Tyr Met Pro Ser Ala Ser Met305 310 315 320Thr Arg Leu Met Arg Ser Arg Thr Ala Ser Gly Ser Ser Val Thr Ser 325 330 335Leu Asp Gly Thr Arg Ser Arg Ser His Thr Ser Glu Gly Thr Arg Ser 340 345 350Arg Ser His Thr Ser Glu Gly Thr Arg Ser Arg Ser His Thr Ser Glu 355 360 365Gly Ala His Leu Asp Ile Thr Pro Asn Ser Gly Ala Ala Gly Asn Ser 370 375 380Ala Gly Pro Lys Ser Met Glu Val Ser Cys385 390892401DNAhumanCDS(301)...(762) 89gcgtccccga agaggccggg aacggagccc aggaaaaact acaactccca ggaggcgtcg 60ggagggccgg cccggagcca gcggaagaaa ctacaactcc cagaaggcgt cgggcgtgcc 120ggcgcggggc ggtgacgtac ggggaccggc gcggagcgct gattcggccg gagctgccag 180cggggaggct gcagccgcgg gttgttacag ctgctggagc agcagcggcc cccgctcccg 240ggaaccgttc ccgggccgtt gatcttcggc cccacacgaa cagcagagag gggcagcagg 300atg aat gtg ggc aca gcg cac agc gag gtg aac ccc aac acg cgg gtg 348Met Asn Val Gly Thr Ala His Ser Glu Val Asn Pro Asn Thr Arg Val1 5 10 15atg aac agc cgt ggc atc tgg ctc tcc tac gtg ctg gcc atc ggt ctc 396Met Asn Ser Arg Gly Ile Trp Leu Ser Tyr Val Leu Ala Ile Gly Leu 20 25 30ctc cac atc gtg ctg ctg agc atc ccg ttt gtg agt gtc cct gtc gtc 444Leu His Ile Val Leu Leu Ser Ile Pro Phe Val Ser Val Pro Val Val 35 40 45tgg acc ctc acc aac ctc att cac aac atg ggc atg tat atc ttc ctg 492Trp Thr Leu Thr Asn Leu Ile His Asn Met Gly Met Tyr Ile Phe Leu 50 55 60cac acg gtg aag ggg aca ccc ttt gag acc ccg gac cag ggc aag gcg 540His Thr Val Lys Gly Thr Pro Phe Glu Thr Pro Asp Gln Gly Lys Ala65 70 75 80agg ctg cta acc cac tgg gag cag atg gat tat ggg gtc cag ttc acg 588Arg Leu Leu Thr His Trp Glu Gln Met Asp Tyr Gly Val Gln Phe Thr 85 90 95gcc tct cgg aag ttc ttg acc atc aca ccc atc gtg ctg tac ttc ctc 636Ala Ser Arg Lys Phe Leu Thr Ile Thr Pro Ile Val Leu Tyr Phe Leu 100 105 110acc agc ttc tac act aag tac gac cag atc cat ttt gtg ctc aac acc 684Thr Ser Phe Tyr Thr Lys Tyr Asp Gln Ile His Phe Val Leu Asn Thr 115 120 125gtg tcc ctg atg agc gtg ctt atc ccc aag ctg ccc cag ctc cac gga 732Val Ser Leu Met Ser Val Leu Ile Pro Lys Leu Pro Gln Leu His Gly 130 135 140gtc cgg att ttt gga atc aat aag tac tga gagtgcagcc ccttcccctg 782Val Arg Ile Phe Gly Ile Asn Lys Tyr *145 150cccagggtgg caggggaggg gtagggtaaa aggcatgtgc tgcaacactg aagacagaaa 842gaagaagcct ctggacactg ccagagatgg gggttgagcc tctggcctaa tttcccccct 902cgcttccccc agtagccaac ttggagtagc ttgtagtggg gttggggtag gccccctggg 962ctctgacctt ttctgaattt tttgatcttt tccttttgct ttttgaatag agactccatg 1022gagttggtca tggaatgggc tgggctcctg ggctgaacat ggaccacgca gttgcgacag 1082gaggccaggg gaaaaacccc tgctcacttg tttgccctca ggcagccaaa gcactttaac 1142ccctgcatag ggagcagagg gcggtacggc ttctggattg tttcactgtg attcctaggt 1202tttttcgatg ccacgcagtg tgtgcttttg tgtatggaag caagtgtggg atgggtcttt 1262gcctttctgg gtagggagct gtctaatcca agtcccaggc ttttggcagc ttctctgcaa 1322cccaccgtgg gtcctggttg ggagtgggga gggtcaggtt ggggaaagat ggggtagagt 1382gtagatggct tggttccaga ggtgaggggg ccagggctgc tgccatcctg gcctggtgga 1442ggttggggag ctgtaggaga gctagtgagt cgagacttag aagaatgggg ccacatagca 1502gcagaggact ggtgtaaggg agggaggggt agggacagaa gctagaccca atctcctttg 1562ggatgtgggc agggagggaa gcaggcttgg agggttaatt tacccacaga atgtgatagt 1622aataggggag ggaggctgct gtgggtttaa ctcctgggtt ggctgttggg tagacaggtg 1682gggaaaaggc ccgtgagtca ttgtaagcac aggtccaact tggccctgac tcctgcgggg 1742gtatggggaa gctgtgacag aaacgatggg tgctgtggtc ctctgcaggc cctcacccct 1802taacttcctc atacagactg gcactgggca gggcctctca tgtggcagcc acatgtggcg 1862ttgtgaggcc accccatgtg gggtctgtgg tgagagtcct gtaggatccc tgctcaagca 1922gcacagagga aggggcaaga cgtggcctgt aggcactgtc tcagcctgca gagaagaaag 1982tgaggccggg agcctgagcc tgggctggag ccttctcccc tccccagttg gactaggggc 2042agtgttaatt ttgaaaaggt gtgggtccct gtgtcctctt ccaggggtcc aagggaacag 2102gagaggtcac tgggcctgtt ttctccctcc tgaccctgca tctcccaccc cgtgtatcat 2162agggaacttt caccttaaaa tctttctaag caaagtgtga ataggatttt tactcccttt 2222gtacagtatt ctgagaaacg caaataaaag ggcaacatgt ttctgtttcc ctgtgtctgg 2282ccttcgcttc ctggaaggct gaggggaggg ggcaggggtg tgggcagcgg ctcccgctga 2342ggtgctggtg gggcatcagt gcagctctga cggtggcagg aggggcgctg ggactgctg 240190153PRThuman 90Met Asn Val Gly Thr Ala His Ser Glu Val Asn Pro Asn Thr Arg Val1 5 10 15Met Asn Ser Arg Gly Ile Trp Leu Ser Tyr Val Leu Ala Ile Gly Leu 20 25 30Leu His Ile Val Leu Leu Ser Ile Pro Phe Val Ser Val Pro Val Val 35 40 45Trp Thr Leu Thr Asn Leu Ile His Asn Met Gly Met Tyr Ile Phe Leu 50 55 60His Thr Val Lys Gly Thr Pro Phe Glu Thr Pro Asp Gln Gly Lys Ala65 70 75 80Arg Leu Leu Thr His Trp Glu Gln Met Asp Tyr Gly Val Gln Phe Thr 85 90 95Ala Ser Arg Lys Phe Leu Thr Ile Thr Pro Ile Val Leu Tyr Phe Leu 100 105 110Thr Ser Phe Tyr Thr Lys Tyr Asp Gln Ile His Phe Val Leu Asn Thr 115 120 125Val Ser Leu Met Ser Val Leu Ile Pro Lys Leu Pro Gln Leu His Gly 130 135 140Val Arg Ile Phe Gly Ile Asn Lys Tyr145 15091778DNAhumanCDS(52)...(711) 91caggttggaa accagtgccc caggcggcga ggagagcggt gccttgcagg g atg ctg 57 Met Leu 1cgg gcg gga gca cca acc ggg gac tta ccc cgg gcg gga gaa gtc cac 105Arg Ala Gly Ala Pro Thr Gly Asp Leu Pro Arg Ala Gly Glu Val His 5 10 15acc ggg acc acc atc atg gca gtg gag ttt gac ggg ggc gtt gtg atg 153Thr Gly Thr Thr Ile Met Ala Val Glu Phe Asp Gly Gly Val Val Met 20 25 30ggt tct gat tcc cga gtg tct gca ggc gag gcg gtg gtg aac cga gtg 201Gly Ser Asp Ser Arg Val Ser Ala Gly Glu Ala Val Val Asn Arg Val35 40 45 50ttt gac aag ctg tcc ccg ctg cac gag cgc atc tac tgt gca ctc tct 249Phe Asp Lys Leu Ser Pro Leu His Glu Arg Ile Tyr Cys Ala Leu Ser 55 60 65ggt tca gct gct gat gcc caa gcc gtg gcc gac atg gcc gcc tac cag 297Gly Ser Ala Ala Asp Ala Gln Ala Val Ala Asp Met Ala Ala Tyr Gln 70 75 80ctg gag ctc cat ggg ata gaa ctg gag gaa cct cca ctt gtt ttg gct 345Leu Glu Leu His Gly Ile Glu Leu Glu Glu Pro Pro Leu Val Leu Ala 85 90 95gct gca aat gtg gtg aga aat atc agc tat aaa tat cga gag gac ttg 393Ala Ala Asn Val Val Arg Asn Ile Ser Tyr Lys Tyr Arg Glu Asp Leu 100 105 110tct gca cat ctc atg gta gct ggc tgg gac caa cgt gaa gga ggt cag 441Ser Ala His Leu Met Val Ala Gly Trp Asp Gln Arg Glu Gly Gly Gln115 120 125 130gta tat gga acc ctg gga gga atg ctg act cga cag cct ttt gcc att 489Val Tyr Gly Thr Leu Gly Gly Met Leu Thr Arg Gln Pro Phe Ala Ile 135 140 145ggt ggc tcc ggc agc acc ttt atc tat ggt tat gtg gat gca gca tat 537Gly Gly Ser Gly Ser Thr Phe Ile Tyr Gly Tyr Val Asp Ala Ala Tyr 150 155 160aag cca ggc atg tct ccc gag gag tgc agg cgc ttc acc aca gac gct 585Lys Pro Gly Met Ser Pro Glu Glu Cys Arg Arg Phe Thr Thr Asp Ala 165 170 175att gct ctg gcc atg agc cgg gat ggc tca agc ggg ggt gtc atc tac 633Ile Ala Leu Ala Met Ser Arg Asp Gly Ser Ser Gly Gly Val Ile Tyr 180 185 190ctg gtc act att aca gct gcc ggt gtg gac cat cga gtc atc ttg ggc 681Leu Val Thr Ile Thr Ala Ala Gly Val Asp His Arg Val Ile Leu Gly195 200 205 210aat gaa ctg cca aaa ttc tat gat gag tga accttcccca gacttctctt 731Asn Glu Leu Pro Lys Phe Tyr Asp Glu * 215tcttattttg taataaactc tctagggcca aaaaaaaaaa aaaaaaa 77892219PRThuman 92Met Leu Arg Ala Gly Ala Pro Thr Gly Asp Leu Pro Arg Ala Gly Glu1 5 10 15Val His Thr Gly Thr Thr Ile Met Ala Val Glu Phe Asp Gly Gly Val 20 25 30Val Met Gly Ser Asp Ser Arg Val Ser Ala Gly Glu Ala Val Val Asn 35 40 45Arg Val Phe Asp Lys Leu Ser Pro Leu His Glu Arg Ile Tyr Cys Ala 50 55 60Leu Ser Gly Ser Ala Ala Asp Ala Gln Ala Val Ala Asp Met Ala Ala65 70 75 80Tyr Gln Leu Glu Leu His Gly Ile Glu Leu Glu Glu Pro Pro Leu Val 85 90 95Leu Ala Ala Ala Asn Val Val Arg Asn Ile Ser Tyr Lys Tyr Arg Glu 100 105 110Asp Leu Ser Ala His Leu Met Val Ala Gly Trp Asp Gln Arg Glu Gly 115 120 125Gly Gln Val Tyr Gly Thr Leu Gly Gly Met Leu Thr Arg Gln Pro Phe 130 135 140Ala Ile Gly Gly Ser Gly Ser Thr Phe Ile Tyr Gly Tyr Val Asp Ala145 150 155 160Ala Tyr Lys Pro Gly Met Ser Pro Glu Glu Cys Arg Arg Phe Thr Thr 165 170 175Asp Ala Ile Ala Leu Ala Met Ser Arg Asp Gly Ser Ser Gly Gly Val 180 185 190Ile Tyr Leu Val Thr Ile Thr Ala Ala Gly Val Asp His Arg Val Ile 195

200 205Leu Gly Asn Glu Leu Pro Lys Phe Tyr Asp Glu 210 215931374DNAhumanCDS(103)...(1047) 93ggacagcttg gagatagggc ccggaattgc gggcgtcact ctgctcctgc gacctagcca 60ggcgtgaggg agtgacagca gcgcattcgc gggacgagag cg atg agt gag aac 114 Met Ser Glu Asn 1gcc gca cca ggt ctg atc tca gag ctg aag ctg gct gtg ccc tgg ggc 162Ala Ala Pro Gly Leu Ile Ser Glu Leu Lys Leu Ala Val Pro Trp Gly5 10 15 20cac atc gca gcc aaa gcc tgg ggc tcc ctg cag ggc cct cca gtt ctc 210His Ile Ala Ala Lys Ala Trp Gly Ser Leu Gln Gly Pro Pro Val Leu 25 30 35tgc ctg cac ggc tgg ctg gac aat gcc agc tcc ttc gac aga ctc atc 258Cys Leu His Gly Trp Leu Asp Asn Ala Ser Ser Phe Asp Arg Leu Ile 40 45 50cct ctt ctc ccg caa gac ttt tat tac gtt gcc atg gat ttc gga ggt 306Pro Leu Leu Pro Gln Asp Phe Tyr Tyr Val Ala Met Asp Phe Gly Gly 55 60 65cat ggg ctc tcg tcc cat tac agc cca ggt gtc cca tat tac ctc cag 354His Gly Leu Ser Ser His Tyr Ser Pro Gly Val Pro Tyr Tyr Leu Gln 70 75 80act ttt gtg agt gag atc cga aga gtt gtg gca gcc ttg aaa tgg aat 402Thr Phe Val Ser Glu Ile Arg Arg Val Val Ala Ala Leu Lys Trp Asn85 90 95 100cga ttc tcc att ctg ggc cac agc ttc ggt ggc gtc gtg ggc gga atg 450Arg Phe Ser Ile Leu Gly His Ser Phe Gly Gly Val Val Gly Gly Met 105 110 115ttt ttc tgt acc ttc ccc gag atg gtg gat aaa ctt atc ttg ctg gac 498Phe Phe Cys Thr Phe Pro Glu Met Val Asp Lys Leu Ile Leu Leu Asp 120 125 130acg ccg ctc ttt ctc ctg gaa tca gat gaa atg gag aac ttg ctg acc 546Thr Pro Leu Phe Leu Leu Glu Ser Asp Glu Met Glu Asn Leu Leu Thr 135 140 145tac aag cgg aga gcc ata gag cac gtg ctg cag gta gag gcc tcc cag 594Tyr Lys Arg Arg Ala Ile Glu His Val Leu Gln Val Glu Ala Ser Gln 150 155 160gag ccc tcg cac gtg ttc agc ctg aag cag ctg ctg cag agg tta ctg 642Glu Pro Ser His Val Phe Ser Leu Lys Gln Leu Leu Gln Arg Leu Leu165 170 175 180aag agc aat agc cac ttg agt gag gag tgc ggg gag ctt ctc ctg caa 690Lys Ser Asn Ser His Leu Ser Glu Glu Cys Gly Glu Leu Leu Leu Gln 185 190 195aga gga acc acg aag gtg gcc aca ggt ctg gtt ctg aac aga gac cag 738Arg Gly Thr Thr Lys Val Ala Thr Gly Leu Val Leu Asn Arg Asp Gln 200 205 210agg ctc gcc tgg gca gag aac agc att gac ttc atc agc agg gag ctg 786Arg Leu Ala Trp Ala Glu Asn Ser Ile Asp Phe Ile Ser Arg Glu Leu 215 220 225tgt gcg cat tcc atc agg aag ctg cag gcc cat gtc ctg ttg atc aaa 834Cys Ala His Ser Ile Arg Lys Leu Gln Ala His Val Leu Leu Ile Lys 230 235 240gca gtc cac gga tat ttt gat tca aga cag aat tac tct gag aag gag 882Ala Val His Gly Tyr Phe Asp Ser Arg Gln Asn Tyr Ser Glu Lys Glu245 250 255 260tcc ctg tcg ttc atg ata gac acg atg aaa tcc acc ctc aaa gag cag 930Ser Leu Ser Phe Met Ile Asp Thr Met Lys Ser Thr Leu Lys Glu Gln 265 270 275ttc cag ttt gtg gaa gtc cca ggc aat cac tgt gtc cac atg agc gaa 978Phe Gln Phe Val Glu Val Pro Gly Asn His Cys Val His Met Ser Glu 280 285 290ccc cag cac gtg gcc agt atc atc agc tcc ttc tta cag tgc aca cac 1026Pro Gln His Val Ala Ser Ile Ile Ser Ser Phe Leu Gln Cys Thr His 295 300 305atg ctc cca gcc cag ctg tag ctctgggcct ggaactatga agacctagtg 1077Met Leu Pro Ala Gln Leu * 310ctcccagact caacactggg actctgagtt cctgagcccc acaacaaggc cagggatggt 1137ggggacaggc ctcactagtc ttgaggccca gcctaggatg gtagtcaggg gaaggagcga 1197gattccaact tcaacatctg tgacctcaag ggggagacag agtctgggtt ccagggctgc 1257tttctcctgg ctaataataa atatccagcc agctggagga aggaagggca ggctgggccc 1317acctagcctt tccctgctgc ccaactggat ggaaaataaa aggttcttgt attctca 137494314PRThuman 94Met Ser Glu Asn Ala Ala Pro Gly Leu Ile Ser Glu Leu Lys Leu Ala1 5 10 15Val Pro Trp Gly His Ile Ala Ala Lys Ala Trp Gly Ser Leu Gln Gly 20 25 30Pro Pro Val Leu Cys Leu His Gly Trp Leu Asp Asn Ala Ser Ser Phe 35 40 45Asp Arg Leu Ile Pro Leu Leu Pro Gln Asp Phe Tyr Tyr Val Ala Met 50 55 60Asp Phe Gly Gly His Gly Leu Ser Ser His Tyr Ser Pro Gly Val Pro65 70 75 80Tyr Tyr Leu Gln Thr Phe Val Ser Glu Ile Arg Arg Val Val Ala Ala 85 90 95Leu Lys Trp Asn Arg Phe Ser Ile Leu Gly His Ser Phe Gly Gly Val 100 105 110Val Gly Gly Met Phe Phe Cys Thr Phe Pro Glu Met Val Asp Lys Leu 115 120 125Ile Leu Leu Asp Thr Pro Leu Phe Leu Leu Glu Ser Asp Glu Met Glu 130 135 140Asn Leu Leu Thr Tyr Lys Arg Arg Ala Ile Glu His Val Leu Gln Val145 150 155 160Glu Ala Ser Gln Glu Pro Ser His Val Phe Ser Leu Lys Gln Leu Leu 165 170 175Gln Arg Leu Leu Lys Ser Asn Ser His Leu Ser Glu Glu Cys Gly Glu 180 185 190Leu Leu Leu Gln Arg Gly Thr Thr Lys Val Ala Thr Gly Leu Val Leu 195 200 205Asn Arg Asp Gln Arg Leu Ala Trp Ala Glu Asn Ser Ile Asp Phe Ile 210 215 220Ser Arg Glu Leu Cys Ala His Ser Ile Arg Lys Leu Gln Ala His Val225 230 235 240Leu Leu Ile Lys Ala Val His Gly Tyr Phe Asp Ser Arg Gln Asn Tyr 245 250 255Ser Glu Lys Glu Ser Leu Ser Phe Met Ile Asp Thr Met Lys Ser Thr 260 265 270Leu Lys Glu Gln Phe Gln Phe Val Glu Val Pro Gly Asn His Cys Val 275 280 285His Met Ser Glu Pro Gln His Val Ala Ser Ile Ile Ser Ser Phe Leu 290 295 300Gln Cys Thr His Met Leu Pro Ala Gln Leu305 31095598DNAhumanCDS(23)...(421) 95cagagtcact cctgccttca cc atg aag tcc agc ggc ctc ttc ccc ttc ctg 52 Met Lys Ser Ser Gly Leu Phe Pro Phe Leu 1 5 10gtg ctg ctt gcc ctg gga act ctg gca cct tgg gct gtg gaa ggc tct 100Val Leu Leu Ala Leu Gly Thr Leu Ala Pro Trp Ala Val Glu Gly Ser 15 20 25gga aag tcc ttc aaa gct gga gtc tgt cct cct aag aaa tct gcc cag 148Gly Lys Ser Phe Lys Ala Gly Val Cys Pro Pro Lys Lys Ser Ala Gln 30 35 40 tgc ctt aga tac aag aaa cct gag tgc cag agt gac tgg cag tgt cca 196Cys Leu Arg Tyr Lys Lys Pro Glu Cys Gln Ser Asp Trp Gln Cys Pro 45 50 55ggg aag aag aga tgt tgt cct gac act tgt ggc atc aaa tgc ctg gat 244Gly Lys Lys Arg Cys Cys Pro Asp Thr Cys Gly Ile Lys Cys Leu Asp 60 65 70cct gtt gac acc cca aac cca aca agg agg aag cct ggg aag tgc cca 292Pro Val Asp Thr Pro Asn Pro Thr Arg Arg Lys Pro Gly Lys Cys Pro75 80 85 90gtg act tat ggc caa tgt ttg atg ctt aac ccc ccc aat ttc tgt gag 340Val Thr Tyr Gly Gln Cys Leu Met Leu Asn Pro Pro Asn Phe Cys Glu 95 100 105atg gat ggc cag tgc aag cgt gac ttg aag tgt tgc atg ggc atg tgt 388Met Asp Gly Gln Cys Lys Arg Asp Leu Lys Cys Cys Met Gly Met Cys 110 115 120ggg aaa tcc tgc gtt tcc cct gtg aaa gct tga ttcctgccat atggaggagg 441Gly Lys Ser Cys Val Ser Pro Val Lys Ala * 125 130ctctggagtc ctgctctgtg tggtccaggt cctttccacc ctgagacttg gctccaccac 501tgatatcctc ctttggggaa aggcttggca cacagcaggc tttcaagaag tgccagttga 561tcaatgaata aataaacgag cctatttctc tttgcac 59896132PRThuman 96Met Lys Ser Ser Gly Leu Phe Pro Phe Leu Val Leu Leu Ala Leu Gly1 5 10 15Thr Leu Ala Pro Trp Ala Val Glu Gly Ser Gly Lys Ser Phe Lys Ala 20 25 30Gly Val Cys Pro Pro Lys Lys Ser Ala Gln Cys Leu Arg Tyr Lys Lys 35 40 45Pro Glu Cys Gln Ser Asp Trp Gln Cys Pro Gly Lys Lys Arg Cys Cys 50 55 60Pro Asp Thr Cys Gly Ile Lys Cys Leu Asp Pro Val Asp Thr Pro Asn65 70 75 80Pro Thr Arg Arg Lys Pro Gly Lys Cys Pro Val Thr Tyr Gly Gln Cys 85 90 95Leu Met Leu Asn Pro Pro Asn Phe Cys Glu Met Asp Gly Gln Cys Lys 100 105 110Arg Asp Leu Lys Cys Cys Met Gly Met Cys Gly Lys Ser Cys Val Ser 115 120 125Pro Val Lys Ala 130

Claims

1. A method of assessing whether a patient is afflicted with breast cancer, the method comprising: a) determining the level of expression of a marker in a patient sample, wherein the marker is selected from the group consisting of the markers listed in Table 1 and the markers listed in Table 2; b) determining the level of expression of the marker in a control sample; and c) comparing the level of expression of the marker in the patient sample and the level of expression of the marker in the control sample, wherein a difference between the level of expression of the marker in the patient sample as compared to the level of expression of the marker in the control sample is an indication that the patient is afflicted with breast cancer.

2. The method of claim 1, wherein the control sample comprises breast cells from the patient which are non-cancerous.

3. The method of claim 1, wherein the level of expression of the marker in the control sample is predetermined using an average of the levels of expression of the marker in samples from a population of subjects having indolent breast tumors or no breast tumors.

4. The method of claim 1, wherein the marker comprises a transcribed polynucleotide or portion thereof.

5. The method of claim 1, wherein the patient sample comprises cells obtained from the patient.

6. The method of claim 1, wherein the patient sample comprises a fluid selected from the group consisting of blood fluid, lymph, cystic fluid, nipple aspirates, and fluid collected from a lump biopsy.

7. The method of claim 1, wherein the level of expression of the marker in the patient sample is assessed by detecting the presence of a marker protein in the sample.

8. The method of claim 7, wherein the presence of the marker protein is detected using a reagent which specifically binds with the protein.

9. The method of claim 8, wherein the reagent is selected from the group consisting of an antibody, an antibody derivative, an antigen-binding antibody fragment, and a non-antibody peptide which specifically binds the protein.

10. The method of claim 9, wherein the antibody or antigen-binding antibody fragment is a monoclonal antibody or antigen-binding fragment thereof, or a polyclonal antibody or antigen-binding fragment thereof.

11. The method of claim 9, wherein the antibody or antigen-binding antibody fragment is labelled.

12. The method of claim 11, wherein the antibody or antigen-binding antibody fragment is radio-labelled, biotin-labelled, chromophore labelled, fluorophore labelled, or enzyme labelled.

13. The method of claim 1, wherein the level of expression of the marker in the patient sample is assessed by detecting the presence in the patient sample of a transcribed polynucleotide or portion thereof, corresponding to a nucleic acid marker.

14. The method of claim 13, wherein the transcribed polynucleotide is a mRNA or a cDNA.

15. The method of claim 13, wherein the step of detecting a transcribed polynucleotide further comprises amplifying the transcribed polynucleotide.

16. The method of claim 1, wherein the level of expression of the marker in the patient sample is assessed by detecting the presence in the patient sample of a transcribed polynucleotide which anneals with a nucleic acid marker or a portion thereof under stringent hybridization conditions.

17. The method of claim 1, wherein the level of expression of the marker in the patient sample differs from the level of expression of the marker in the control sample by a factor selected from the group consisting of: a factor of at least about 2, a factor of at least about 3, a factor of at least about 4, and a factor of at least about 5.

18. The method of claim 1, wherein the level of expression of the marker in the patient sample is assessed using a technique selected from the group consisting of: Northern hybridization, polymerase chain reaction analysis, RT-PCR, probe array and in situ hybridization.

19. A method of assessing whether a patient is afflicted with breast cancer, the method comprising: a) determining the level of expression in a patient sample of at least two markers independently selected from the markers listed in Table 1 and Table 2; b) determining the level of expression of each of the markers in a control sample; and c) comparing the level of expression of the marker in the patient sample and the level of expression of the marker in the control sample; wherein a difference in the level of expression of more than one of the markers in the patient sample as compared to the corresponding level of expression of the markers in the control sample, is an indication that the patient is afflicted with breast cancer.

20. The method of claim 19, wherein the level of expression of at least three markers or at least five markers is determined.

21. A method for assessing whether a patient has breast cancer that has metastasized or is likely to metastasize, comprising: a) determining the level of expression of a marker in a patient sample, wherein the marker is selected from the markers listed in Table 2, b) determining the level of expression of the marker in a control sample, and c) comparing the level of expression of the marker in the patient sample and the level of expression of the marker in the control sample; wherein a higher level of expression in the patient sample as compared to the level of expression of the marker in the control sample is an indication that the breast cancer has metastasized or is likely to metastasize.

22. The method of claim 21, wherein the assessment is indicative of whether the patient is afflicted with metastatic breast cancer that has metastasized to lymph nodes, or is likely to metastasize to lymph nodes.

23. A method for predicting the clinical outcome of a breast cancer patient, the method comprising: a) determining the level of expression of a marker in a patient sample, wherein the marker is selected from the markers listed in Table 2, b) determining the level of expression of the marker in a sample from a control subject having a good clinical outcome; and c) comparing the level of expression of the marker in the patient sample and the level of expression of the marker in the sample from the control subject; wherein a higher level of expression of the marker in the patient sample as compared to the level of expression of the marker in the sample from the control subject is an indication that the patient has a poor clinical outcome.

24. A method for monitoring the progression of breast cancer in a patient, the method comprising: a) determining the level of expression of a marker in a patient sample from a first point in time, wherein the marker is selected from the group consisting of the markers listed in Table 1 and the markers listed in Table 2; b) determining the level of expression of the marker in a sample from the patient at a subsequent point in time; and c) comparing the level of expression detected in steps a) and b), thereby monitoring the progression of breast cancer in the patient, wherein a change in the level of expression of the marker is indicative of either progression or regression of breast cancer.

25. The method of claim 24, wherein the patient has undergone surgery to remove a tumor between the first point in time and the subsequent point in time.

26. The method of claim 24, wherein the first and second samples are portions of a single sample obtained from the patient, or portions of pooled samples obtained from the patient.

27. A method of assessing the efficacy of a therapy for inhibiting breast cancer in a patient, the method comprising: a) determining the level of expression of a marker in a first sample obtained from the patient prior to administering at least a portion of the therapy to the patient, wherein the marker is selected from the group consisting of the markers listed in Table 1 and the markers listed in Table 2, b) determining the level of expression of the marker in a second sample obtained from the patient subsequent to administering the portion of the therapy; c) comparing the level of expression of the marker in the first sample as compared to the level of expression of the marker in the second sample; and d) determining that the therapy is efficacious for inhibiting breast cancer in the patient when there is a lower level of expression of the marker in the second sample, relative to the first sample.

28. A kit for assessing whether a patient is afflicted with breast cancer, the kit comprising reagents for assessing expression at least one marker selected from the group consisting of the markers listed in Table 1 and the markers listed in Table 2.