59079 and 12599, protein kinase family members and uses therefor

Abstract

The invention provides isolated nucleic acids molecules, designated 59079 and 12599 nucleic acid molecules, which encode novel protein kinase family members. The invention also provides antisense nucleic acid molecules, recombinant expression vectors containing 59079 or 12599 nucleic acid molecules, host cells into which the expression vectors have been introduced, and nonhuman transgenic animals in which a 59079 or 12599 gene has been introduced or disrupted. The invention still further provides isolated 59079 and 12599 proteins, fusion proteins, antigenic peptides and anti-59079 and anti-12599 antibodies. Diagnostic and therapeutic methods utilizing compositions of the invention are also provided.

Description

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application is a divisional of U.S. patent application Ser. No. 10/077,130, filed Feb. 15, 2002, which claims priority to U.S. Provisional Application No. 60/269,201, filed Feb. 15, 2001, now abandoned. Each of these applications is hereby incorporated in its entirety by reference herein.

BACKGROUND OF THE INVENTION

[0002] Phosphate tightly associated with a molecule, e.g., a protein, has been known since the late nineteenth century. Since then, a variety of covalent linkages of phosphate to proteins have been found. The most common involve esterification of phosphate to serine, threonine, and tyrosine with smaller amounts being linked to lysine, arginine, histidine, aspartic acid, glutamic acid, and cysteine. The occurrence of phosphorylated molecules, e.g., proteins, implies the existence of one or more kinases, e.g., protein kinases, capable of phosphorylating various molecules, e.g., amino acid residues on proteins, and also of phosphatases, e.g., protein phosphatases, capable of hydrolyzing various phosphorylated molecules, e.g., phosphorylated amino acid residues on proteins.

[0003] Protein kinases play critical roles in the regulation of biochemical and morphological changes associated with cellular growth and division (D'Urso et al. (1990) Science 250:786-791; Birchmeier et al. (1993) Bioessays 15:185-189). For example, these kinases have been shown to participate in the transmission of signals from growth-factor receptors (Sturgill et al. (1988) Nature 344:715-718; Gomez et al. (1991) Nature 353:170-173), control of entry of cells into mitosis (Nurse (1990) Nature 344:503-508; Maller (1991) Curr. Opin. Cell Biol. 3:269-275), and regulation of actin bundling (Husain-Chishti et al. (1988) Nature 334:718-721). Protein kinases serve as growth factor receptors and signal transducers and have been implicated in cellular transformation and malignancy (Hunter et al. (1992) Cell 70:375-387; Posada et al. (1992) Mol. Biol. Cell 3:583-592; Hunter et al. (1994) Cell 79:573-582). Alterations in kinase genes and their products can lead to deregulated cell proliferation, a hallmark of cancer. Modulation of these genes and their regulatory activities may permit the control of tumor cell proliferation and invasion.

[0004] Protein kinases can be divided into different groups based on either amino acid sequence similarity or specificity for either serine/threonine or tyrosine residues. A small number of dual-specificity kinases have also been described. Within the broad classification, kinases can be further subdivided into families whose members share a higher degree of catalytic domain amino acid sequence identity and also have similar biochemical properties. Most protein kinase family members also share structural features outside the kinase catalytic domain that reflect their particular cellular roles. These include regulatory domains that control kinase activity or interaction with other proteins (Hanks et al. (1988) Science 241:42-52).

[0005] Extracellular signal-regulated kinases/mitogen-activated protein kinases (ERKs.backslash.MAPKs) and cyclin-directed kinases (Cdks) represent two large families of serine-threonine kinases (see Songyang et al. (1996) Mol. Cell. Biol. 16: 6486-6493). Both types of kinases function in cell growth, cell division, and cell differentiation in response to extracellular stimuli. The ERK.backslash.MAPK family members are critical participants in intracellular signaling pathways. Upstream activators as well as the ERK.backslash.MAPK components are phosphorylated following contact of cells with growth factors or hormones or in response to cellular stressors, for example, heat, ultraviolet light, and inflammatory cytokines. These kinases transport messages that have been relayed from the plasma membrane to the cytoplasm by upstream kinases into the nucleus where they phosphorylate transcription factors and effect gene transcription modulation (Karin et al. (1995) Curr. Biol. 5: 747-757). Substrates of the ERK.backslash.MAPK family include c-fos, c-jun, APF2, and ETS family members Elk1, Sap1a, and c-Ets-1 (cited in Brott et al. (1998) Proc. Natl. Acad. Sci. USA 95: 963-968).

[0006] Signal-transduction pathways that employ members of the ERK/MAPK family of serine/threonine kinases are widely conserved among eukaryotes. The multiplicity of these pathways allows the cell to respond to divergent extracellular stimuli by initiating a broad array of responses ranging from cell growth to apoptosis. ERK/MAPK pathways are comprised of a three-tiered core-signaling module wherein ERK/MAPKs are regulated by MAPK/ERK kinases (MEKs), and MEKs, in turn, are regulated by MAPK kinase kinases (MAPKKKs). Mammalian stress-activated ERK/MAPK pathways have been implicated in numerous important physiological functions, including cell growth and proliferation, inflammatory responses, and apoptosis. For example, activation of the ERK1,2 signaling pathway by a mitogenic growth factor, a tumor promoter, or by transformation suppresses decorin gene expression in fibroblasts, which in turn may promote proliferation and migration of normal and malignant cells (Laine et al. (2000) Biochem. J. 349: 19-25).

[0007] Cdks regulate transitions between successive stages of the cell cycle. The activity of these molecules is controlled by phosphorylation events and by association with cyclin. Cdk activity is negatively regulated by the association of small inhibitory molecules (Dynlacht (1997) Nature 389:148-152). Cdk targets include various transcriptional activators such as p110Rb, p107, and transcription factors, such as p53, E2F, and RNA polymerase II, as well as various cytoskeletal proteins and cytoplasmic signaling proteins (cited in Brott et al. (1998) Proc. Natl. Acad. Sci. USA 95: 963-968).

[0008] Protein kinases play critical roles in cellular growth, particularly in the transduction of signals for cell proliferation, differentiation, and apoptosis. Therefore, novel protein kinase polynucleotides and proteins are useful for modulating cellular growth, differentiation, and/or development.

SUMMARY OF THE INVENTION

[0009] The present invention is based, in part, on the discovery of novel human protein kinase family members, referred to herein as "59079" and "12599". The nucleotide sequence of a cDNA encoding 59079 is shown in SEQ ID NO:1, and the amino acid sequence of a 59079 polypeptide is shown in SEQ ID NO:2. In addition, the nucleotide sequence of the coding region is depicted in SEQ ID NO:3. The nucleotide sequence of a cDNA encoding 12599 is shown in SEQ ID NO:4, and the amino acid sequence of a 12599 polypeptide is shown in SEQ ID NO:5. In addition, the nucleotide sequence of the coding region is depicted in SEQ ID NO:6.

[0010] Accordingly, in one aspect, the invention features nucleic acid molecules which encode a 59079 protein or polypeptide or a 12599 protein or polypeptide, e.g., a biologically active portion of the 59079 or 12599 protein. In a preferred embodiment the isolated nucleic acid molecule encodes a polypeptide having the amino acid sequence of SEQ ID NO:2 or 5. In other embodiments, the invention provides isolated 59079 and 12599 nucleic acid molecules having the nucleotide sequence shown in SEQ ID NOs:1, 3, 4, or 6. In still other embodiments, the invention provides nucleic acid molecules that are substantially identical (e.g., naturally occurring allelic variants) to the nucleotide sequence shown in SEQ ID NOs:1, 3, 4, or 6. In other embodiments, the invention provides a nucleic acid molecule which hybridizes under stringent hybridization conditions to a nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:1, 3, 4, or 6, wherein the nucleic acid encodes a full length 59079 or 12599 protein, or a biologically active fragment thereof.

[0011] In a related aspect, the invention further provides nucleic acid constructs which include a 59079 or 12599 nucleic acid molecule 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 the 59079 or 12599 nucleic acid molecules of the invention, e.g., vectors and host cells suitable for producing 59079 or 12599 polypeptides.

[0012] In another related aspect, the invention provides nucleic acid fragments suitable as primers or hybridization probes for the detection of 59079- or 12599-encoding nucleic acids.

[0013] In still another related aspect, isolated nucleic acid molecules that are antisense to a 59079- or 12599-encoding nucleic acid molecule are provided.

[0014] In another aspect, the invention features 59079 and 12599 polypeptides, and biologically active or antigenic fragments thereof, that are useful, e.g., as reagents or targets in assays applicable to treatment and diagnosis of 59079- or 12599-mediated or -related disorders. In another embodiment, the invention provides 59079 polypeptides having a 59079 activity and 12599 polypeptides having a 12599 activity. Preferred polypeptides are 59079 and 12599 proteins including at least one protein kinase catalytic domain, and, preferably, having a 59079 or 12599 activity, e.g., a 59079 or 12599 activity as described herein.

[0015] In other embodiments, the invention provides 59079 and 12599 polypeptides, e.g., a 59079 or 12599 polypeptide having the amino acid sequence shown in SEQ ID NO:2 or 5; an amino acid sequence that is substantially identical to the amino acid sequence shown in SEQ ID NO:2 or 5; or an amino acid sequence encoded by a nucleic acid molecule having a nucleotide sequence which hybridizes under stringent hybridization conditions to a nucleic acid molecule comprising the nucleotide sequence of SEQ ID NOs:1, 3, 4, or 6, wherein the nucleic acid encodes a full length 59079 or 12599 protein, or a biologically active fragment thereof.

[0016] In a related aspect, the invention further provides nucleic acid constructs which include a 59079 or 12599 nucleic acid molecule described herein.

[0017] In a related aspect, the invention provides 59079 and 12599 polypeptides, or fragments thereof, operatively linked to non-59079 or non-12599 polypeptides to form fusion proteins.

[0018] In another aspect, the invention features antibodies, and antigen-binding fragments thereof, that react with, or more preferably, specifically or selectively bind 59079 or 12599 polypeptides.

[0019] In another aspect, the invention provides methods of screening for compounds that modulate the expression or activity of the 59079 polypeptides or nucleic acids or the 12599 polypeptides or nucleic acids.

[0020] In still another aspect, the invention provides a process for modulating 59079 polypeptide or nucleic acid expression or activity, e.g., using the compounds identified in the screens. In certain embodiments, the methods involve treatment of conditions or disorders related to aberrant activity or expression of the 59079 or 12599 polypeptides or nucleic acids, such as conditions involving aberrant or deficient 59079 or 12599 protein or nucleic acid expression or activity. In a preferred embodiment, the disorder characterized by aberrant 59079 or 12599 protein activity or nucleic acid expression is a nervous system disorder, a cardiovascular disorder, a sugar or fatty acid metabolism disorder, an inflammatory or immune disorder, a musculoskeletal disorder, or a disorder involving aberrant cellular proliferation, differentiation, or migration.

[0021] The invention also provides assays for determining the activity of or the presence or absence of 59079 or 12599 polypeptides or nucleic acid molecules in a biological sample, including for disease diagnosis.

[0022] In a further aspect, the invention provides assays for determining the presence or absence of a genetic alteration in a 59079 or 12599 polypeptide or nucleic acid molecule, including for disease diagnosis.

[0023] Other features and advantages of the invention will be apparent from the following detailed description and from the claims.

DETAILED DESCRIPTION OF THE INVENTION

[0024] The human 59079 nucleic acid sequence (SEQ ID NO:1), which is approximately 8106 nucleotides long including untranslated regions, contains a predicted methionine-initiated coding sequence of about 7893 nucleotides, including the termination codon (shown as the nucleotides of SEQ ID NO:1 indicated as coding, and the sequence shown in SEQ ID NO:3). The coding sequence encodes a 2631 amino acid protein (SEQ ID NO:2).

[0025] The human 12599 nucleic acid sequence (SEQ ID NO:4), which is approximately 24,120 nucleotides long including untranslated regions, contains a predicted methionine-initiated coding sequence of about 23,907 nucleotides, including the termination codon (shown as the nucleotides of SEQ ID NO:4 indicated as coding, and the sequence shown in SEQ ID NO:6). The coding sequence encodes a 7968 amino acid protein (SEQ ID NO:5).

[0026] To determine whether a polypeptide or protein of interest has a conserved sequence or domain common to members of a protein family, the amino acid sequence of the protein can be searched against a database of profile hidden Markov models (profile HMMs), which uses statistical descriptions of a sequence family's consensus (e.g., HMMER, version 2.1.1) and PFAM, a collection of multiple sequence alignments and hidden Markov models covering many common protein domains (e.g., PFAM, version 5.5) using the default parameters (http://www.sanger.ac.uk/Software/Pfam_- HMM search). For example, the hmmsf program, which is available as part of the HMMER package of search programs, is a family specific default program for MILPAT0063 and a score of 15 is the default threshold score for determining a hit. Alternatively, the threshold score for determining a hit can be lowered (e.g., to 8 bits). A description of the PFAM database can be found in Sonhammer et al., (1997) Proteins 28(3):405-420 and a detailed description of HMMs can be found, for example, in Gribskov et al., (1990) Meth. Enzymol. 183:146-159; Gribskov et al., (1987) Proc. Natl. Acad. Sci. USA 84:4355-4358; Krogh et al., (1994) J. Mol. Biol. 235:1501-1531; and Stultz et al., (1993) Protein Sci. 2:305-314, the contents of which are incorporated herein by reference. See also, for example, http://hmmer.wustl.edu/. For general information regarding PFAM identifiers, PS prefix and PF prefix domain identification numbers, refer to Sonnhammer et al. (1997) Protein 28:405-420 and http://pfam.wustl.edu/. See also, for example, http://www.expasy.ch/prosi- te and http://smart.embl-heidelberg.de/.

[0027] Using such search tools, the 59079 and 12599 protein sequences were found to contain significant structural characteristics in common with members of the protein kinase family of molecules. Some of these structural characteristics include, for example, a protein kinase catalytic domain (e.g., PFAM Accession No. PF00069), a pleckstrin homology domain consensus sequence (e.g., PFAM Accession No. PF00169), a fibronectin type III domain (e.g., PFAM Accession No. PF00041), a RhoGEF domain (e.g., PFAM Accession No. PF00621), and a IQ calmodulin-binding motif (e.g., PFAM Accession No. PF00612).

[0028] As used herein, the term "protein kinase" includes a protein or polypeptide which is capable of modulating its own phosphorylation state or the phosphorylation state of another molecule, e.g., protein or polypeptide. Protein kinases can have a specificity for (i.e., a specificity to phosphorylate) serine/threonine residues, tyrosine residues, or both serine/threonine and tyrosine residues, e.g., the dual specificity kinases.

[0029] The term "family" when referring to the protein and nucleic acid molecules of the invention is intended to mean two or more proteins or nucleic acid molecules having a common structural domain or signature sequence and having sufficient amino acid or nucleotide sequence homology as defined herein. Such family members can be naturally or non-naturally occurring and can be from either the same or different species. For example, a family can contain a first protein of human origin, as well as other distinct proteins of human origin, or alternatively, can contain homologues of non-human origin, e.g., rat or mouse proteins. Members of a family can also have common functional characteristics.

[0030] With regard to common structural characteristics described above, the protein kinases of the present invention include a protein kinase catalytic core or domain and can include at least one of the following signature sequences or motifs within the catalytic core: a protein kinase ATP-binding region signature sequence, a serine/threonine protein kinase active site signature sequence, and a tyrosine kinase active site signature sequence (see Hanks et al. (1988) Science 241:42-52).

[0031] As used herein, a "protein kinase catalytic core or domain" includes a consensus sequence, e.g., PFAM Accession No. PF00069, that includes the catalytic domain of the enzyme. The catalytic domain can be characterized by the presence of an ATP binding signature sequence (e.g., Prosite Accession No. PS00107) and/or a serine/threonine or tyrosine kinase active-site signature sequence (e.g., Prosite Accession No. PS00108 or Prosite Accession No. PS00109). The protein kinase catalytic domain of the present invention preferably includes a catalytic domain of about 150-400 amino acid residues in length, preferably about 200-300 amino acid residues in length, or more preferably about 225-300 amino acid residues in length, which includes at least one of the signature sequences or motifs described herein.

[0032] Accordingly, protein kinase polypeptides having at least 50-60% homology, preferably about 60-70%, more preferably about 70-80%, or about 80-90% homology with a protein kinase catalytic domain of 59079 or 12599 are within the scope of the invention.

[0033] The protein kinase ATP-binding region signature sequence is located in the N-terminal extremity of the catalytic domain and typically includes a glycine-rich stretch of residues in the vicinity of a lysine residue. A consensus sequence (Prosite Accession No. PS00107; SEQ ID NO:7) for this region is [LIV]-G-{P}-G-{P}-[FYWMGSTNH]-[SGA]-{PW}-[LIVCAT- ]-{PD}-x-[GSTACLIVMFY]-x(5,18)-[LIVMFYWCSTAR]-[AIVP]-[LIV MFAGCKR]-K. In the above consensus sequence pattern, lysine (K) binds ATP.

[0034] In this and the following consensus sequence patterns, each element in the pattern is separated by a dash (-); square brackets, [ ], indicate the particular residues that are accepted at that position; ornate brackets, { }, indicate the residues that are not accepted at that position; x indicates any residue is accepted at that position; repetition of a particular element is indicated by following the element with a numerical value or a numerical range enclosed in parentheses (i.e., above, x(5,18) indicates anywhere from 5 to 18 residues are present in the element, and any amino acid residue is accepted at each of these 5 to 18 residue positions); and the standard IUPAC one-letter code for the amino acids is used.

[0035] Analysis of the 59079 polypeptide for sequence patterns in the Prosite database showed a match to a protein kinase ATP binding region signature pattern of Prosite Accession No. PS00107 at about amino acids 1136 to 1159 and at about amino acid residues 2340 to 2363 of SEQ ID NO:2. The lysine residue at position 1145, 1150, 1153, 1159, 2354, and/or 2363 of SEQ ID NO:2 can be involved in ATP binding. Each of these protein kinase ATP-binding region signature sequences lies within a protein kinase catalytic domain identified in a PFAM search against the HMM database (HMMER2.1.1); the first, in the protein kinase catalytic domain spanning amino acid residues 1130 to 1383; the second, in the protein kinase catalytic domain from amino acid residues 2334 to 2586 of SEQ ID NO:2.

[0036] Analysis of the 12599 polypeptide for sequence patterns in the Prosite database showed a match to a protein kinase ATP binding region signature pattern of Prosite Accession No. PS00107 at about amino acids 6474 to 6497 of SEQ ID NO:5. The lysine residue at position 6483, 6488, 6491, and/or 6497 of SEQ ID NO:5 can be involved in ATP binding. This protein kinase ATP binding region signature pattern lies within a protein kinase catalytic domain identified in a PFAM search against the HMM database (HMMER2.1.1) and located from amino acid residues 6468 to 6721 of SEQ ID NO:5.

[0037] Another region, located in the central part of the catalytic core or domain, contains a conserved aspartic acid residue, which is important for the catalytic activity of the enzyme (Knighton et al. (1991) Science 253:407-414). Two active-site signature sequences have been described for this region: one specific for serine/threonine kinases and one for tyrosine kinases. In both signature sequences aspartic acid (D) is conserved and is an active site residue. A consensus sequence for the serine/threonine kinases (Prosite Accession No. PS00108; SEQ ID NO:8) is [LIVMFYC]-x-[HY]-x-D-[LIVMFY]-K-x(2)-N-[LIVMFYCT](3). A consensus sequence for the tyrosine kinases (Prosite Accession No. PS00109; SEQ ID NO:9) is [LIVMFYC]-x-[HY]-x-D-[LIVMFY]-[RSTAC]-x(2)-N-[LIVMFYC](3).

[0038] Analysis of the 59079 polypeptide for sequence patterns in the Prosite database showed a match of amino acid residues 1245 to 1257 of SEQ ID NO:2 to the serine/threonine kinase active-site signature sequence of Prosite Accession No. PS00108. The aspartic acid residue (D) at position 1249 of SEQ ID NO:2 is an active site residue. This serine/threonine kinase active-site signature sequence lies within the protein kinase catalytic domain spanning amino acid residues 1130 to 1383 of SEQ ID NO:2.

[0039] Analysis of the 12599 polypeptide for sequence patterns in the Prosite database showed a match of amino acid residues 6583 to 6595 of SEQ ID NO:5 to the serine/threonine kinase active-site signature sequence of Prosite Accession No. PS00108. The aspartic acid residue (D) at position 6587 of SEQ ID NO:5 is an active site residue. This serine/threonine kinase active-site signature sequence lies within the protein kinase catalytic domain spanning amino acid residues 6468 to 6721 of SEQ ID NO:2.

[0040] Analysis of the 59079 polypeptide for other sequence patterns in the Prosite database showed a match of amino acid residues 2449 to 2461 of SEQ ID NO:2 to the tyrosine protein kinase active site signature sequence of Prosite Accession No. PS00109. The aspartic acid residue (D) at position 2453 of SEQ ID NO:2 is an active site residue. This tyrosine protein kinase active site signature sequence lies within the protein kinase catalytic domain spanning amino acid residues 2334 to 2586 of SEQ ID NO:2.

[0041] Analysis of the 12599 polypeptide for other sequence patterns in the Prosite database showed a match of amino acid residues 7787 to 7799 of SEQ ID NO:5 to the tyrosine protein kinase active site signature sequence of Prosite Accession No. PS00109. The aspartic acid residue (D) at position 7791 of SEQ ID NO:5 is an active site residue. This tyrosine protein kinase active site signature sequence lies within the protein kinase catalytic domain spanning amino acid residues 7672 to 7924 of SEQ ID NO:5.

[0042] As used herein, a "pleckstrin homology domain" is a domain that is characterized by the matrix profile described by PFAM Accession No. PF00169 or Prosite Accession No. PS50003. The pleckstrin homology domain is a domain of about 100 amino acid residues that can occur in protein kinases, e.g., serine/threonine protein kinases belonging to the Akt/Rac family, the beta-adrenergic receptor kinase family, the trypanosomal NrkA family, and the mu isoform of protein kinase C, and tyrosine protein kinases, e.g., belonging to the Btk/Itk/Tec subfmaily. This domain is likely involved in binding phosphorylated serine/threonine residues. The presence of a pleckstrin homology domain was identified in 59079 at about amino acid residues 558 to 666 of SEQ ID NO:2 and in 12599 at about amino acid residues 5896 to 6004 of SEQ ID NO:5.

[0043] The sequence analyses of the 59079 and 12599 proteins demonstrate that the 59079 and 12599 proteins can act as serine/threonine or tyrosine protein kinases, and can also include a pleckstrin homology domain. Based on the above-described sequence similarities, the 59079 and 12599 molecules of the present invention have similar biological or functional activities as protein kinase family members.

[0044] As used interchangeably herein, he terms, a "59079- and/or 12599-mediated activity", "biological activity of 59079 and/or 12599" or "functional activity of 59079 and/or 12599", refer to an activity exerted by a 59079 or 12599 protein, polypeptide or nucleic acid molecule on, e.g., a 59079- or 12599-responsive cell or tissue, or on a 59079 or 12599 substrate, ligand, or target molecule, e.g., a protein substrate or target molecule, as determined in vivo, in vitro, or in situ according to standard techniques.

[0045] In one embodiment, a 59079 or 12599 activity is a direct activity, such as an association with a 59079 or 12599 ligand, binding partner, or target molecule. As used interchangeably herein, a "ligand", "binding partner", or "target molecule" is a molecule with which a 59079 or 12599 protein binds or interacts in nature, such that a 59079- or 12599-mediated function is achieved. A 59079 or 12599 target molecule can be a 59079 or a 12599 protein or polypeptide of the present invention or a non-59079 or non-12599 protein molecule. In one embodiment, a 59079 or 12599 target molecule can be a non-59079 or a non-12599 protein molecule. In an exemplary embodiment, a 59079 or 12599 target molecule is a 59079 ligand, e.g., a protein kinase ligand, e.g., serine, threonine, or tyrosine containing polypeptide.

[0046] Protein kinases play a role in signalling pathways associated with cellular growth. For example, protein kinases are involved in the regulation of signal transmission from cellular receptors, e.g., growth-factor receptors; entry of cells into mitosis; and the regulation of cytoskeleton function, e.g., actin bundling. Thus, the 59079 and 12599 molecules of the present invention can be involved in: 1) the regulation of transmission of signals from cellular receptors, e.g., cell growth factor receptors; 2) the modulation of the entry of cells, e.g., precursor cells, into mitosis; 3) the modulation of cellular differentiation; 4) the modulation of cell death; and 5) the regulation of cytoskeleton function, e.g., actin bundling. These kinases can function in these biological activities because of their ability to phosphorylate themselves or other substrate molecules.

[0047] Substrates of tyrosine protein kinases are generally characterized by a lysine or an arginine seven residues to the N-terminal side of the phosphorylated tyrosine. An acidic residue (aspartic acid or glutatmic acid) is often found at either three or four residues to the N-terminal side of the tyrosine (see Patschinsky et al. (1982) Proc. Natl. Acad. Sci. U.S.A. 79:973-977; Hunter T. (1982) J. Biol. Chem. 257:4843-4848; Cooper et al. (1984) J. Biol. Chem. 259:7835-7841).

[0048] A 59079 or 12599 activity can also be an indirect activity, such as an activity mediated by interaction of the 59079 or 12599 protein with a 59079 or 12599 target molecule such that the target molecule modulates a downstream cellular activity, e.g., a cellular signaling activity modulated indirectly by an interaction of the 59079 or 12599 protein with a 59079 or 12599 target molecule.

[0049] The 59079 and 12599 molecules of the invention can modulate the activities of cells in tissues where they are expressed. For example, 59079 and 12599 mRNA are expressed in normal heart and upregulated in diseased heart. Accordingly, the 59079 and 12599 molecules of the invention can act as therapeutic or diagnostic agents for cardiovascular disorders.

[0050] Cardiovascular disorders include, but are not limited to, heart failure, including but not limited to, cardiac hypertrophy, left-sided heart failure, and right-sided heart failure; ischemic heart disease, including but not limited to angina pectoris, myocardial infarction, chronic ischemic heart disease, and sudden cardiac death; hypertensive heart disease, including but not limited to, systemic (left-sided) hypertensive heart disease and pulmonary (right-sided) hypertensive heart disease; valvular heart disease, including but not limited to, valvular degeneration caused by calcification, such as calcification of a congenitally bicuspid aortic valve, and mitral annular calcification, and myxomatous degeneration of the mitral valve (mitral valve prolapse), rheumatic fever and rheumatic heart disease, infective endocarditis, and noninfected vegetations, such as nonbacterial thrombotic endocarditis and endocarditis of systemic lupus erythematosus (Libman-Sacks disease), carcinoid heart disease, and complications of artificial valves; myocardial disease, including but not limited to dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, and myocarditis; pericardial disease, including but not limited to, pericardial effusion and hemopericardium and pericarditis, including acute pericarditis and healed pericarditis, and rheumatoid heart disease; neoplastic heart disease, including but not limited to, primary cardiac tumors, such as myxoma, lipoma, papillary fibroelastoma, rhabdomyoma, and sarcoma, and cardiac effects of noncardiac neoplasms; congenital heart disease, including but not limited to, left-to-right shunts--late cyanosis, such as atrial septal defect, ventricular septal defect, patent ductus arteriosus, and atrioventricular septal defect, right-to-left shunts-early cyanosis, such as tetralogy of fallot, transposition of great arteries, truncus arteriosus, tricuspid atresia, and total anomalous pulmonary venous connection, obstructive congenital anomalies, such as coarctation of aorta, pulmonary stenosis and atresia, and aortic stenosis and atresia, disorders involving cardiac transplantation, and congestive heart failure.

[0051] Disorders involving blood vessels include, but are not limited to, responses of vascular cell walls to injury, such as endothelial dysfunction and endothelial activation and intimal thickening; vascular diseases including, but not limited to, congenital anomalies, such as arteriovenous fistula, atherosclerosis, and hypertensive vascular disease, such as hypertension; inflammatory disease--the vasculitides, such as giant cell (temporal) arteritis, Takayasu arteritis, polyarteritis nodosa (classic), Kawasaki syndrome (mucocutaneous lymph node syndrome), microscopic polyanglitis (microscopic polyarteritis, hypersensitivity or leukocytoclastic anglitis), Wegener granulomatosis, thromboanglitis obliterans (Buerger disease), vasculitis associated with other disorders, and infectious arteritis; Raynaud disease; aneurysms and dissection, such as abdominal aortic aneurysms, syphilitic (luetic) aneurysms, and aortic dissection (dissecting hematoma); disorders of veins and lymphatics, such as varicose veins, thrombophlebitis and phlebothrombosis, obstruction of superior vena cava (superior vena cava syndrome), obstruction of inferior vena cava (inferior vena cava syndrome), and lymphangitis and lymphedema; tumors, including benign tumors and tumor-like conditions, such as hemangioma, lymphangioma, glomus tumor (glomangioma), vascular ectasias, and bacillary angiomatosis, and intermediate-grade (borderline low-grade malignant) tumors, such as Kaposi's sarcoma and hemangloendothelioma, and malignant tumors, such as angiosarcoma and hemangiopericytoma; and pathology of therapeutic interventions in vascular disease, such as balloon angioplasty and related techniques and vascular replacement, such as coronary artery bypass graft surgery.

[0052] Blood platelet disorders include, but are not limited to, thrombocytopenia due to a reduced number of megakaryocytes in the bone marrow, for example, as a result of chemotherapy; invasive disorders, such as leukemia, idiopathic or drug- or toxin-induced aplasia of the marrow, or rare hereditary amegakaryocytic thrombocytopenias; ineffective thrombopoiesis, for example, as a result of megaloblastic anemia, alcohol toxicity, vitamin B12 or folate deficiency, myelodysplastic disorders, or rare hereditary disorders (e.g., Wiskott-Aldrich syndrome and May-hegglin anomaly); a reduction in platelet distribution, for example, as a result of cirrhosis, a splenic invasive disease (e.g., Gaucher's disease), or myelofibrosis with extramedullary myeloid metaplasia; increased platelet destruction, for example, as a result of removal of IgG-coated platelets by the mononuclear phagocytic system (e.g., idiopathic thrombocytopenic purpura (ITP), secondary immune thrombocytopenia (e.g., systemic lupus erythematosus, lymphoma, or chronic lymphocytic leukemia), drug-related immune thrombocytopenias (e.g., as with quinidine, aspirin, and heparin), post-transfusion purpura, and neonatal thrombocytopenia as a result of maternal platelet autoantibodies or maternal platelet alloantibodies). Also included are thrombocytopenia secondary to intravascular clotting and thrombin induced damage to platelets as a result of, for example, obstetric complications, metastatic tumors, severe gram-negative bacteremia, thrombotic thrombocytopenic purpura, or severe illness. Also included is dilutional thrombocytopenia, for example, due to massive hemorrhage. Blood platelet disorders also include, but are not limited to, essential thrombocytosis and thrombocytosis associated with, for example, splenectomy, acute or chronic inflammatory diseases, hemolytic anemia, carcinoma, Hodgkin's disease, lymphoproliferative disorders, and malignant lymphomas.

[0053] As the 59079 and 12599 molecules of the present invention share structural features with protein kinases and can modulate protein kinase-mediated activities, the 59079 and 12599 compositions of the invention (e.g., nucleic acids, polypeptides, proteins, antibodies, and modulators of 59079 or 12599 gene expression or biological activity) are useful for developing novel diagnostic and therapeutic agents for protein kinase associated disorders. As used herein, a "protein kinase associated disorder" includes a disorder, disease, or condition which is caused by, characterized by, or associated with a misregulation (e.g., an aberrant downregulation or upregulation) of a protein kinase mediated activity. Protein kinase associated disorders can result in, e.g., upregulated or downregulated, cell growth and/or proliferation.

[0054] Protein kinase associated disorders can detrimentally affect cellular functions such as cellular proliferation, growth, differentiation, and cellular regulation of homeostasis, e.g., glucose homeostasis; inter- or intra-cellular communication; tissue function, such as cardiac function or musculoskeletal function; systemic responses in an organism, such as nervous system responses, hormonal responses (e.g., insulin response), or immune responses; and protection of cells from toxic compounds (e.g., carcinogens, toxins, mutagens, and toxic byproducts of metabolic activity, e.g., reactive oxygen species). Accordingly, the 59079 molecules of the invention, as protein kinases, can mediate various protein kinase associated disorders, including cellular proliferative and/or differentiative disorders, hormonal disorders, immune and inflammatory disorders, neurological disorders, cardiovascular disorders, blood vessel disorders, and platelet disorders.

[0055] Examples of cellular proliferative and/or differentiative disorders include cancer, e.g., carcinoma, sarcoma, metastatic disorders or hematopoietic neoplastic disorders, e.g., leukemias. A metastatic tumor can arise from a multitude of primary tumor types, including but not limited to those of prostate, colon, lung, breast and liver origin.

[0056] As used herein, the term "cancer" (also used interchangeably with the terms, "hyperproliferative" and "neoplastic") refers to cells having the capacity for autonomous growth, i.e., an abnormal state or condition characterized by rapidly proliferating cell growth. Cancerous disease states may be categorized as pathologic, i.e., characterizing or constituting a disease state, e.g., malignant tumor growth, or may be categorized as non-pathologic, i.e., a deviation from normal but not associated with a disease state, e.g., cell proliferation associated with wound repair. The term is meant to include all types of cancerous growths or oncogenic processes, metastatic tissues or malignantly transformed cells, tissues, or organs, irrespective of histopathologic type or stage of invasiveness. The term "cancer" includes malignancies of the various organ systems, such as those affecting lung, breast, thyroid, lymphoid, gastrointestinal, and genito-urinary tract, as well as adenocarcinomas which include malignancies such as most colon cancers, renal-cell carcinoma, prostate cancer and/or testicular tumors, non-small cell carcinoma of the lung, cancer of the small intestine and cancer of the esophagus. The term "carcinoma" is art recognized and refers to malignancies of epithelial or endocrine tissues including respiratory system carcinomas, gastrointestinal system carcinomas, genitourinary system carcinomas, testicular carcinomas, breast carcinomas, prostatic carcinomas, endocrine system carcinomas, and melanomas. Exemplary carcinomas include those forming from tissue of the cervix, lung, prostate, breast, head and neck, colon and ovary. The term "carcinoma" also includes carcinosarcomas, e.g., which include malignant tumors composed of carcinomatous and sarcomatous tissues. An "adenocarcinoma" refers to a carcinoma derived from glandular tissue or in which the tumor cells form recognizable glandular structures. The term "sarcoma" is art recognized and refers to malignant tumors of mesenchymal derivation.

[0057] The 59079 molecules of the invention can be used to monitor, treat and/or diagnose a variety of proliferative disorders. Such disorders include hematopoietic neoplastic disorders. As used herein, the term "hematopoietic neoplastic disorders" includes diseases involving hyperplastic/neoplastic cells of hematopoietic origin, e.g., arising from myeloid, lymphoid or erythroid lineages, or precursor cells thereof. Typically, the diseases arise from poorly differentiated acute leukemias, e.g., erythroblastic leukemia and acute megakaryoblastic leukemia. Additional exemplary myeloid disorders include, but are not limited to, acute promyeloid leukemia (APML), acute myelogenous leukemia (AML) and chronic myelogenous leukemia (CML) (reviewed in Vaickus, L., (1991) Crit. Rev. in Oncol./Hemotol. 11:267-97); lymphoid malignancies include, but are not limited to acute lymphoblastic leukemia (ALL) which includes B-lineage ALL and T-lineage ALL, chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), hairy cell leukemia (HLL) and Waldenstrom's macroglobulinemia (WM). Additional forms of malignant lymphomas include, but are not limited to non-Hodgkin lymphoma and variants thereof, peripheral T cell lymphomas, adult T cell leukemia/lymphoma (ATL), cutaneous T-cell lymphoma (CTCL), large granular lymphocytic leukemia (LGF), Hodgkin's disease and Reed-Sternberg disease.

[0058] Protein kinase associated disorders can include hormonal disorders, such as conditions or diseases in which the production and/or regulation of hormones in an organism is aberrant. Examples of such disorders and diseases include type I and type II diabetes mellitus, pituitary disorders (e.g., growth disorders), thyroid disorders (e.g., hypothyroidism or hyperthyroidism), and reproductive or fertility disorders (e.g., disorders which affect the organs of the reproductive system, e.g., the prostate gland, the uterus, or the vagina; disorders which involve an imbalance in the levels of a reproductive hormone in a subject; disorders affecting the ability of a subject to reproduce; and disorders affecting secondary sex characteristic development, e.g., adrenal hyperplasia).

[0059] Protein kinase associated disorders also include immune and inflammatory disorders, such as autoimmune disorders or immune deficiency disorders, e.g., congenital X-linked infantile hypogammaglobulinemia, transient hypogammaglobulinemia, common variable immunodeficiency, selective IgA deficiency, chronic mucocutaneous candidiasis, or severe combined immunodeficiency. Other examples of disorders include autoimmune diseases (including, for example, diabetes mellitus, arthritis (including rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, psoriatic arthritis), multiple sclerosis, encephalomyelitis, myasthenia gravis, systemic lupus erythematosis, autoimmune thyroiditis, dermatitis (including atopic dermatitis and eczematous dermatitis), psoriasis, Sjogren's Syndrome, inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), aphthous ulcer, iritis, conjunctivitis, keratoconjunctivitis, respiratory inflammation (e.g., asthma, allergic asthma, and chronic obstructive pulmonary disease), cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, drug eruptions, leprosy reversal reactions, erythema nodosum leprosum, autoimmune uveitis, allergic encephalomyelitis, acute necrotizing hemorrhagic encephalopathy, idiopathic bilateral progressive sensorineural hearing loss, aplastic anemia, pure red cell anemia, idiopathic thrombocytopenia, polychondritis, Wegener's granulomatosis, chronic active hepatitis, Stevens-Johnson syndrome, idiopathic sprue, lichen planus, Graves' disease, sarcoidosis, primary biliary cirrhosis, uveitis posterior, and interstitial lung fibrosis), graft-versus-host disease, cases of transplantation, and allergy such as, atopic allergy.

[0060] Additional protein kinase associated disorders are neurological disorders. Such neurological disorders include, for example, disorders involving neurons, and disorders involving glia, such as astrocytes, oligodendrocytes, ependymal cells, and microglia; cerebral edema, raised intracranial pressure and herniation, and hydrocephalus; malformations and developmental diseases, such as neural tube defects, forebrain anomalies, posterior fossa anomalies, and syringomyelia and hydromyelia; perinatal brain injury; cerebrovascular diseases, such as those related to hypoxia, ischemia, and infarction, including hypotension, hypoperfusion, and low-flow states--global cerebral ischemia and focal cerebral ischemia--infarction from obstruction of local blood supply, intracranial hemorrhage, including intracerebral (intraparenchymal) hemorrhage, subarachnoid hemorrhage and ruptured berry aneurysms, and vascular malformations, hypertensive cerebrovascular disease, including lacunar infarcts, slit hemorrhages, and hypertensive encephalopathy; infections, such as acute meningitis, including acute pyogenic (bacterial) meningitis and acute aseptic (viral) meningitis, acute focal suppurative infections, including brain abscess, subdural empyema, and extradural abscess, chronic bacterial meningoencephalitis, including tuberculosis and mycobacterioses, neurosyphilis, and neuroborreliosis (Lyme disease), viral meningoencephalitis, including arthropod-borne (Arbo) viral encephalitis, Herpes simplex virus Type 1, Herpes simplex virus Type 2, Varicella-zoster virus (Herpes zoster), cytomegalovirus, poliomyelitis, rabies, and human immunodeficiency virus 1, including HIV-1 meningoencephalitis (subacute encephalitis), vacuolar myelopathy, AIDS-associated myopathy, peripheral neuropathy, and AIDS in children, progressive multifocal leukoencephalopathy, subacute sclerosing panencephalitis, fungal meningoencephalitis, other infectious diseases of the nervous system; transmissible spongiform encephalopathies (prion diseases); demyelinating diseases, including multiple sclerosis, multiple sclerosis variants, acute disseminated encephalomyelitis and acute necrotizing hemorrhagic encephalomyelitis, and other diseases with demyelination; degenerative diseases, such as degenerative diseases affecting the cerebral cortex, including Alzheimer's disease and Pick's disease, degenerative diseases of basal ganglia and brain stem, including Parkinsonism, idiopathic Parkinson's disease (paralysis agitans), progressive supranuclear palsy, corticobasal degenration, multiple system atrophy, including striatonigral degenration, Shy-Drager syndrome, and olivopontocerebellar atrophy, and Huntington's disease; spinocerebellar degenerations, including spinocerebellar ataxias, including Friedreich ataxia, and ataxia-telanglectasia, degenerative diseases affecting motor neurons, including amyotrophic lateral sclerosis (motor neuron disease), bulbospinal atrophy (Kennedy syndrome), and spinal muscular atrophy; inborn errors of metabolism, such as leukodystrophies, including Krabbe disease, metachromatic leukodystrophy, adrenoleukodystrophy, Pelizaeus-Merzbacher disease, and Canavan disease, mitochondrial encephalomyopathies, including Leigh disease and other mitochondrial encephalomyopathies; toxic and acquired metabolic diseases, including vitamin deficiencies such as thiamine (vitamin B.sub.1) deficiency and vitamin B.sub.12 deficiency, neurologic sequelae of metabolic disturbances, including hypoglycemia, hyperglycemia, and hepatic encephatopathy, toxic disorders, including carbon monoxide, methanol, ethanol, and radiation, including combined methotrexate and radiation-induced injury; tumors, such as gliomas, including astrocytoma, including fibrillary (diffuse) astrocytoma and glioblastoma multiforme, pilocytic astrocytoma, pleomorphic xanthoastrocytoma, and brain stem glioma, oligodendroglioma, and ependymoma and related paraventricular mass lesions, neuronal tumors, poorly differentiated neoplasms, including medulloblastoma, other parenchymal tumors, including primary brain lymphoma, germ cell tumors, and pineal parenchymal tumors, meningiomas, metastatic tumors, paraneoplastic syndromes, peripheral nerve sheath tumors, including schwannoma, neurofibroma, and malignant peripheral nerve sheath tumor (malignant schwannoma), and neurocutaneous syndromes (phakomatoses), including neurofibromotosis, including Type 1 neurofibromatosis (NF1) and TYPE 2 neurofibromatosis (NF2), tuberous sclerosis, and Von Hippel-Lindau disease.

[0061] The 59079 and 12599 proteins, fragments thereof, and derivatives and other variants of the sequences in SEQ ID NO:2 and SEQ ID NO:5 are collectively referred to as "polypeptides or proteins of the invention" or "59079 and/or 12599 polypeptides or proteins". Nucleic acid molecules encoding such polypeptides or proteins are collectively referred to as "nucleic acids of the invention" or "59079 and/or 12599 nucleic acids."

[0062] As used herein, the term "nucleic acid molecule" includes DNA molecules (e.g., a cDNA or genomic DNA) and RNA molecules (e.g., an mRNA) and analogs of the DNA or RNA generated, e.g., by the use of nucleotide analogs. The nucleic acid molecule can be single-stranded or double-stranded, but preferably is double-stranded DNA.

[0063] The term "isolated or purified nucleic acid molecule" includes nucleic acid molecules which are separated from other nucleic acid molecules which are present in the natural source of the nucleic acid. For example, with regards to genomic DNA, the term "isolated" includes nucleic acid molecules which are separated from the chromosome with which the genomic DNA is naturally associated. Preferably, an "isolated" nucleic acid is free of sequences which naturally flank the nucleic acid (i.e., sequences located at the 5' and/or 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 5' and/or 3' 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.

[0064] As used herein, the term "hybridizes under stringent conditions" describes conditions for hybridization and washing. Stringent conditions are known to those skilled in the art and can be found in Current Protocols in Molecular Biology, John Wiley & Sons, N.Y. (1989), 6.3.1-6.3.6. Aqueous and nonaqueous methods are described in that reference and either can be used. A preferred, 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.degree. C. Another example of stringent hybridization conditions are hybridization in 6.times.SSC at about 45.degree. C., followed by one or more washes in 0.2.times.SSC, 0.1% SDS at 55.degree. C. A further example of stringent hybridization conditions are hybridization in 6.times.SSC at about 45.degree. C., followed by one or more washes in 0.2.times.SSC, 0.1% SDS at 60.degree. C. Preferably, stringent hybridization conditions are hybridization in 6.times.SSC at about 45.degree. C., followed by one or more washes in 0.2.times.SSC, 0.1% SDS at 65.degree. C. Particularly preferred stringency conditions (and the conditions that should be used if the practitioner is uncertain about what conditions should be applied to determine if a molecule is within a hybridization limitation of the invention) are 0.5M sodium phosphate, 7% SDS at 65.degree. C., followed by one or more washes at 0.2.times.SSC, 1% SDS at 65.degree. C. Preferably, an isolated nucleic acid molecule of the invention that hybridizes under stringent conditions to the sequence of SEQ ID NOs:1, 3, 4, or 6, corresponds to a naturally-occurring nucleic acid molecule.

[0065] As used herein, a "naturally-occurring" nucleic acid molecule refers to an RNA or DNA molecule having a nucleotide sequence that occurs in nature (e.g., encodes a natural protein).

[0066] As used herein, the terms "gene" and "recombinant gene" refer to nucleic acid molecules which include an open reading frame encoding a 59079 or 12599 protein, preferably a mammalian 59079 or 12599 protein, and can further include non-coding regulatory sequences, and introns.

[0067] An "isolated" or "purified" polypeptide or protein 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 from chemical precursors or other chemicals when chemically synthesized. In one embodiment, the language "substantially free" means a preparation of 59079 or 12599 protein having less than about 30%, 20%, 10% and more preferably 5% (by dry weight), of non-59079 or non-12599 protein (also referred to herein as a "contaminating protein"), or of chemical precursors or non-59079 or non-12599 chemicals. When the 59079 or 12599 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%, more preferably less than about 10%, and most preferably less than about 5% of the volume of the protein preparation. The invention includes isolated or purified preparations of at least 0.01, 0.1, 1.0, and 10 milligrams in dry weight.

[0068] A "non-essential" amino acid residue is a residue that can be altered from the wild-type sequence of 59079 (e.g., the sequence of SEQ ID NO:1 or 3) or 12599 (e.g., the sequence of SEQ ID NO:4 or 6) without abolishing or more preferably, without substantially altering a biological activity, whereas an "essential" amino acid residue results in such a change. For example, amino acid residues that are conserved among the polypeptides of the present invention, e.g., those present in the protein kinasedomain, are predicted to be particularly unamenable to alteration.

[0069] 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), nonpolar 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). Thus, a predicted nonessential amino acid residue in a 59079 or 12599 protein is preferably replaced with another amino acid residue from the same side chain family. Alternatively, in another embodiment, mutations can be introduced randomly along all or part of a 59079 or 12599 coding sequence, such as by saturation mutagenesis, and the resultant mutants can be screened for 59079 or 12599 biological activity to identify mutants that retain activity. Following mutagenesis of SEQ ID NOs:1, 3, 4, or 6, the encoded protein can be expressed recombinantly and the activity of the protein can be determined.

[0070] As used herein, a "biologically active portion" of a 59079 or 12599 protein includes a fragment of a 59079 or 12599 protein which participates in an interaction between a 59079 molecule and a non-59079 molecule or in an interaction between a 12599 molecule and a non-12599 molecule. Biologically active portions of a 59079 or 12599 protein include peptides comprising amino acid sequences sufficiently identical to or derived from the amino acid sequence of the 59079 protein, e.g., the amino acid sequence shown in SEQ ID NO:2, or the amino acid sequence of the 12599 protein, e.g., the amino acid sequence shown in SEQ ID NO:5 which include less amino acids than the full length 59079 or 12599 proteins, and exhibit at least one activity of a 59079 or 12599 protein. Typically, biologically active portions comprise a domain or motif with at least one activity of the 59079 or 12599 protein, including, e.g., the ability to as a protein kinase or activate a protein kinase activity.

[0071] A biologically active portion of a 59079 or 12599 protein can be a polypeptide which is, for example, 10, 25, 50, 100, 200, or more, amino acids in length. Biologically active portions of a 59079 or 12599 protein can be used as targets for developing agents which modulate a 59079- or 12599-mediated activity as described herein.

[0072] Calculations of homology or sequence identity (the terms are used interchangeably herein) between sequences are performed as follows:

[0073] To determine the percent identity of two amino acid sequences, or of two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second amino acid or nucleic acid sequence for optimal alignment and non-homologous sequences can be disregarded for comparison purposes). In a preferred embodiment, the length of a reference sequence aligned for comparison purposes is at least 30%, preferably at least 40%, more preferably at least 50%, even more preferably at least 60%, and even more preferably at least 70%, 80%, 90%, 100% of the length of the reference sequence (e.g., when aligning a second sequence to the 59079 amino acid sequence of SEQ ID NO:2, at least 789, preferably at least 1052, more preferably at least 1315, even more preferably at least 1578, and even more preferably at least 1841, 2104, 2367, or 2630 amino acid residues of the two sequences are aligned; and when aligning a second sequence to the 12599 amino acid sequence of SEQ ID NO:5, at least 2391, preferably at least 3187, more preferably at least 3984, even more preferably at least 4781, and even more preferably at least 5578, 6374, 7171, or 7968 amino acid residues of the two sequences are aligned). 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 (as used herein amino acid or nucleic acid "identity" is equivalent to amino acid or nucleic acid "homology"). The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences.

[0074] The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. In a preferred embodiment, the percent identity between two amino acid sequences is determined using the Needleman and Wunsch ((1970) J. Mol. Biol. 48:444-453) algorithm which has been incorporated into the GAP program in the GCG software package (available at http://www.gcg.com), using either a Blossum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6. In yet another preferred embodiment, the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package (available at http://www.gcg.com), using a NWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. A particularly preferred set of parameters (and the one that should be used if the practitioner is uncertain about what parameters should be applied to determine if a molecule is within a sequence identity or homology limitation of the invention) are a Blossum 62 scoring matrix with a gap penalty of 12, a gap extend penalty of 4, and a frameshift gap penalty of 5.

[0075] The percent identity between two amino acid or nucleotide sequences can be determined using the algorithm of E. Meyers and W. Miller ((1989) CABIOS, 4:11-17) which has been incorporated into the ALIGN program (version 2.0), using a PAM 120 weight residue table, a gap length penalty of 12 and a gap penalty of 4.

[0076] The nucleic acid and protein sequences described herein can be used as a "query sequence" to perform a search against public databases to, for example, identify other family members or related sequences. Such searches can be performed using the NBLAST and XBLAST programs (version 2.0) of Altschul, et al. (1990) J. Mol. Biol. 215:403-10. BLAST nucleotide searches can be performed with the NBLAST program, score=100, wordlength=12 to obtain nucleotide sequences homologous to 59079 nucleic acid molecules of the invention. BLAST protein searches can be performed with the XBLAST program, score=50, wordlength=3 to obtain amino acid sequences homologous to 59079 protein molecules of the invention. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al., (1997) Nucleic Acids Res. 25:3389-3402. When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used. See http://www.ncbi.nlm.nih.gov.

[0077] Particular 59079 and 12599 polypeptides of the present invention have an amino acid sequence sufficiently identical or substantially identical to the amino acid sequence of SEQ ID NO:2 or SEQ ID NO:5. The term "sufficiently identical" or "substantially identical" is used herein to refer to a first amino acid or nucleotide sequence that contains a sufficient or minimum number of identical or equivalent (e.g., with a similar side chain) amino acid residues or nucleotides to a second amino acid or nucleotide sequence such that the first and second amino acid or nucleotide sequences have a common structural domain or common functional activity. For example, amino acid or nucleotide sequences that contain a common structural domain having at least about 60%, or 65% identity, likely 75% identity, more likely 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity are defined herein as sufficiently or substantially identical.

[0078] "Misexpression or aberrant expression", as used herein, refers to a non-wild type pattern of gene expression, at the RNA or protein level. It includes: expression at non-wild type levels, i.e., over- or under-expression; a pattern of expression that differs from wild type in terms of the time or stage at which the gene is expressed, e.g., increased or decreased expression (as compared with wild type) at a predetermined developmental period or stage; a pattern of expression that differs from wild type in terms of decreased expression (as compared with wild type) in a predetermined cell type or tissue type; a pattern of expression that differs from wild type in terms of the splicing size, amino acid sequence, post-transitional modification, or biological activity of the expressed polypeptide; a pattern of expression that differs from wild type in terms of the effect of an environmental stimulus or extracellular stimulus on expression of the gene, e.g., a pattern of increased or decreased expression (as compared with wild type) in the presence of an increase or decrease in the strength of the stimulus.

[0079] "Subject", as used herein, can refer to a mammal, e.g., a human, or to an experimental or animal or disease model. The subject can also be a non-human animal, e.g., a horse, cow, goat, or other domestic animal.

[0080] A "purified preparation of cells", as used herein, refers to, in the case of plant or animal cells, an in vitro preparation of cells and not an entire intact plant or animal. In the case of cultured cells or microbial cells, it consists of a preparation of at least 10% and more preferably 50% of the subject cells.

[0081] Various aspects of the invention are described in further detail below.

[0082] Isolated Nucleic Acid Molecules

[0083] In one aspect, the invention provides, an isolated or purified, nucleic acid molecule that encodes a 59079 or 12599 polypeptide described herein, e.g., a full length 59079 or 12599 protein or a fragment thereof, e.g., a biologically active portion of a 59079 or 12599 protein. Also included is a nucleic acid fragment suitable for use as a hybridization probe, which can be used, e.g., to identify a nucleic acid molecule encoding a polypeptide of the invention, 59079 or 12599 mRNA, and fragments suitable for use as primers, e.g., PCR primers for the amplification or mutation of nucleic acid molecules.

[0084] In one embodiment, an isolated nucleic acid molecule of the invention includes the nucleotide sequence shown in SEQ ID NO:1, or a portion or fragment thereof. In one embodiment, the nucleic acid molecule includes sequences encoding the human 59079 protein (i.e., "the coding region", from nucleotides 72 to 7964 of SEQ ID NO:1, including the termination codon, shown as in SEQ ID NO:3), as well as untranslated (e.g., noncoding) sequences, e.g., 5' untranslated sequence (i.e., nucleotides 1 to 71 of SEQ ID NO:1) and/or 3' untranslated sequence (i.e., nucleotides 7965 to 8106 of SEQ ID NO:1). Alternatively, the nucleic acid molecule can include only the coding region of SEQ ID NO:1 (e.g., nucleotides 1 to 7893 of SEQ ID NO:3) and, e.g., no flanking sequences which normally accompany the subject sequence. In another embodiment, the nucleic acid molecule encodes a sequence corresponding to the mature protein of SEQ ID NO:2. In yet another embodiment, the nucleic acid molecule encodes a sequence corresponding to a fragment of the protein from about amino acids 1130 to 1383 or from about amino acids 2334 to 2586 of SEQ ID NO:2.

[0085] In another embodiment, an isolated nucleic acid molecule of the invention includes the nucleotide sequence shown in SEQ ID NO:4, or a portion or fragment thereof. In one embodiment, the nucleic acid molecule includes sequences encoding the human 59079 protein (i.e., "the coding region", from nucleotides 72 to 23,978 of SEQ ID NO:4, including the termination codon, shown as in SEQ ID NO:3), as well as untranslated (e.g., noncoding) sequences, e.g., 5' untranslated sequence (i.e., nucleotides 1 to 71 of SEQ ID NO:4) and/or 3' untranslated sequence (i.e., nucleotides 23,979 to 24,120 of SEQ ID NO:4). Alternatively, the nucleic acid molecule can include only the coding region of SEQ ID NO:4 (e.g., nucleotides 1 to 23,907 of SEQ ID NO:6) and, e.g., no flanking sequences which normally accompany the subject sequence. In another embodiment, the nucleic acid molecule encodes a sequence corresponding to the mature protein of SEQ ID NO:5. In yet another embodiment, the nucleic acid molecule encodes a sequence corresponding to a fragment of the protein from about amino acids 6468 to 6721 or from about amino acids 7672 to 7924 of SEQ ID NO:5.

[0086] In another embodiment, an isolated nucleic acid molecule of the invention includes a nucleic acid molecule which is a complement of the nucleotide sequence shown in SEQ ID NOs:1, 3, 4, or 6, or a portion or fragment thereof. In other embodiments, the nucleic acid molecule of the invention is sufficiently complementary to the nucleotide sequence shown in SEQ ID NOs:1, 3, 4, or 6 such that it can hybridize to the nucleotide sequence shown in SEQ ID NO:1 or 3, thereby forming a stable duplex.

[0087] In one embodiment, an isolated nucleic acid molecule of the present invention includes a nucleotide sequence which is at least about: 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more, homologous to the entire length of the nucleotide sequence shown in SEQ ID NOs:1, 3, 4, or 6, or a portion or fragment thereof, preferably of the same length, of any of these nucleotide sequences.

[0088] 59079 Nucleic Acid Fragments

[0089] A nucleic acid molecule of the invention can include only a portion or fragment of the nucleic acid sequence of SEQ ID NO:1, 3, 4, or 6. For example, such a nucleic acid molecule can include a fragment which can be used as a probe or primer or a fragment encoding a portion of a 59079 or 12599 protein, e.g., an immunogenic or biologically active portion of a 59079 or 12599 protein. A fragment or portion can comprise those nucleotides of SEQ ID NO:1 or 4 which encode a protein kinase catalytic domain of human 59079 or 12599. The nucleotide sequences determined from the cloning of the 59079 gene allows for the generation of probes and primers designed for use in identifying and/or cloning other 59079 family members, e.g., 12599, or fragments thereof, as well as 59079 homologues, or fragments thereof, from other species.

[0090] In another embodiment, a nucleic acid includes a nucleotide sequence that includes part, or all, of the coding region and extends into either (or both) the 5' or 3' noncoding or untranslated region. Other embodiments include a fragment which includes a nucleotide sequence encoding an amino acid fragment described herein. Nucleic acid fragments can encode a specific domain or site described herein or fragments thereof, particularly fragments thereof which are at least 75 amino acids in length. Fragments also include nucleic acid sequences corresponding to specific amino acid sequences described above or fragments thereof. Nucleic acid fragments should not to be construed as encompassing those fragments that may have been disclosed prior to the invention.

[0091] A nucleic acid fragment can include a sequence corresponding to a domain, region, or functional site described herein. A nucleic acid fragment can also include one or more domain, region, or functional site described herein. Thus, for example, a 59079 nucleic acid fragment can include a sequence corresponding to a protein kinase catalytic domain.

[0092] 59079 and 12599 probes and primers are provided. Typically a probe/primer is an isolated or purified oligonucleotide. The oligonucleotide typically includes a region of nucleotide sequence that hybridizes under stringent conditions to at least about 7, 12 or 15, preferably about 20 or 25, more preferably about 30, 35, 40, 45, 50, 55, 60, 65, or 75 consecutive nucleotides of a sense or antisense sequence of SEQ ID NOs:1, 3, 4, or 6, or of a naturally occurring allelic variant or mutant of SEQ ID NOs:1, 3, 4, or 6.

[0093] In a preferred embodiment the nucleic acid is a probe which is at least 5 or 10, and less than 200, more preferably less than 100, or less than 50, base pairs in length. It should be identical, or differ by 1, or less than in 5 or 10 bases, from a sequence disclosed herein. If alignment is needed for this comparison the sequences should be aligned for maximum homology. "Looped" out sequences from deletions or insertions, or mismatches, are considered differences.

[0094] A probe or primer can be derived from the sense or anti-sense strand of a nucleic acid which encodes a protein kinase catalytic domain (e.g., the nucleotides encoding amino acid residues 1130 to 1383 or 2334 to 2586 of SEQ ID NO:2, and the nucleotides encoding amino acid residues 6468 to 6721 or 7672 to 7924 of SEQ ID NO:5) or a pleckstrin homology domain (e.g., the nucleotides encoding amino acid residues 558 to 666 of SEQ ID NO:2, or the nucleotides encoding amino acid residues 5896 to 6004 of SE ID NO:5), or a fragment thereof.

[0095] In another embodiment, a set of primers is provided, e.g., primers suitable for use in a PCR, which can be used to amplify a selected region of a 59079 orm12599 sequence, e.g., a domain, region, site or other sequence described herein. The primers should be at least 5, 10, or 50 base pairs in length and less than 100, or less than 200, base pairs in length. The primers should be identical, or differs by one base from a sequence disclosed herein or from a naturally occurring variant. For example, primers suitable for amplifying all or a portion of any of the following regions are provided: protein kinase catalytic domain from about amino acids 1130 to 1383 or 2334 to 2586 of SEQ ID NO:2, or from about amino acids 6468 to 6721 or 7672 to 7924 of SEQ ID NO:5, and a pleckstrin homology domain from about amino acids 558 to 666 of SEQ ID NO:2, or from about amino acids 5896 to 6004 of SEQ ID NO:5.

[0096] A nucleic acid fragment can encode an epitope bearing region of a polypeptide described herein.

[0097] A nucleic acid fragment encoding a "biologically active portion of a 59079 or a 12599 polypeptide" can be prepared by isolating a portion of the nucleotide sequence of SEQ ID NO:1, 3, 4, or 6 which encodes a polypeptide having a 59079 or 12599 biological activity (e.g., any of the biological activities of the 59079 and 12599 proteins described herein), expressing the encoded portion of the 59079 or 12599 protein (e.g., by recombinant expression in vitro) and assessing the activity of the encoded portion of the 59079 or 12599 protein. For example, a nucleic acid fragment encoding a biologically active portion of 59079 or 12599 includes a protein kinase catalytic domain, e.g., amino acid residues from about 1130 to 1383 or 2334 to 2586 of SEQ ID NO:2, or amino acid residues from about 6468 to 6721 or 7672 to 7924 of SEQ ID NO:5. A nucleic acid fragment encoding a biologically active portion of a 59079 or 12599 polypeptide, may comprise a nucleotide sequence which is greater than 700 or more nucleotides in length.

[0098] In preferred embodiments, a nucleic acid includes a nucleotide sequence which is about 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 2000, 3000, 4000, 5000, 5500, 6000, 6500, 7000, 12,000, 15,000, 18,000, 20,000, 21,000, 22,000, 23,000, 24,000, or more, nucleotides in length and hybridizes under stringent hybridization conditions to a nucleic acid molecule of SEQ ID NO:1, 3, 4, or 6, or a complement thereof.

[0099] 59079 and 12599 Nucleic Acid Variants

[0100] The invention further encompasses nucleic acid molecules that differ from the nucleotide sequence shown in SEQ ID NOs:1, 3, 4, or 6. Such differences can be due to degeneracy of the genetic code and result in a nucleic acid which encodes the same 59079 proteins as those encoded by the nucleotide sequence disclosed herein. In another embodiment, an isolated nucleic acid molecule of the invention has a nucleotide sequence encoding a protein having an amino acid sequence which differs, by at least 1, but less than 10, 50, 75, 100, 200, 400, or 500 amino acid residues shown in SEQ ID NO:2, or by at least 1, but less than 100, 200, 300, 400, 500, 700, 1000, 1200, or 1500 amino acid residues shown in SEQ ID NO:5. If alignment is needed for this comparison, the sequences should be aligned for maximum homology. "Looped" out sequences from deletions or insertions, or mismatches, are considered differences.

[0101] Nucleic acids of the inventor can be chosen for having codons which are preferred or non-preferred for a particular expression system. For example, the nucleic acid can be one in which at least one codon, preferably at least 10% or 20% of the codons, has been altered such that the sequence is optimized for expression in bacterial (e.g., E. coli), yeast, human, insect, or nonhuman mammalian (e.g., CHO) cells.

[0102] Nucleic acid variants can be naturally occurring, such as allelic variants (same locus), homologs (different locus), and orthologs (different organism) or can be non-naturally occurring. Non-naturally occurring variants can be made by mutagenesis techniques, including those applied to polynucleotides, cells, or organisms. The variants can contain nucleotide substitutions, deletions, inversions and insertions. Variation can occur in either or both the coding and non-coding regions. The variations can produce both conservative and non-conservative amino acid substitutions (as compared in the encoded product).

[0103] In a preferred embodiment, the nucleic acid differs from that of SEQ ID NO:1, 3, 4, or 6, e.g., as follows: by at least one but less than 10, 20, 30, or 40 nucleotides; at least one, but less than 1%, 5%, 10% or 20%, of the nucleotides in the subject nucleic acid. If necessary for this analysis the sequences should be aligned for maximum homology. "Looped" out sequences from deletions or insertions, or mismatches, are considered differences.

[0104] Orthologs, homologs, and allelic variants can be identified using methods known in the art. These variants comprise a nucleotide sequence encoding a polypeptide that is 50%, at least about 55%, typically at least about 70-75%, more typically at least about 80-85%, and most typically at least about 90-95% or more, identical to the nucleotide sequence shown in SEQ ID NO:2, or a fragment of this sequence. Such nucleic acid molecules can readily be identified as being able to hybridize under stringent conditions to the nucleotide sequence shown in SEQ ID NO:2 or 5, or a fragment of the sequence. Nucleic acid molecules corresponding to orthologs, homologs, and allelic variants of the 59079 and 12599 cDNAs of the invention can further be isolated by mapping to the same chromosome or locus as the 59079 or 12599 genes.

[0105] Preferred variants include those that are correlated with at least one of the following 59079 and 12599 biological activities: (1) the ability to act as a protein kinase; (2) the ability to activate a protein kinase activity; (3) the ability to regulate transmission of signals from cellular receptors, e.g., cell growth factor receptors; (4) the ability to modulate the entry of cells, e.g., precursor cells, into mitosis; (5) the ability to modulate cellular differentiation; (6) the ability to modulate cell death; and (7) the ability to regulate cytoskeleton function, e.g., actin bundling.

[0106] Allelic variants of 59079 and 12599, e.g., human 59079 and human 12599, include both functional and non-functional proteins. Functional allelic variants are naturally occurring amino acid sequence variants of the 59079 or 12599 proteins within a population that maintain at least one of the 59079 or 12599 biological activities described herein.

[0107] Functional allelic variants will typically contain only conservative substitution of one or more amino acids of SEQ ID NO:2 or 5, or substitution, deletion or insertion of non-critical residues in non-critical regions of the protein. Non-functional allelic variants are naturally occurring amino acid sequence variants of the 59079 or 12599, e.g., human 59079, protein within a population that do not have any of the 59079 biological activities described herein. Non-functional allelic variants can typically contain a non-conservative substitution, a deletion, or insertion, or premature truncation of the amino acid sequence of SEQ ID NO:2 or 5, or a substitution, insertion, or deletion in critical residues or critical regions of the protein.

[0108] Moreover, nucleic acid molecules encoding other 59079 and 12599 family members, and, thus, which have a nucleotide sequence which differs from the 59079 sequences of SEQ ID NOs:1, 3, 4, or 6 are intended to be within the scope of the invention.

[0109] Antisense Nucleic Acid Molecules, Ribozymes and Modified 59079 Nucleic Acid Molecules

[0110] In another aspect, the invention features, an isolated nucleic acid molecule which is antisense to 59079 or 12599. An "antisense" nucleic acid can include a nucleotide sequence which is complementary to a "sense" nucleic acid encoding a protein, e.g., complementary to the coding strand of a double-stranded cDNA molecule or complementary to an mRNA sequence. The antisense nucleic acid can be complementary to an entire 59079 or 12599 coding strand, or to only a portion thereof (e.g., the coding region of human 59079 corresponding to SEQ ID NO:3, or the coding region of human 12599 corresponding to SEQ ID NO:5). In another embodiment, the antisense nucleic acid molecule is antisense to a "noncoding region" of the coding strand of a nucleotide sequence encoding 59079 or 12599 (e.g., the 5' and 3' untranslated regions).

[0111] An antisense nucleic acid can be designed such that it is complementary to the entire coding region of 59079 or 12599 mRNA, but more preferably is an oligonucleotide which is antisense to only a portion of the coding or noncoding region of 59079 or 12599 mRNA. For example, the antisense oligonucleotide can be complementary to the region surrounding the translation start site of 59079 or 12599 mRNA, e.g., between the -10 and +10 regions of the target gene nucleotide sequence of interest. An antisense oligonucleotide can be, for example, about 7, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, or more nucleotides in length.

[0112] 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. The antisense nucleic acid also can be produced biologically using an expression vector into which a nucleic acid has been subcloned 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).

[0113] The antisense nucleic acid molecules of the invention are typically administered to a subject (e.g., by direct injection at a tissue site), or generated in situ such that they hybridize with or bind to cellular mRNA and/or genomic DNA encoding a 59079 or 12599 protein to thereby inhibit expression of the protein, e.g., by inhibiting transcription and/or translation. Alternatively, antisense nucleic acid molecules can be modified to target selected cells and then administered systemically. 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.

[0114] In yet another embodiment, the antisense nucleic acid molecule of the invention is 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 .beta.-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).

[0115] In still another embodiment, an antisense nucleic acid of the invention is a ribozyme. A ribozyme having specificity for a 59079- or 12599-encoding nucleic acid can include one or more sequences complementary to the nucleotide sequence of a 59079 or 12599 cDNA disclosed herein (i.e., SEQ ID NOs:1, 3, 4, or 6), and a sequence having known catalytic sequence responsible for mRNA cleavage (see U.S. Pat. No. 5,093,246 or Haselhoff and Gerlach (1988) Nature 334:585-591). 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 in a 59079-encoding mRNA. See, e.g., Cech et al. U.S. Pat. No. 4,987,071; and Cech et al. U.S. Pat. No. 5,116,742. Alternatively, 59079 mRNA can be used to select a catalytic RNA having a specific ribonuclease activity from a pool of RNA molecules. See, e.g., Bartel, D. and Szostak, J. W. (1993) Science 261:1411-1418.

[0116] 59079 and 12599 gene expression can be inhibited by targeting nucleotide sequences complementary to the regulatory region of 59079 or 12599 (e.g., the 59079 or 12599 promoter and/or enhancers) to form triple helical structures that prevent transcription of the 59079 gene in target cells. See generally, Helene, C. (1991) Anticancer Drug Des. 6:569-84; Helene, C. i (1992) Ann. N.Y. Acad. Sci. 660:27-36; and Maher, L. J. (1992) Bioassays 14:807-15. The potential sequences that can be targeted for triple helix formation can be increased by creating a so called "switchback" nucleic acid molecule. Switchback molecules are synthesized in an alternating 5'-3',3'-5' manner, such that they base pair with first one strand of a duplex and then the other, eliminating the necessity for a sizeable stretch of either purines or pyrimidines to be present on one strand of a duplex.

[0117] The invention also provides detectably labeled oligonucleotide primer and probe molecules. Typically, such labels are chemiluminescent, fluorescent, radioactive, or colorimetric.

[0118] A 59079 or 12599 nucleic acid molecule 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 acid molecules can be modified to generate peptide nucleic acids (see Hyrup B. et al. (1996) Bioorganic & Medicinal Chemistry 4: 5-23). As used herein, the terms "peptide nucleic acid" or "PNA" refers to a nucleic acid mimic, e.g., a DNA mimic, in which the deoxyribose phosphate backbone is replaced by a pseudopeptide backbone and only the four natural nucleobases are retained. The neutral backbone of a PNA can 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 B. et al. (1996) supra; Perry-O'Keefe et al. Proc. Natl. Acad. Sci. 93: 14670-675.

[0119] PNAs of 59079 and 12599 nucleic acid molecules 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, for example, inducing transcription or translation arrest or inhibiting replication. PNAs of 59079 and 12599 nucleic acid molecules can also be used in the analysis of single base pair mutations in a gene, (e.g., by PNA-directed PCR clamping); as `artificial restriction enzymes` when used in combination with other enzymes, (e.g., S1 nucleases (Hyrup B. et al. (1996) supra)); or as probes or primers for DNA sequencing or hybridization (Hyrup B. et al. (1996) supra; Perry-O'Keefe supra).

[0120] In other embodiments, the oligonucleotide may 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. WO88/09810) or the blood-brain barrier (see, e.g., PCT Publication No. WO89/10134). 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 may be conjugated to another molecule, (e.g., a peptide, hybridization triggered cross-linking agent, transport agent, or hybridization-triggered cleavage agent).

[0121] The invention also includes molecular beacon oligonucleotide primer and probe molecules having at least one region which is complementary to a 59079 or 12599 nucleic acid of the invention, two complementary regions one having a fluorophore and one a quencher such that the molecular beacon is useful for quantitating the presence of the 59079 or 12599 nucleic acid of the invention in a sample. Molecular beacon nucleic acids are described, for example, in Lizardi et al., U.S. Pat. No. 5,854,033; Nazarenko et al., U.S. Pat. No. 5,866,336, and Livak et al., U.S. Pat. No. 5,876,930.

[0122] Isolated 59079 Polypeptides

[0123] In another aspect, the invention features, isolated 59079 and 12599 proteins, or a fragment, e.g., a biologically active portion, for use as immunogens or antigens to raise or test (or more generally to bind) anti-59079 and anti-12599 antibodies. 59079 and 12599 proteins can be isolated from cells or tissue sources using standard protein purification techniques. 59079 and 12599 proteins, or fragments thereof, can be produced by recombinant DNA techniques or synthesized chemically.

[0124] Polypeptides of the invention include those which arise as a result of the existence of multiple genes, alternative transcription events, alternative RNA splicing events, and alternative translational and post-translational events. The polypeptide can be expressed in systems, e.g., cultured cells, which result in substantially the same post-translational modifications present when expressed the polypeptide is expressed in a native cell, or in systems which result in the alteration or omission of post-translational modifications, e.g., glycosylation or cleavage, present when expressed in a native cell.

[0125] In a preferred embodiment, a 59079 and a 12599 polypeptide each has one or more of the following characteristics:

[0126] the ability to act as a protein kinase, activate a protein kinase activity, act as a substrate for a protein kinase or perform any of the 59079 or 12599 biological activities described herein;

[0127] a molecular weight, e.g., a deduced molecular weight, amino acid composition or other physical characteristic of the polypeptide of SEQ ID NO:2 or 5;

[0128] an overall sequence similarity of at least 50%, preferably at least 60%, more preferably at least 70, 80, 90, 95%, 96%, 97%, or 98%, with a polypeptide of SEQ ID NO:2 or 5; and

[0129] a protein kinase catalytic domain which preferably has an overall sequence similarity of about 70%, 80%, 90% or 95% with amino acid residues 1130 to 1383 or 2334 to 2586 of SEQ ID NO:2 or amino acid residues 6468 to 6721 or 7672 to 7924 of SEQ ID NO:5; and

[0130] In a preferred embodiment, the 59079 and 12599 proteins, or a fragment thereof, differs from the corresponding sequence in SEQ ID NO:2 or 5. In one embodiment it differs by at least one, but by less than 15, 10 or 5, amino acid residues. In another it differs from the corresponding sequence in SEQ ID NO:2 or 5 by at least one residue, but less than 20%, 15%, 10% or 5%, of the residues in it differ from the corresponding sequence in SEQ ID NO:2 or 5. (If this comparison requires alignment the sequences should be aligned for maximum homology. "Looped" out sequences from deletions or insertions, or mismatches, are considered differences.) The differences are, preferably, differences or changes at a nonessential residue or a conservative substitution. In a preferred embodiment the differences are not in the protein kinase catalytic domain. In another preferred embodiment one or more differences are in the protein kinase catalytic domain.

[0131] Other embodiments include a protein that contain one or more changes in amino acid sequence, e.g., a change in an amino acid residue which is not essential for activity. Such 59079 and 12599 proteins differ in amino acid sequence from SEQ ID NO:2 and 5, yet retain biological activity.

[0132] In one embodiment, the protein includes an amino acid sequence at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or more, homologous to SEQ ID NO:2 or 5.

[0133] A 59079 protein or fragment is provided which varies from the sequences of SEQ ID NO.2 in regions defined by amino acids from about 1 to 1129, 1384 to 2333, or 2587 to 2630 by at least one, but by less than 50, 15, 10 or 5, amino acid residues in the protein or fragment, but which does not differ from SEQ ID NO.2 in a region defined by amino acids about 1130 to 1383 or 2334 to 2586. A 12599 protein or fragment is provided which varies from the sequence of SEQ ID NO:5 in regions defined by amino acids from about 1 to 6467, 6722 to 7671, or 7925 to 7968 by least one, but by less than 50, 15, 10, or 5, amino acid residues in the protein or fragment, but which does not differ from SEQ ID NO:5 in a region defind by amino acids at about 6468 to 6721 or 7672 to 7924 of SEQ ID NO:5. (If this comparison requires alignment the sequences should be aligned for maximum homology. "Looped" out sequences from deletions or insertions, or mismatches, are considered differences.) In some embodiments the difference is at a non essential residue or is a conservative substitution, while in others the difference is at an essential residue or is a non conservative substitution.

[0134] In one embodiment, a biologically active portion of a 59079 or 12599 protein includes a protein kinase catalytic domain. Moreover, other biologically active portions, in which other regions of the protein are deleted, can be prepared by recombinant techniques and evaluated for one or more of the functional activities of a native 59079 or 12599 protein.

[0135] In a preferred embodiment, the 59079 protein has an amino acid sequence shown in SEQ ID NO:2. In other embodiments, the 59079 protein is substantially identical to SEQ ID NO:2. In yet another embodiment, the 59079 protein is substantially identical to SEQ ID NO:2 and retains the functional activity of the protein of SEQ ID NO:2, as described herein.

[0136] In a preferred embodiment, the 12599 protein has an amino acid sequence shown in SEQ ID NO:5. In other embodiments, the 12599 protein is substantially identical to SEQ ID NO:5. In yet another embodiment, the 12599 protein is substantially identical to SEQ ID NO:5 and retains the functional activity of the protein of SEQ ID NO:5, as described herein.

[0137] 59079 and 12599 Chimeric or Fusion Proteins

[0138] In another aspect, the invention provides 59079 and 12599 chimeric or fusion proteins. As used herein, a 59079 or 12599 "chimeric protein" or "fusion protein" includes a 59079 or 12599 polypeptide linked to a non-59079 or non-12599 polypeptide. A "non-59079 polypeptide" or a "non-12599 polypeptide" refers to a polypeptide having an amino acid sequence corresponding to a protein which is not substantially homologous to the 59079 or 12599 protein, e.g., a protein which is different from the 59079 or 12599 protein and which is derived from the same or a different organism. The 59079 or 12599 polypeptide of the fusion protein can correspond to all or a portion, e.g., a fragment, described herein of a 59079 or 12599 amino acid sequence. In a preferred embodiment, a 59079 fusion protein includes at least one (or two) biologically active portion of a 59079 protein. In another preferred embodiment, a 12599 fusion protein includes at least one (or two) biologically active portion of a 12599 protein. The non-59079 and non-12599 polypeptides can be fused to the N-terminus or C-terminus of the 59079 or 12599 polypeptide.

[0139] The fusion protein can include a moiety which has a high affinity for a ligand. For example, the fusion protein can be a GST-59079 or -12599 fusion protein in which the 59079 or 12599 sequences are fused to the C-terminus of the GST sequences. Such fusion proteins can facilitate the purification of recombinant 59079 or 12599. Alternatively, the fusion protein can be a 59079 or 12599 protein containing a heterologous signal sequence at its N-terminus. In certain host cells (e.g., mammalian host cells), expression and/or secretion of 59079 or 12599 can be increased through use of a heterologous signal sequence.

[0140] Fusion proteins can include all or a part of a serum protein, e.g., a portion of an immunoglobulin (e.g., IgG, IgA, or IgE), e.g., an Fc region and/or the hinge C1 and C2 sequences of an immunoglobulin or human serum albumin.

[0141] The 59079 and 12599 fusion proteins of the invention can be incorporated into pharmaceutical compositions and administered to a subject in vivo. The 59079 or 12599 fusion proteins can be used to affect the bioavailability of a 59079 or 12599 substrate. 59079 and 12599 fusion proteins can be used therapeutically for the treatment of disorders caused by, for example, (i) aberrant modification or mutation of a gene encoding a 59079 or 12599 protein; (ii) mis-regulation of the 59079 or 12599 gene; and (iii) aberrant post-translational modification of a 59079 or 12599 protein.

[0142] Moreover, the 59079 and 12599 fusion proteins of the invention can be used as immunogens to produce anti-59079 or anti-12599 antibodies in a subject, to purify 59079 or 12599 ligands and in screening assays to identify molecules which inhibit the interaction of 59079 with a 59079 substrate or the interaction of 12599 with a 12599 substrate.

[0143] Expression vectors are commercially available that already encode a fusion moiety (e.g., a GST polypeptide). A 59079-encoding nucleic acid can be cloned into such an expression vector such that the fusion moiety is linked in-frame to the 59079 protein.

[0144] Variants of 59079 and 12599 Proteins

[0145] In another aspect, the invention also features a variant of a 59079 and 12599 polypeptide, e.g., which functions as an agonist (mimetics) or as an antagonist. Variants of the 59079 and 12599 proteins can be generated by mutagenesis, e.g., discrete point mutation, the insertion or deletion of sequences or the truncation of a 59079 or 12599 protein. An agonist of the 59079 or 12599 proteins can retain substantially the same, or a subset, of the biological activities of the naturally occurring form of a 59079 or 12599 protein. An antagonist of a 59079 or 12599 protein can inhibit one or more of the activities of the naturally occurring form of the 59079 or 12599 protein by, for example, competitively modulating a 59079- or 12599-mediated activity of a 59079 or 12599 protein. Thus, specific biological effects can be elicited by treatment with a variant of limited function. Preferably, treatment of a subject with a variant having a subset of the biological activities of the naturally occurring form of the protein has fewer side effects in a subject relative to treatment with the naturally occurring form of the 59079 or 12599 protein.

[0146] Variants of a 59079 or 12599 protein can be identified by screening combinatorial libraries of mutants, e.g., truncation mutants, of a 59079 or 12599 protein for agonist or antagonist activity.

[0147] Libraries of fragments, e.g., N terminal, C terminal, or internal fragments, of a 59079 protein coding sequence can be used to generate a variegated population of fragments for screening and subsequent selection of variants of a 59079 or 12599 protein.

[0148] Variants in which a cysteine residues is added or deleted or in which a residue which is glycosylated is added or deleted are particularly preferred.

[0149] Methods 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. Recursive ensemble mutagenesis (REM), a new technique which enhances the frequency of functional mutants in the libraries, can be used in combination with the screening assays to identify 59079 and 12599 variants (Arkin and Yourvan (1992) Proc. Natl. Acad. Sci. USA 89:7811-7815; Delgrave et al. (1993) Protein Engineering 6:327-331).

[0150] Cell based assays can be exploited to analyze a variegated 59079 library. For example, a library of expression vectors can be transfected into a cell line, e.g., an endothelial cell line, which ordinarily responds to 59079 or 12599 in a particular 59079 or 12599 substrate-dependent manner. The transfected cells are then contacted with 59079 or 12599 and the effect of expression of the mutant on signaling by the 59079 or 12599 substrate can be detected, e.g., by monitoring intracellular calcium, IP3, or diacylglycerol concentration, phosphorylation profile of intracellular proteins, or the activity of an 59079- or 12599-regulated transcription factor. Plasmid DNA can then be recovered from the cells which score for inhibition, or alternatively, potentiation of signaling by the HST-1 substrate, and the individual clones further characterized.

[0151] In another aspect, the invention features a method of making a 59079 or 12599 polypeptide, e.g., a peptide having a non-wild type activity, e.g., an antagonist, agonist, or super agonist of a naturally occurring 59079 or 12599 polypeptide, e.g., a naturally occurring 59079 or 12599 polypeptide. The method includes: altering the sequence of a 59079 polypeptide, e.g., altering the sequence, e.g., by substitution or deletion of one or more residues of a non-conserved region, a domain or residue disclosed herein, and testing the altered polypeptide for the desired activity.

[0152] In another aspect, the invention features a method of making a fragment or analog of a 59079 or 12599 polypeptide a biological activity of a naturally occurring 59079 or 12599 polypeptide. The method includes: altering the sequence, e.g., by substitution or deletion of one or more residues, of a 59079 or 12599 polypeptide, e.g., altering the sequence of a non-conserved region, or a domain or residue described herein, and testing the altered polypeptide for the desired activity.

[0153] Anti-59079 and Andti-12599 Antibodies

[0154] In another aspect, the invention provides an anti-59079 and anti-12599 antibodies. The term "antibody" as used herein refers to an immunoglobulin molecule and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain an antigen binding site which specifically binds (immunoreacts with) an antigen, such as a 59079 or 12599 molecule. Examples of immunologically active portions of immunoglobulin molecules include scFV and dcFV fragments, Fab and F(ab').sub.2 fragments which can be generated by treating the antibody with an enzyme such as papain or pepsin, respectively.

[0155] The antibody can be a polyclonal, monoclonal, recombinant, e.g., a chimeric, humanized, fully human, non-human (e.g., murine, rat, rabbit, or goat), or single chain antibody. In a preferred embodiment it has effector function and can fix complement. The antibody can be coupled to a toxin or imaging agent.

[0156] 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 of 59079 or 12599. A monoclonal antibody composition thus typically displays a single binding affinity for a particular 59079 or 12599 protein with which it immunoreacts.

[0157] Polyclonal anti-59079 and anti-12599 antibodies can be prepared as described above by immunizing a suitable subject with a 59079 or 12599 immunogen. The specific 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 59079 or 12599. If desired, the antibody molecules directed against 59079 or 12599 can be isolated from the mammal (e.g., from the blood) and further purified by well known techniques, such as protein A chromatography to obtain the IgG fraction. At an appropriate time after immunization, e.g., when the anti-59079 or anti-12599 antibody titers are highest, antibody-producing cells can be obtained from the subject and used to prepare monoclonal antibodies by standard techniques, such as the hybridoma technique originally described by Kohler and Milstein (1975) Nature 256:495-497) (see also, Brown et al. (1981) J. Immunol. 127:539-46; Brown et al. (1980) J. Biol. Chem 255:4980-83; Yeh et al. (1976) Proc. Natl. Acad. Sci. USA 76:2927-31; and Yeh et al. (1982) Int. J. Cancer 29:269-75), the more recent human B cell hybridoma technique (Kozbor et al. (1983) Immunol Today 4:72), the EBV-hybridoma technique (Cole et al. (1985), Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc., pp. 77-96) or trioma techniques. The technology for producing monoclonal antibody hybridomas is well known (see generally R. H. Kenneth, in Monoclonal Antibodies: A New Dimension In Biological Analyses, Plenum Publishing Corp., New York, N.Y. (1980); E. A. Lerner (1981) Yale J. Biol. Med., 54:387-402; M. L. Gefter et al. (1977) Somatic Cell Genet. 3:231-36). Briefly, an immortal cell line (typically a myeloma) is fused to lymphocytes (typically splenocytes) from a mammal immunized with a 59079 immunogen as described above, and the culture supernatants of the resulting hybridoma cells are screened to identify a hybridoma producing a monoclonal antibody that binds 59079.

[0158] Any of the many well known protocols used for fusing lymphocytes and immortalized cell lines can be applied for the purpose of generating an anti-59079 monoclonal antibody (see, e.g., G. Galfre et al. (1977) Nature 266:55052; Gefter et al. Somatic Cell Genet., cited supra; Lerner, Yale J. Biol. Med., cited supra; Kenneth, Monoclonal Antibodies, cited supra). Moreover, the ordinarily skilled worker will appreciate that there are many variations of such methods which also would be useful. Typically, the immortal cell line (e.g., a myeloma cell line) is derived from the same mammalian species as the lymphocytes. For example, murine hybridomas can be made by fusing lymphocytes from a mouse immunized with an immunogenic preparation of the present invention with an immortalized mouse cell line. Preferred immortal cell lines are mouse myeloma cell lines that are sensitive to culture medium containing hypoxanthine, aminopterin and thymidine ("HAT medium"). Any of a number of myeloma cell lines can be used as a fusion partner according to standard techniques, e.g., the P3-NS1/1-Ag4-1, P3-x63-Ag8.653 or Sp2/O-Ag14 myeloma lines. These myeloma lines are available from ATCC. Typically, HAT-sensitive mouse myeloma cells are fused to mouse splenocytes using polyethylene glycol ("PEG"). Hybridoma cells resulting from the fusion are then selected using HAT medium, which kills unfused and unproductively fused myeloma cells (unfused splenocytes die after several days because they are not transformed). Hybridoma cells producing a monoclonal antibody of the invention are detected by screening the hybridoma culture supernatants for antibodies that bind 59079, e.g., using a standard ELISA assay.

[0159] Alternative to preparing monoclonal antibody-secreting hybridomas, a monoclonal anti-59079 or anti-12599 antibody can be identified and isolated by screening a recombinant combinatorial immunoglobulin library (e.g., an antibody phage display library) with 59079 or 12599 to thereby isolate immunoglobulin library members that bind 59079 or 12599. 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.TM. 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, Ladner et al. U.S. Pat. No. 5,223,409; Kang et al. PCT International Publication No. WO 92/18619; Dower et al. PCT International Publication No. WO 91/17271; Winter et al. PCT International Publication WO 92/20791; Markland et al. PCT International Publication No. WO 92/15679; Breitling et al. PCT International Publication WO 93/01288; McCafferty et al. PCT International Publication No. WO 92/01047; Garrard et al. PCT International Publication No. WO 92/09690; Ladner et al. PCT International 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; Hawkins et al. (1992) J. Mol. Biol. 226:889-896; Clarkson et al. (1991) Nature 352:624-628; Gram et al. (1992) Proc. Natl. Acad. Sci. USA 89:3576-3580; Garrad et al. (1991) Bio/Technology 9:1373-1377; Hoogenboom et al. (1991) Nuc. Acid Res. 19:4133-4137; Barbas et al. (1991) Proc. Natl. Acad. Sci. USA 88:7978-7982; and McCafferty et al. Nature (1990) 348:552-554.

[0160] Additionally, chimeric, humanized, and completely human antibodies are also within the scope of the invention. Chimeric, humanized, but most preferably, completely human antibodies are desirable for applications which include repeated administration, e.g., therapeutic treatment of human patients, and some diagnostic applications.

[0161] Chimeric and humanized monoclonal antibodies, comprising both human and non-human portions, can be made using standard recombinant DNA techniques. Such chimeric and humanized monoclonal antibodies can be produced by recombinant DNA techniques known in the art, for example using methods described in Robinson et al. International Application No. PCT/US86/02269; Akira, et al. European Patent Application 184,187; Taniguchi, M., European Patent Application 171,496; Morrison et al. European Patent Application 173,494; Neuberger et al. PCT International Publication No. WO 86/01533; Cabilly et al. U.S. Pat. No. 4,816,567; Cabilly et al. 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) Canc. 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, S. L. (1985) Science 229:1202-1207; Oi et al. (1986) BioTechniques 4:214; Winter 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.

[0162] Completely human antibodies are particularly desirable for therapeutic treatment of human patients. Such antibodies can be produced using transgenic mice that are incapable of expressing endogenous immunoglobulin heavy and light chains genes, but which can express human heavy and light chain genes. See, for example, Lonberg and Huszar (1995) Int. Rev. Immunol. 13:65-93); and U.S. Pat. Nos. 5,625,126; 5,633,425; 5,569,825; 5,661,016; and 5,545,806. In addition, companies such as Abgenix, Inc. (Fremont, Calif.) and Medarex, Inc. (Princeton, N.J.), can be engaged to provide human antibodies directed against a selected antigen using technology similar to that described above.

[0163] Completely human antibodies that 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. This technology is described by Jespers et al. (1994) Bio/Technology 12:899-903).

[0164] A full-length 59079 or 12599 protein, or an antigenic peptide fragment of 59079 or 12599, can be used as an immunogen or can be used to identify anti-59079 or anti-12599 antibodies made with other immunogens, e.g., cells, membrane preparations, and the like. The antigenic peptides of 59079 should include at least 8 amino acid residues of the amino acid sequence shown in SEQ ID NO:2 and encompass an epitope of 59079, respectively. The antigenic peptides of 12599 should include at least 8 amino acid residues of the amino acid sequence shown in SEQ ID NO:5 and encompass an epitope of 12599, respectively. Preferably, the antigenic peptide includes at least 10 amino acid residues, more preferably at least 15 amino acid residues, even more preferably at least 20 amino acid residues, and most preferably at least 30 amino acid residues.

[0165] Fragments of 59079 which include, e.g., residues 1130 to 1383 or 2334 to 2586 of SEQ ID NO:2, can be used as immunogens to make an antibody against the protein kinase catalytic domain of the 59079 protein.

[0166] Fragments of 12599 which include, e.g., residues 6468 to 6721 or 7672 to 7924 of SEQ ID NO:5, can be used as immunogens to make an antibody against the protein kinase catalytic domain of the 12599 protein.

[0167] Antibodies reactive with, or specific or selective for, any of these regions, or other regions or domains described herein are provided.

[0168] In an alternative embodiment, the antibody fails to bind to an Fc receptor, e.g., it is a type which does not support Fc receptor binding or has been modified, e.g., by deletion or other mutation, such that is does not have a functional Fc receptor binding region.

[0169] Preferred epitopes encompassed by the antigenic peptide are regions of 59079 and 12599 which are located on the surface of the protein, e.g., hydrophilic regions, as well as regions with high antigenicity. For example, an Emini surface probability analysis of the human 59079 and 12599 protein sequences can be used to identify the regions that have a particularly high probability of being localized to the surface of the 59079 or 12599 protein, and are thus likely to constitute surface residues useful for targeting antibody production.

[0170] In a preferred embodiment the antibody binds an epitope on any domain or region on 59079 proteins described herein.

[0171] In another preferred embodiment, the antibody binds an epitope on any domain or region on 12599 proteins described herein.

[0172] The anti-59079 or anti-12599 antibody can be a single chain antibody. A single-chain antibody (scFV) may be engineered as described, for example, in Colcher, D. et al., (1999) Ann. NY Acad. Sci. 880: 263-80; and Reiter, Y., Clin. Cancer Res. 1996 February; 2(2):245-52. The single chain antibody can be dimerized or multimerized to generate multivalent antibodies having specificities for different epitopes of the same target 59079 protein.

[0173] Anti-59079 and anti-12599 antibodies (e.g., monoclonal antibodies) can be used to isolate 59079 or 12599, respectively, by standard techniques, such as affinity chromatography or immunoprecipitation. Moreover, an anti-59079 or anti-12599 antibody can be used to detect 59079 or 12599 protein, respectively, (e.g., in a cellular lysate or cell supernatant) in order to evaluate the abundance and pattern of expression of the protein. Anti-59079 and anti-12599 antibodies can be used diagnostically to monitor protein levels in tissue 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 coupling (i.e., physically linking) the antibody to a detectable substance (i.e., antibody labeling). 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.

[0174] Recombinant Expression Vectors, Host Cells and Genetically Engineered Cells

[0175] In another aspect, the invention includes, vectors, preferably expression vectors, containing a nucleic acid encoding a polypeptide described herein. As used herein, the term "vector" refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked and can include a plasmid, cosmid or viral vector. The vector can be capable of autonomous replication or it can integrate into a host DNA. Viral vectors include, e.g., replication defective retroviruses, adenoviruses and adeno-associated viruses.

[0176] A vector can include a 59079 or 12599 nucleic acid in a form suitable for expression of the nucleic acid in a host cell. Preferably the recombinant expression vector includes one or more regulatory sequences operatively linked to the nucleic acid sequence to be expressed. The term "regulatory sequence" includes promoters, enhancers and other expression control elements (e.g., polyadenylation signals). Regulatory sequences include those which direct constitutive expression of a nucleotide sequence, as well as tissue-specific regulatory and/or inducible sequences. 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 polypeptides, including fusion proteins or polypeptides, encoded by nucleic acids as described herein (e.g., 59079 and 12599 proteins, mutant forms of 59079 and 12599 proteins, fusion proteins, and the like).

[0177] The recombinant expression vectors of the invention can be designed for expression of 59079 or 12599 proteins in prokaryotic or eukaryotic cells. For example, polypeptides of the invention can be expressed in E. coli, insect cells (e.g., using baculovirus expression vectors), yeast cells or mammalian cells. Suitable host cells are discussed further in Goeddel, (1990) Gene Expression Technology: Methods in Enzymology 185, Academic Press, San Diego, Calif. Alternatively, the recombinant expression vector can be transcribed and translated in vitro, for example using T7 promoter regulatory sequences and T7 polymerase.

[0178] 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, 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, D. B. and Johnson, K. S. (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.

[0179] Purified fusion proteins can be used in 59079 or 12599 activity assays, (e.g., direct assays or competitive assays described in detail below), or to generate antibodies specific for 59079 or 12599 proteins. In a preferred embodiment, a fusion protein expressed in a retroviral expression vector of the present invention can be used to infect bone marrow cells which are subsequently transplanted into irradiated recipients. The pathology of the subject recipient is then examined after sufficient time has passed (e.g., six weeks).

[0180] 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, S., (1990) Gene Expression Technology: Methods in Enzymology 185, Academic Press, San Diego, Calif. 119-128). 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.

[0181] The 59079 and 12599 expression vector can be a yeast expression vector, a vector for expression in insect cells, e.g., a baculovirus expression vector or a vector suitable for expression in mammalian cells.

[0182] 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.

[0183] 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). 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 (Campes and Tilghman (1989) Genes Dev. 3:537-546).

[0184] The invention further provides a recombinant expression vector comprising a DNA molecule of the invention cloned into the expression vector in an antisense orientation. Regulatory sequences (e.g., viral promoters and/or enhancers) operatively linked to a nucleic acid cloned in the antisense orientation can be chosen which direct the constitutive, tissue specific or cell type specific expression of antisense RNA in a variety of cell types. The antisense expression vector can be in the form of a recombinant plasmid, phagemid or attenuated virus. For a discussion of the regulation of gene expression using antisense genes see Weintraub, H. et al., (1986) Antisense RNA as a molecular tool for genetic analysis, Reviews--Trends in Genetics 1:1.

[0185] Another aspect the invention provides a host cell which includes a nucleic acid molecule described herein, e.g., a 59079 or 12599 nucleic acid molecule within a recombinant expression vector or a 59079 or 12599 nucleic acid molecule containing sequences which allow it to homologously recombine into a specific site of the host cell's genome. The terms "host cell" and "recombinant host cell" are used interchangeably herein. 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.

[0186] A host cell can be any prokaryotic or eukaryotic cell. For example, a 59079 or 12599 protein can be expressed in bacterial cells such as E. coli, insect cells, yeast or mammalian cells (such as Chinese hamster ovary cells (CHO) or COS cells). Other suitable host cells are known to those skilled in the art.

[0187] Vector DNA can be introduced into host 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 (e.g., DNA) into a host cell, including calcium phosphate or calcium chloride co-precipitation, DEAE-dextran-mediated transfection, lipofection, or electroporation.

[0188] A host cell of the invention can be used to produce (i.e., express) a 59079 or 12599 protein. Accordingly, the invention further provides methods for producing a 59079 or 12599 protein using the host cells of the invention. In one embodiment, the method includes culturing the host cell of the invention (into which a recombinant expression vector encoding a 59079 or 12599 protein has been introduced) in a suitable medium such that a 59079 or 12599 protein is produced. In another embodiment, the method further includes isolating a 59079 or 12599 protein from the medium or the host cell.

[0189] In another aspect, the invention features a cell or a purified preparation of cells which includes a 59079 or 12599 transgene, or which otherwise misexpresses 59079 or 12599. The cell preparation can consist of human or nonhuman cells, e.g., rodent cells, e.g., mouse or rat cells, rabbit cells, or pig cells. In preferred embodiments, the cell, or cells, include a 59079 or 12599 transgene, e.g., a heterologous form of 59079 or 12599, e.g., a gene derived from humans (in the case of a non-human cell). The 59079 or 12599 transgene can be misexpressed, e.g., overexpressed or underexpressed. In other preferred embodiments, the cell, or cells, includes a gene which misexpresses an endogenous 59079 or 12599, e.g., a gene, the expression of which is disrupted, e.g., a knockout. Such cells can serve as a model for studying disorders which are related to mutated or mis-expressed 59079 or 12599 alleles or for use in drug screening.

[0190] In another aspect, the invention features, a human cell, e.g., a hematopoietic stem cell, transformed with nucleic acid which encodes a subject 59079 or 12599 polypeptide.

[0191] Also provided are cells, preferably human cells, e.g., human hematopoietic or fibroblast cells, in which an endogenous 59079 or 12599 gene is under the control of a regulatory sequence that does not normally control the expression of the endogenous 59079 or 12599 gene. The expression characteristics of an endogenous gene within a cell, e.g., a cell line or microorganism, can be modified by inserting a heterologous DNA regulatory element into the genome of the cell such that the inserted regulatory element is operably linked to the endogenous 59079 or 12599 gene. For example, an endogenous 59079 or 12599 gene which is "transcriptionally silent," e.g., not normally expressed, or expressed only at very low levels, may be activated by inserting a regulatory element which is capable of promoting the expression of a normally expressed gene product in that cell. Techniques such as targeted homologous recombinations, can be used to insert the heterologous DNA as described in, e.g., Chappel, U.S. Pat. No. 5,272,071; WO 91/06667, published in May 16, 1991.

[0192] Transgenic Animals

[0193] The invention provides non-human transgenic animals. Such animals are useful for studying the function and/or activity of a 59079 or a 12599 protein and for identifying and/or evaluating modulators of 59079 or 12599 activity. 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, and the like. A transgene is exogenous DNA or a rearrangement, e.g., a deletion of endogenous chromosomal DNA, which preferably is integrated into or occurs in the genome of the cells of a transgenic animal. A transgene can direct the expression of an encoded gene product in one or more cell types or tissues of the transgenic animal, other transgenes, e.g., a knockout, reduce expression. Thus, a transgenic animal can be one in which an endogenous 59079 or 12599 gene has been altered by, e.g., 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.

[0194] 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 a transgene of the invention to direct expression of a 59079 or 12599 protein to particular cells. A transgenic founder animal can be identified based upon the presence of a 59079 or 12599 transgene in its genome and/or expression of 59079 or 12599 mRNA 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 a transgene encoding a 59079 or 12599 protein can further be bred to other transgenic animals carrying other transgenes.

[0195] 59079 and 12599 proteins or polypeptides can be expressed in transgenic animals or plants, e.g., a nucleic acid encoding the protein or polypeptide can be introduced into the genome of an animal. In preferred embodiments the nucleic acid is placed under the control of a tissue specific promoter, e.g., a milk or egg specific promoter, and recovered from the milk or eggs produced by the animal. Suitable animals are mice, pigs, cows, goats, and sheep.

[0196] The invention also includes a population of cells from a transgenic animal, as discussed, e.g., below.

[0197] Uses

[0198] The nucleic acid molecules, proteins, protein homologues, and antibodies described herein can be used in one or more of the following methods: a) screening assays; b) predictive medicine (e.g., diagnostic assays, prognostic assays, monitoring clinical trials, and pharmacogenetics); and c) methods of treatment (e.g., therapeutic and prophylactic).

[0199] The isolated nucleic acid molecules of the invention can be used, for example, to express a 59079 or 12599 protein (e.g., via a recombinant expression vector in a host cell in gene therapy applications), to detect a 59079 or 12599 mRNA (e.g., in a biological sample) or a genetic alteration in a 59079 or 12599 gene, and to modulate 59079 or 12599 activity, as described further below. The 59079 and 12599 proteins can be used to treat disorders characterized by insufficient or excessive production of a 59079 or 12599 substrate or production of 59079 or 12599 inhibitors. In addition, the 59079 and 12599 proteins can be used to screen for naturally occurring 59079 or 12599 substrates, to screen for drugs or compounds which modulate 59079 or 12599 activity, as well as to treat disorders characterized by insufficient or excessive production of 59079 or 12599 protein or production of 59079 or 12599 protein forms which have decreased, aberrant or unwanted activity compared to 59079 or 12599 wild type protein. Moreover, the anti-59079 and anti-12599 antibodies of the invention can be used to detect and isolate 59079 or 12599 proteins, regulate the bioavailability of 59079 or 12599 proteins, and modulate 59079 or 12599 activity.

[0200] A method of evaluating a compound for the ability to interact with, e.g., bind, a subject 59079 or 12599 polypeptide is provided. The method includes: contacting the compound with the subject 59079 or 12599 polypeptide; and evaluating ability of the compound to interact with, e.g., to bind or form a complex with the subject 59079 or 12599 polypeptide. This method can be performed in vitro, e.g., in a cell free system, or in vivo, e.g., in a two-hybrid interaction trap assay. This method can be used to identify naturally occurring molecules which interact with subject 59079 or 12599 polypeptide. It can also be used to find natural or synthetic inhibitors of subject 59079 or 12599 polypeptide. Screening methods are discussed in more detail below.

[0201] Screening Assays:

[0202] The invention provides methods (also referred to herein as "screening assays") for identifying modulators, i.e., candidate or test compounds or agents (e.g., proteins, peptides, peptidomimetics, peptoids, small molecules or other drugs) which bind to 59079 or 12599 proteins, have a stimulatory or inhibitory effect on, for example, 59079 or 12599 expression or 59079 or 12599 activity, or have a stimulatory or inhibitory effect on, for example, the expression or activity of a 59079 or 12599 substrate. Compounds thus identified can be used to modulate the activity of target gene products (e.g., 59079 and 12599 genes) in a therapeutic protocol, to elaborate the biological function of the target gene product, or to identify compounds that disrupt normal target gene interactions.

[0203] In one embodiment, the invention provides assays for screening candidate or test compounds which are substrates of a 59079 or 12599 protein or polypeptide or a biologically active portion thereof. In another embodiment, the invention provides assays for screening candidate or test compounds which bind to or modulate the activity of a 59079 or 12599 protein or polypeptide or a biologically active portion thereof.

[0204] The test compounds of the present invention can be obtained using 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, R. N. 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, K. S. (1997) Anticancer Drug Des. 12:145).

[0205] 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. 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 (Ladner, U.S. Pat. No. 5,223,409), spores (Ladner U.S. Pat. No. '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.).

[0206] In another embodiment, an assay is a cell-based assay comprising contacting a cell expressing a 59079 or 12599 target molecule (e.g., a 59079 or 12599 phosphorylation substrate) with a test compound and determining the ability of the test compound to modulate (e.g., stimulate or inhibit) the activity of the 59079 or 12599 target molecule. Determining the ability of the test compound to modulate the activity of a 59079 or 12599 target molecule can be accomplished, for example, by determining the ability of the 59079 or 12599 protein to bind to or interact with the 59079 or 12599 target molelcule, or by determining the ability of the 59079 or 12599 protein to phosphorylate the 59079 or 12599 target molecule.

[0207] The ability of the 59079 or 12599 protein to phosphorylate a substrate or target molecule can be determined by, for example, an in vitro kinase assay. Briefly, a substrate or target molecule, e.g., an immunoprecipitated substrate or target molecule from a cell line expressing such a molecule, can be incubated with the 59079 or 12599 protein and radioactive ATP, e.g., [.gamma.-.sup.32P] ATP, in a buffer containing MgCl.sub.2 and MnCl.sub.2, e.g., 10 mM MgCl.sub.2 and 5 mM MnCl.sub.2. Following the incubation, the immunoprecipitated substrate/target molecule can be separated by SDS-polyacrylamide gel electrophoresis under reducing conditions, transferred to a membrane, e.g., a PVDF membrane, and autoradiographed. The appearance of detectable bands on the autoradiograph indicates that the 59079 or 12599 substrate or target molecule has been phosphorylated. Phosphoamino acid analysis of the phosphorylated substrate or target molecule can also be performed in order to determine which residues on the 59079 or 12599 substrate or target molecule are phosphorylated and isolated by SDS polyacrylamidge gel electrophoresis. Briefly, the radiophosphorylated protein band can be excised from the SDS gel and subjected to partial acid hydrolysis. The products can then be separated by one-dimensional electrophoresis and analyzed on, for example, a phosphoimager and compared to ninhydrin-stained phosphoaminoacid standards.

[0208] The ability of the test compound to modulate 59079 or 12599 binding to a compound, e.g., a 59079 or 12599 substrate, or to bind to 59079 or 12599 can also be evaluated. This can be accomplished, for example, by coupling the compound, e.g., the substrate, with a radioisotope or enzymatic label such that binding of the compound, e.g., the substrate, to 59079 or 12599 can be determined by detecting the labeled compound, e.g., substrate, in a complex. Alternatively, 59079 or 12599 could be coupled with a radioisotope or enzymatic label to monitor the ability of a test compound to modulate 59079 or 12599 binding to a 59079 or 12599 substrate in a complex. For example, compounds (e.g., 59079 or 12599 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 radioemmission or by scintillation counting. Alternatively, compounds 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.

[0209] The ability of a compound (e.g., a 59079 or 12599 substrate) to interact with 59079, with or without the labeling of any of the interactants, can be evaluated. For example, a microphysiometer can be used to detect the interaction of a compound with 59079 or 12599 without the labeling of either the compound or the 59079 or 12599. McConnell, H. M. et al. (1992) Science 257:1906-1912. As used herein, a "microphysiometer" (e.g., Cytosensor) is an analytical instrument that measures the rate at which a cell acidifies its environment using a light-addressable potentiometric sensor (LAPS). Changes in this acidification rate can be used as an indicator of the interaction between a compound and 59079 or between a compound and 12599.

[0210] In yet another embodiment, a cell-free assay is provided in which a 59079 or a 12599 protein, or biologically active portion thereof, is contacted with a test compound and the ability of the test compound to bind to the 59079 or 12599 protein, or biologically active portion thereof, is evaluated. Preferred biologically active portions of the 59079 and 12599 proteins to be used in assays of the present invention include fragments which participate in interactions with non-59079 or non-12599 molecules, e.g., fragments with high surface probability scores.

[0211] Soluble and/or membrane-bound forms of isolated proteins (e.g., 59079 and 12599 proteins, or biologically active portions thereof) can be used in the cell-free assays of the invention. When membrane-bound forms of the protein are used, it may be desirable to utilize a solubilizing agent. Examples of such solubilizing agents include non-ionic detergents such as n-octylglucoside, n-dodecylglucoside, n-dodecylmaltoside, octanoyl-N-methylglucamide, decanoyl-N-methylglucamide, Triton.RTM. X-100, Triton.RTM. X-114, Thesit.RTM., Isotridecypoly(ethylene glycol ether).sub.n, 3-[(3-cholamidopropyl)dimethylamminio]-1-propane sulfonate (CHAPS), 3-[(3-cholamidopropyl)dimethylamminio]-2-hydroxy-1-propane sulfonate (CHAPSO), or N-dodecyl=N,N-dimethyl-3-ammonio-1-propane sulfonate.

[0212] Cell-free assays involve preparing a reaction mixture of the target gene protein and the test compound under conditions and for a time sufficient to allow the two components to interact and bind, thus forming a complex that can be removed and/or detected.

[0213] The interaction between two molecules can also be detected, e.g., using fluorescence energy transfer (FET) (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 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, the spatial relationship 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).

[0214] In another embodiment, determining the ability of the 59079 and 12599 protein to bind to a target molecule can be accomplished using 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). "Surface plasmon resonance" or "BIA" detects 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.

[0215] In one embodiment, the target gene product or the test substance is anchored onto a solid phase. The target gene product/test compound complexes anchored on the solid phase can be detected at the end of the reaction. Preferably, the target gene product can be anchored onto a solid surface, and the test compound, (which is not anchored), can be labeled, either directly or indirectly, with detectable labels discussed herein.

[0216] It may be desirable to immobilize 59079 or 12599, an anti-59079 or anti-12599 antibody, or a 59079 or 12599 target molecule to facilitate separation of complexed from uncomplexed forms of one or both of the proteins, as well as to accommodate automation of the assay. Binding of a test compound to a 59079 or 12599 protein, or interaction of a 59079 or 12599 protein with a target molecule in the presence and absence of a candidate compound, can be accomplished in any vessel suitable for containing the reactants. Examples of such vessels include microtiter plates, test tubes, and micro-centrifuge tubes. In one embodiment, a fusion protein can be provided which adds a domain that allows one or both of the proteins to be bound to a matrix. For example, glutathione-S-transferase/59079 fusion proteins or glutathione-S-transferase/12599 fusion proteins or glutathione-S-transferase/target fusion proteins 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 target protein or 59079 or 12599 protein, and the mixture incubated under conditions conducive to complex formation (e.g., at physiological conditions for salt and pH). Following incubation, the beads or microtiter plate wells are washed to remove any unbound components, the matrix immobilized in the case of beads, complex determined either directly or indirectly, for example, as described above. Alternatively, the complexes can be dissociated from the matrix, and the level of 59079 or 12599 binding or activity determined using standard techniques.

[0217] Other techniques for immobilizing either a 59079 or 12599 protein or a target molecule on matrices include using conjugation of biotin and streptavidin. Biotinylated 59079 or 12599 protein or target molecules can be prepared from biotin-NHS(N-hydroxysuccinimide) 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).

[0218] In order to conduct the assay, the non-immobilized component is added to the coated surface containing the anchored component. After the reaction is complete, unreacted components are removed (e.g., by washing) under conditions such that 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 previously non-immobilized component is pre-labeled, the detection of label immobilized on the surface indicates that complexes were formed. Where the previously 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 immobilized component (the antibody, in turn, can be directly labeled or indirectly labeled with, e.g., a labeled anti-Ig antibody).

[0219] In one embodiment, this assay is performed utilizing antibodies reactive with 59079 or 12599 protein or target molecules but which do not interfere with binding of the 59079 or 12599 protein to its target molecule. Such antibodies can be derivatized to the wells of the plate, and unbound target or 59079 or 12599 protein trapped in the wells by antibody conjugation. Methods for detecting such complexes, in addition to those described above for the GST-immobilized complexes, include immunodetection of complexes using antibodies reactive with the 59079 or 12599 protein or target molecule, as well as enzyme-linked assays which rely on detecting an enzymatic activity associated with the 59079 or 12599 protein or target molecule.

[0220] Alternatively, cell-free assays can be conducted in a liquid phase. In such an assay, the reaction products are separated from unreacted components, by any of a number of standard techniques, including but not limited to: differential centrifugation (see, for example, Rivas, G., and Minton, A. P., (1993) Trends Biochem Sci 18:284-7); chromatography (gel filtration chromatography, ion-exchange chromatography); electrophoresis (see, e.g., Ausubel, F. et al., eds. Current Protocols in Molecular Biology 1999, J. Wiley: New York); and immunoprecipitation (see, for example, Ausubel, F. et al., eds. (1999) Current Protocols in Molecular Biology, J. Wiley: New York). Such resins and chromatographic techniques are known to one skilled in the art (see, e.g., Heegaard, N. H., (1998) J Mol Recognit 11: 141-8; Hage, D. S., and Tweed, S. A. (1997) J Chromatogr B Biomed Sci Appl. 699:499-525). Further, fluorescence energy transfer may also be conveniently utilized, as described herein, to detect binding without further purification of the complex from solution.

[0221] In a preferred embodiment, the assay includes contacting the 59079 or 12599 protein, or biologically active portion thereof, with a known compound which binds 59079 or 12599 to form an assay mixture, contacting the assay mixture with a test compound, and determining the ability of the test compound to interact with a 59079 or 12599 protein, wherein determining the ability of the test compound to interact with a 59079 protein includes determining the ability of the test compound to preferentially bind to 59079 or 12599, or biologically active portion thereof, or to modulate the activity of a target molecule, as compared to the known compound.

[0222] The target gene products of the invention can, in vivo, interact with one or more cellular or extracellular macromolecules, such as proteins. For the purposes of this discussion, such cellular and extracellular macromolecules are referred to herein as "binding partners." Compounds that disrupt such interactions can be useful in regulating the activity of the target gene product. Such compounds can include, but are not limited to, molecules such as antibodies, peptides, and small molecules. The preferred target genes/products for use in this embodiment are the 59079 and 12599 genes herein identified. In an alternative embodiment, the invention provides methods for determining the ability of the test compound to modulate the activity of a 59079 or 12599 protein through modulation of the activity of a downstream effector of a 59079 or 12599 target molecule. For example, the activity of the effector molecule on an appropriate target can be determined, or the binding of the effector to an appropriate target can be determined, as previously described.

[0223] To identify compounds that interfere with the interaction between the target gene product and its cellular or extracellular binding partner(s), a reaction mixture containing the target gene product and the binding partner is prepared, under conditions and for a time sufficient, to allow the two products to form complex. In order to test an inhibitory agent, the reaction mixture is provided 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 target gene and its cellular or extracellular binding partner. Control reaction mixtures are incubated without the test compound or with a placebo. The formation of any complexes between the target gene product and the cellular or extracellular binding partner is then detected. The formation of a complex in the control reaction, but not in the reaction mixture containing the test compound, indicates that the compound interferes with the interaction of the target gene product and the interactive binding partner. Additionally, complex formation within reaction mixtures containing the test compound and normal target gene product can also be compared to complex formation within reaction mixtures containing the test compound and mutant target gene product. This comparison can be important in those cases wherein it is desirable to identify compounds that disrupt interactions of mutant but not normal target gene products.

[0224] These assays can be conducted in a heterogeneous or homogeneous format. Heterogeneous assays involve anchoring either the target gene product or the binding partner onto a solid phase, and detecting complexes anchored on 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 target gene products and the binding partners, e.g., by competition, can be identified by conducting the reaction in the presence of the test substance. 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.

[0225] In a heterogeneous assay system, either the target gene product or the interactive cellular or extracellular binding partner, is anchored onto a solid surface (e.g., a microtiter plate), while the non-anchored species is labeled, either directly or indirectly. The anchored species can be immobilized by non-covalent or covalent attachments. Alternatively, an immobilized antibody specific for the species to be anchored can be used to anchor the species to the solid surface.

[0226] In order to conduct the assay, the partner of the immobilized species is exposed to the coated surface with or without the test compound. After the reaction is complete, unreacted components are removed (e.g., by washing) and any complexes formed will remain immobilized on the solid surface. Where the non-immobilized species is pre-labeled, the detection of label immobilized on the surface indicates that complexes were formed. Where the non-immobilized species 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 that inhibit complex formation or that disrupt preformed complexes can be detected.

[0227] Alternatively, the reaction can be conducted in a liquid phase in the presence or absence of the test compound, the reaction products separated from unreacted components, and complexes detected; e.g., using an immobilized antibody specific for one of the binding components to anchor any complexes formed in solution, and a labeled antibody specific for the other partner to detect anchored complexes. Again, depending upon the order of addition of reactants to the liquid phase, test compounds that inhibit complex or that disrupt preformed complexes can be identified.

[0228] In an alternate embodiment of the invention, a homogeneous assay can be used. For example, a preformed complex of the target gene product and the interactive cellular or extracellular binding partner product is prepared in that either the target gene products or their binding partners are labeled, but the signal generated by the label is quenched due to complex formation (see, e.g., U.S. Pat. No. 4,109,496 that utilizes this approach for immunoassays). The addition of a test substance that competes with and displaces one of the species from the preformed complex will result in the generation of a signal above background. In this way, test substances that disrupt target gene product-binding partner interaction can be identified.

[0229] In yet another aspect, the 59079 proteins can be used as "bait proteins" 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; and Brent WO94/10300), to identify other proteins, which bind to or interact with 59079 or 12599 ("59079-binding proteins" or "59079-bps", "12599-binding proteins" or "12599-bps") and are involved in 59079 or 12599 activity. Such 59079-bps and 12599-bps can be activators or inhibitors of signals by the 59079 or 12599 proteins or 59079 or 12599 targets as, for example, downstream elements of a 59079- or 12599-mediated signaling pathway.

[0230] 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 codes for a 59079 or 12599 protein is 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. (Alternatively the: 59079 or 12599 protein can be the fused to the activator domain.) If the "bait" and the "prey" proteins are able to interact, in vivo, forming a 59079-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 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 59079 protein.

[0231] In another embodiment, modulators of 59079 or 12599 expression are identified. For example, a cell or cell free mixture is contacted with a candidate compound and the expression of 59079 or 12599 mRNA or protein evaluated relative to the level of expression of 59079 or 12599 mRNA or protein in the absence of the candidate compound. When expression of 59079 or 12599 mRNA or protein is greater in the presence of the candidate compound than in its absence, the candidate compound is identified as a stimulator of 59079 or 12599 mRNA or protein expression. Alternatively, when expression of 59079 or 12599 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 59079 or 12599 mRNA or protein expression. The level of 59079 or 12599 mRNA or protein expression can be determined by methods described herein for detecting 59079 or 12599 mRNA or protein.

[0232] 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 59079 or 12599 protein can be confirmed in vivo in an animal model.

[0233] 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 (e.g., a 59079 or 12599 modulating agent, an anti-sense 59079 or 12599 nucleic acid molecule, a 59079- or 12599-specific antibody, or a 59079- or 12599-binding partner) in an appropriate animal model to determine the efficacy, toxicity, side effects, or mechanism of action, of treatment with such an agent. Furthermore, novel agents identified by the above-described screening assays can be used for treatments as described herein.

[0234] Detection Assays

[0235] Portions or fragments of the nucleic acid sequences identified herein can be used as polynucleotide reagents. For example, these sequences can be used to: (i) map their respective genes on a chromosome e.g., to locate gene regions associated with genetic disease or to associate 59079 and 12599 with a disease; (ii) identify an individual from a minute biological sample (tissue typing); and (iii) aid in forensic identification of a biological sample. These applications are described in the subsections below.

[0236] Chromosome Mapping

[0237] The 59079 and 12599 nucleotide sequences or portions thereof can be used to map the location of the 59079 and 12599 genes on a chromosome. This process is called chromosome mapping. Chromosome mapping is useful in correlating the 59079 amd 12599 sequences with genes associated with disease.

[0238] Briefly, 59079 and 12599 genes can be mapped to chromosomes by preparing PCR primers (preferably 15-25 bp in length) from the 59079 or 12599 nucleotide sequences. These primers can then be used for PCR screening of somatic cell hybrids containing individual human chromosomes. Only those hybrids containing the human gene corresponding to the 59079 or 12599 sequences will yield an amplified fragment.

[0239] A panel of somatic cell hybrids in which each cell line contains either a single human chromosome or a small number of human chromosomes, and a full set of mouse chromosomes, can allow easy mapping of individual genes to specific human chromosomes. (D'Eustachio P. et al. (1983) Science 220:919-924).

[0240] Other mapping strategies e.g., in situ hybridization (described in Fan, Y. et al. (1990) Proc. Natl. Acad. Sci. USA, 87:6223-27), pre-screening with labeled flow-sorted chromosomes, and pre-selection by hybridization to chromosome specific cDNA libraries can be used to map 59079 or 12599 to a chromosomal location.

[0241] Fluorescence in situ hybridization (FISH) of a DNA sequence to a metaphase chromosomal spread can further be used to provide a precise chromosomal location in one step. The FISH technique can be used with a DNA sequence as short as 500 or 600 bases. However, clones larger than 1,000 bases have a higher likelihood of binding to a unique chromosomal location with sufficient signal intensity for simple detection. Preferably 1,000 bases, and more preferably 2,000 bases will suffice to get good results at a reasonable amount of time. For a review of this technique, see Verma et al., Human Chromosomes: A Manual of Basic Techniques ((1988) Pergamon Press, New York).

[0242] Reagents for chromosome mapping can be used individually to mark a single chromosome or a single site on that chromosome, or panels of reagents can be used for marking multiple sites and/or multiple chromosomes. Reagents corresponding to noncoding regions of the genes actually are preferred for mapping purposes. Coding sequences are more likely to be conserved within gene families, thus increasing the chance of cross hybridizations during chromosomal mapping.

[0243] Once a sequence has been mapped to a precise chromosomal location, the physical position of the sequence on the chromosome can be correlated with genetic map data. (Such data are found, for example, in V. McKusick, Mendelian Inheritance in Man, available on-line through Johns Hopkins University Welch Medical Library). The relationship between a gene and a disease, mapped to the same chromosomal region, can then be identified through linkage analysis (co-inheritance of physically adjacent genes), described in, for example, Egeland, J. et al. (1987) Nature, 325:783-787.

[0244] Moreover, differences in the DNA sequences between individuals affected and unaffected with a disease associated with the 59079 or 12599 gene, can be determined. If a mutation is observed in some or all of the affected individuals but not in any unaffected individuals, then the mutation is likely to be the causative agent of the particular disease. Comparison of affected and unaffected individuals generally involves first looking for structural alterations in the chromosomes, such as deletions or translocations that are visible from chromosome spreads or detectable using PCR based on that DNA sequence. Ultimately, complete sequencing of genes from several individuals can be performed to confirm the presence of a mutation and to distinguish mutations from polymorphisms.

[0245] Tissue Typing

[0246] 59079 and 12599 sequences can be used to identify individuals from biological samples using, e.g., restriction fragment length polymorphism (RFLP). In this technique, an individual's genomic DNA is digested with one or more restriction enzymes, the fragments separated, e.g., in a Southern blot, and probed to yield bands for identification. The sequences of the present invention are useful as additional DNA markers for RFLP (described in U.S. Pat. No. 5,272,057).

[0247] Furthermore, the sequences of the present invention can also be used to determine the actual base-by-base DNA sequence of selected portions of an individual's genome. Thus, the 59079 and 12599 nucleotide sequences described herein can be used to prepare two PCR primers from the 5' and 3' ends of the sequences. These primers can then be used to amplify an individual's DNA and subsequently sequence it. Panels of corresponding DNA sequences from individuals, prepared in this manner, can provide unique individual identifications, as each individual will have a unique set of such DNA sequences due to allelic differences.

[0248] Allelic variation occurs to some degree in the coding regions of these sequences, and to a greater degree in the noncoding regions. Each of the sequences described herein can, to some degree, be used as a standard against which DNA from an individual can be compared for identification purposes. Because greater numbers of polymorphisms occur in the noncoding regions, fewer sequences are necessary to differentiate individuals. The noncoding sequences of SEQ ID NO:1 and SEQ ID NO:4 can provide positive individual identification with a panel of perhaps 10 to 1,000 primers which each yield a noncoding amplified sequence of 100 bases. If predicted coding sequences, such as those in SEQ ID NO:3 and 5 are used, a more appropriate number of primers for positive individual identification would be 500-2,000.

[0249] If a panel of reagents from 59079 or 12599 nucleotide sequences described herein is used to generate a unique identification database for an individual, those same reagents can later be used to identify tissue from that individual. Using the unique identification database, positive identification of the individual, living or dead, can be made from extremely small tissue samples.

[0250] Use of Partial 59079 and 12599 Sequences in Forensic Biology

[0251] DNA-based identification techniques can also be used in forensic biology. To make such an identification, PCR technology can be used to amplify DNA sequences taken from very small biological samples such as tissues, e.g., hair or skin, or body fluids, e.g., blood, saliva, or semen found at a crime scene. The amplified sequence can then be compared to a standard, thereby allowing identification of the origin of the biological sample.

[0252] The sequences of the present invention can be used to provide polynucleotide reagents, e.g., PCR primers, targeted to specific loci in the human genome, which can enhance the reliability of DNA-based forensic identifications by, for example, providing another "identification marker" (i.e. another DNA sequence that is unique to a particular individual). As mentioned above, actual base sequence information can be used for identification as an accurate alternative to patterns formed by restriction enzyme generated fragments. Sequences targeted to noncoding regions of SEQ ID NO:1 or 4 (e.g., fragments derived from the noncoding regions of SEQ ID NO:1 or 4 having a length of at least 20 bases, preferably at least 30 bases) are particularly appropriate for this use.

[0253] The 59079 and 12599 nucleotide sequences described herein can further be used to provide polynucleotide reagents, e.g., labeled or labelable probes which can be used in, for example, an in situ hybridization technique, to identify a specific tissue. This can be very useful in cases where a forensic pathologist is presented with a tissue of unknown origin. Panels of such 59079 or 12599 probes can be used to identify tissue by species and/or by organ type.

[0254] In a similar fashion, these reagents, e.g., 59079 and 12599 primers or probes can be used to screen tissue culture for contamination (i.e. screen for the presence of a mixture of different types of cells in a culture).

[0255] Predictive Medicine

[0256] The present invention also pertains to the field of predictive medicine in which diagnostic assays, prognostic assays, and monitoring clinical trials are used for prognostic (predictive) purposes to thereby treat an individual.

[0257] Generally, the invention provides, a method of determining if a subject is at risk for a disorder related to a lesion in or the misexpression of a gene which encodes 59079.

[0258] Such disorders include, e.g., a disorder associated with the misexpression of 59079 or 12599 gene.

[0259] The method includes one or more of the following:

[0260] detecting, in a tissue of the subject, the presence or absence of a mutation which affects the expression of the 59079 or 12599 gene, or detecting the presence or absence of a mutation in a region which controls the expression of the gene, e.g., a mutation in the 5' control region;

[0261] detecting, in a tissue of the subject, the presence or absence of a mutation which alters the structure of the 59079 or 12599 gene;

[0262] detecting, in a tissue of the subject, the misexpression of the 59079 or 12599 gene, at the mRNA level, e.g., detecting a non-wild type level of a mRNA; or

[0263] detecting, in a tissue of the subject, the misexpression of the gene, at the protein level, e.g., detecting a non-wild type level of a 59079 or 12599 polypeptide.

[0264] In preferred embodiments the method includes: ascertaining the existence of at least one of: a deletion of one or more nucleotides from the 59079 or 12599 gene; an insertion of one or more nucleotides into the gene, a point mutation, e.g., a substitution of one or more nucleotides of the gene, a gross chromosomal rearrangement of the gene, e.g., a translocation, inversion, or deletion.

[0265] For example, detecting the genetic lesion can include: (i) providing a probe/primer including an oligonucleotide containing a region of nucleotide sequence which hybridizes to a sense or antisense sequence from SEQ ID NO:1 or 4, or naturally occurring mutants thereof or 5' or 3' flanking sequences naturally associated with the 59079 or 12599 gene; (ii) exposing the probe/primer to nucleic acid of the tissue; and detecting, by hybridization, e.g., in situ hybridization, of the probe/primer to the nucleic acid, the presence or absence of the genetic lesion.

[0266] In preferred embodiments detecting the misexpression includes ascertaining the existence of at least one of: an alteration in the level of a messenger RNA transcript of the 59079 or 12599 gene; the presence of a non-wild type splicing pattern of a messenger RNA transcript of the gene; or a non-wild type level of 59079 or 12599.

[0267] Methods of the invention can be used prenatally or to determine if a subject's offspring will be at risk for a disorder.

[0268] In preferred embodiments the method includes determining the structure of a 59079 gene, an abnormal structure being indicative of risk for the disorder.

[0269] In preferred embodiments the method includes contacting a sample from the subject with an antibody to the 59079 protein or a nucleic acid, which hybridizes specifically with the gene. There and other embodiments are discussed below.

[0270] Diagnostic and Prognostic Assays

[0271] The presence, level, or absence of 59079 or 12599 protein or nucleic acid in a biological sample can be evaluated by obtaining a biological sample from a test subject and contacting the biological sample with a compound or an agent capable of detecting 59079 or 12599 protein or nucleic acid (e.g., mRNA, genomic DNA) that encodes 59079 or 12599 protein such that the presence of 59079 or 12599 protein or nucleic acid is detected in the biological sample. The term "biological sample" includes tissues, cells and biological fluids isolated from a subject, as well as tissues, cells and fluids present within a subject. A preferred biological sample is serum. The level of expression of the 59079 or 12599 gene can be measured in a number of ways, including, but not limited to: measuring the mRNA encoded by the 59079 or 12599 genes; measuring the amount of protein encoded by the 59079 or 12599 genes; or measuring the activity of the protein encoded by the 59079 or 12599 genes.

[0272] The level of mRNA corresponding to the 59079 or 12599 gene in a cell can be determined both by in situ and by in vitro formats.

[0273] 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 59079 or 12599 nucleic acid, such as the nucleic acid of SEQ ID NO:1 or 4, 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 59079 or 12599 mRNA or genomic DNA. Other suitable probes for use in the diagnostic assays are described herein.

[0274] In one format, mRNA (or cDNA) is immobilized on a surface and contacted with the probes, 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 probes are immobilized on a surface and the mRNA (or cDNA) is contacted with the probes, for example, in a two-dimensional gene chip array. A skilled artisan can adapt known mRNA detection methods for use in detecting the level of mRNA encoded by the 59079 or 12599 genes.

[0275] The level of mRNA in a sample that is encoded by 59079 or 12599 can be evaluated with nucleic acid amplification, e.g., by rtPCR (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 known in the art. 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.

[0276] For in situ methods, a cell or tissue sample can be prepared/processed and immobilized on a support, typically a glass slide, and then contacted with a probe that can hybridize to mRNA that encodes the 59079 or 12599 gene being analyzed.

[0277] In another embodiment, the methods further contacting a control sample with a compound or agent capable of detecting 59079 or 12599 mRNA, or genomic DNA, and comparing the presence of 59079 or 12599 mRNA or genomic DNA in the control sample with the presence of 59079 or 12599 mRNA or genomic DNA in the test sample.

[0278] A variety of methods can be used to determine the level of protein encoded by 59079 or 12599. In general, these methods include contacting an agent that selectively binds to the protein, such as an antibody with a sample, to evaluate the level of protein in the sample. In a preferred embodiment, the antibody bears a detectable label. Antibodies can be polyclonal, or more preferably, monoclonal. An intact antibody, or a fragment 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 a detectable substance. Examples of detectable substances are provided herein.

[0279] The detection methods can be used to detect 59079 or 12599 protein in a biological sample in vitro, as well as in vivo. In vitro techniques for detection of 59079 or 12599 protein include enzyme linked immunosorbent assays (ELISAs), immunoprecipitations, immunofluorescence, enzyme immunoassay (EIA), radioimmunoassay (RIA), and Western blot analysis. In vivo techniques for detection of 59079 or 12599 protein include introducing into a subject a labeled anti-59079 or anti-12599 antibody. 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.

[0280] In another embodiment, the methods further include contacting the control sample with a compound or agent capable of detecting 59079 or 12599 protein, and comparing the presence of 59079 or 12599 protein in the control sample with the presence of 59079 or 12599 protein in the test sample.

[0281] The invention also includes kits for detecting the presence of 59079 or 12599 in a biological sample. For example, the kit can include a compound or agent capable of detecting 59079 or 12599 protein or mRNA in a biological sample; and a standard. The compound or agent can be packaged in a suitable container. The kit can further comprise instructions for using the kit to detect 59079 or 12599 protein or nucleic acid.

[0282] For antibody-based kits, the kit can include: (1) a first antibody (e.g., attached to a solid support) which binds to a polypeptide corresponding to a marker of the invention; and, optionally, (2) a second, different antibody which binds to either the polypeptide or the first antibody and is conjugated to a detectable agent.

[0283] For oligonucleotide-based kits, the kit can include: (1) an oligonucleotide, e.g., a detectably labeled oligonucleotide, which hybridizes to a nucleic acid sequence encoding a polypeptide corresponding to a marker of the invention, or (2) a pair of primers useful for amplifying a nucleic acid molecule corresponding to a marker of the invention. The kit can also includes a buffering agent, a preservative, or a protein stabilizing agent. The kit can also includes components necessary for detecting the detectable agent (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 contained. 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.

[0284] The diagnostic methods described herein can identify subjects having, or at risk of developing, a disease or disorder associated with misexpressed or aberrant or unwanted 59079 or 12599 expression or activity. As used interchangeably herein, the terms "unwanted" and "undesirable" include an unwanted phenomenon involved in a biological response such as pain or deregulated cell proliferation.

[0285] In one embodiment, a disease or disorder associated with aberrant or unwanted 59079 or 12599 expression or activity is identified. A test sample is obtained from a subject and 59079 or 12599 protein or nucleic acid (e.g., mRNA or genomic DNA) is evaluated, wherein the level, e.g., the presence or absence, of 59079 or 12599 protein or nucleic acid is diagnostic for a subject having or at risk of developing a disease or disorder associated with aberrant or unwanted 59079 or 12599 expression or activity. As used herein, a "test sample" refers to a biological sample obtained from a subject of interest, including a biological fluid (e.g., serum), cell sample, or tissue.

[0286] The prognostic assays described herein can be used to determine whether a subject can be administered an agent (e.g., an agonist, antagonist, peptidomimetic, protein, peptide, nucleic acid, small molecule, or other drug candidate) to treat a disease or disorder associated with aberrant or unwanted 59079 or 12599 expression or activity. For example, such methods can be used to determine whether a subject can be effectively treated with an agent for a cellular proliferative and/or differentiative disorder, a hormonal disorder, an immune or inflammatory disorder, a neurological disorder, a cardiovascular disorder, a blood vessel disorder, or a platelet disorder.

[0287] The methods of the invention can also be used to detect genetic alterations in a 59079 or 12599 gene, thereby determining if a subject with the altered gene is at risk for a disorder characterized by misregulation in 59079 or 12599 protein activity or nucleic acid expression, such as a cellular proliferative and/or differentiative disorder, a hormonal disorder, an immune or inflammatory disorder, a neurological disorder, a cardiovascular disorder, a blood vessel disorder, or a platelet disorder. In preferred embodiments, the methods include detecting, in a sample from the subject, the presence or absence of a genetic alteration characterized by at least one of an alteration affecting the integrity of a gene encoding a 59079 or 12599 protein, or the mis-expression of the 59079 or 12599 gene. For example, such genetic alterations can be detected by ascertaining the existence of at least one of: (1) a deletion of one or more nucleotides from a 59079 or 12599 gene; (2) an addition of one or more nucleotides to a 59079 or 12599 gene; (3) a substitution of one or more nucleotides of a 59079 or 12599 gene, (4) a chromosomal rearrangement of a 59079 or 12599 gene; (5) an alteration in the level of a messenger RNA transcript of a 59079 or 12599 gene; (6) aberrant modification of a 59079 or 12599 gene, such as of the methylation pattern of the genomic DNA; (7) the presence of a non-wild type splicing pattern of a messenger RNA transcript of a 59079 or 12599 gene; (8) a non-wild type level of a 59079 or 12599 protein; (9) allelic loss of a 59079 or 12599 gene; and (10) inappropriate post-translational modification of a 59079 or 12599 protein.

[0288] An alteration can be detected without a probe/primer in a polymerase chain reaction, such as anchor PCR or RACE PCR, or, alternatively, in a ligation chain reaction (LCR), the latter of which can be particularly useful for detecting point mutations in the 59079 or 12599 gene. This method can include the steps of collecting a sample of cells from a subject, isolating nucleic acid (e.g., genomic, mRNA or both) from the sample, contacting the nucleic acid sample with one or more primers which specifically hybridize to a 59079 or 12599 gene under conditions such that hybridization and amplification of the 59079 or 12599 gene (if present) occurs, and detecting the presence or absence of an amplification product, or detecting the size of the amplification product and comparing the length to a control sample. It is anticipated that PCR and/or LCR may be desirable to use as a preliminary amplification step in conjunction with any of the techniques used for detecting mutations described herein. Alternatively, other amplification methods described herein or known in the art can be used.

[0289] In another embodiment, mutations in a 59079 or 12599 gene from a sample cell can be identified by detecting alterations in restriction enzyme cleavage patterns. For example, sample and control DNA is isolated, amplified (optionally), digested with one or more restriction endonucleases, and fragment length sizes are determined, e.g., by gel electrophoresis and compared. Differences in fragment length sizes between sample and control DNA indicates mutations in the sample DNA. Moreover, the use of sequence specific ribozymes (see, for example, U.S. Pat. No. 5,498,531) can be used to score for the presence of specific mutations by development or loss of a ribozyme cleavage site.

[0290] In other embodiments, genetic mutations in 59079 and 12599 can be identified by hybridizing a sample and control nucleic acids, e.g., DNA or RNA, two dimensional arrays, e.g., chip based arrays. Such arrays include a plurality of addresses, each of which is positionally distinguishable from the other. A different probe is located at each address of the plurality. The arrays can have a high density of addresses, e.g., can contain hundreds or thousands of oligonucleotides probes (Cronin, M. T. et al. (1996) Human Mutation 7: 244-255; Kozal, M. J. et al. (1996) Nature Medicine 2: 753-759). For example, genetic mutations in 59079 or 12599 can be identified in two dimensional arrays containing light-generated DNA probes as described in Cronin, M. T. et al. supra. Briefly, a first hybridization array of probes can be used to scan through long stretches of DNA in a sample and control to identify base changes between the sequences by making linear arrays of sequential overlapping probes. This step allows the identification of point mutations. This step is followed by a second hybridization array that allows the characterization of specific mutations by using smaller, specialized probe arrays complementary to all variants or mutations detected. Each mutation array is composed of parallel probe sets, one complementary to the wild-type gene and the other complementary to the mutant gene.

[0291] In yet another embodiment, any of a variety of sequencing reactions known in the art can be used to directly sequence the 59079 and 12599 genes and detect mutations by comparing the sequence of the sample 59079 or 12599 with the corresponding wild-type (control) sequence. Automated sequencing procedures can be utilized when performing the diagnostic assays ((1995) Biotechniques 19:448), including sequencing by mass spectrometry.

[0292] Other methods for detecting mutations in the 59079 or 12599 gene include methods in which protection from cleavage agents is used to detect mismatched bases in RNA/RNA or RNA/DNA heteroduplexes (Myers et al. (1985) Science 230:1242; Cotton et al. (1988) Proc. Natl. Acad Sci USA 85:4397; Saleeba et al. (1992) Methods Enzymol. 217:286-295).

[0293] In still another embodiment, the mismatch cleavage reaction employs one or more proteins that recognize mismatched base pairs in double-stranded DNA (so called "DNA mismatch repair" enzymes) in defined systems for detecting and mapping point mutations in 59079 or 12599 cDNAs obtained from samples of cells. For example, the mutY enzyme of E. coli cleaves A at G/A mismatches and the thymidine DNA glycosylase from HeLa cells cleaves T at G/T mismatches (Hsu et al. (1994) Carcinogenesis 15:1657-1662; U.S. Pat. No. 5,459,039).

[0294] In other embodiments, alterations in electrophoretic mobility will be used to identify mutations in 59079 and 12599 genes. For example, single strand conformation polymorphism (SSCP) may be used to detect differences in electrophoretic mobility between mutant and wild type nucleic acids (Orita et al. (1989) Proc Natl. Acad. Sci USA: 86:2766, see also Cotton (1993) Mutat. Res. 285:125-144; and Hayashi (1992) Genet. Anal. Tech. Appl. 9:73-79). Single-stranded DNA fragments of sample and control 59079 and 12599 nucleic acids will be denatured and allowed to renature. The secondary structure of single-stranded nucleic acids varies according to sequence, the resulting alteration in electrophoretic mobility enables the detection of even a single base change. The DNA fragments may be labeled or detected with labeled probes. The sensitivity of the assay may be enhanced by using RNA (rather than DNA), in which the secondary structure is more sensitive to a change in sequence. In a preferred embodiment, the subject method utilizes heteroduplex analysis to separate double stranded heteroduplex molecules on the basis of changes in electrophoretic mobility (Keen et al. (1991) Trends Genet 7:5).

[0295] In yet another embodiment, the movement of mutant or wild-type fragments in polyacrylamide gels containing a gradient of denaturant is assayed using denaturing gradient gel electrophoresis (DGGE) (Myers et al. (1985) Nature 313:495). When DGGE is used as the method of analysis, DNA will be modified to insure that it does not completely denature, for example by adding a GC clamp of approximately 40 bp of high-melting GC-rich DNA by PCR. In a further embodiment, a temperature gradient is used in place of a denaturing gradient to identify differences in the mobility of control and sample DNA (Rosenbaum and Reissner (1987) Biophys Chem 265:12753).

[0296] Examples of other techniques for detecting point mutations include, but are not limited to, selective oligonucleotide hybridization, selective amplification, or selective primer extension (Saiki et al. (1986) Nature 324:163); Saiki et al. (1989) Proc. Natl. Acad. Sci USA 86:6230).

[0297] Alternatively, allele specific amplification technology which depends on selective PCR amplification may be used in conjunction with the instant invention. Oligonucleotides used as primers for specific amplification may carry the mutation of interest in the center of the molecule (so that amplification depends on differential hybridization) (Gibbs et al. (1989) Nucleic Acids Res. 17:2437-2448) or at the extreme 3' end of one primer where, under appropriate conditions, mismatch can prevent, or reduce polymerase extension (Prossner (1993) Tibtech 11:238). In addition it may be desirable to introduce a novel restriction site in the region of the mutation to create cleavage-based detection (Gasparini et al. (1992) Mol. Cell Probes 6: 1). It is anticipated that in certain embodiments amplification may also be performed using Taq ligase for amplification (Barany (1991) Proc. Natl. Acad. Sci USA 88:189). In such cases, ligation will occur only if there is a perfect match at the 3' end of the 5' sequence making it possible to detect the presence of a known mutation at a specific site by looking for the presence or absence of amplification.

[0298] The methods described herein may be performed, for example, by utilizing prepackaged diagnostic kits comprising at least one probe nucleic acid or antibody reagent described herein, which may be conveniently used, e.g., in clinical settings to diagnose patients exhibiting symptoms or family history of a disease or illness involving a 59079 gene.

[0299] Use of 59079 Molecules as Surrogate Markers

[0300] The 59079 and 12599 molecules of the invention are also useful as markers of disorders or disease states, as markers for precursors of disease states, as markers for predisposition of disease states, as markers of drug activity, or as markers of the pharmacogenomic profile of a subject. Using the methods described herein, the presence, absence and/or quantity of the 59079 or 12599 molecules of the invention may be detected, and may be correlated with one or more biological states in vivo. For example, the 59079 and 12599 molecules of the invention may serve as surrogate markers for one or more disorders or disease states or for conditions leading up to disease states. 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.

[0301] The 59079 and 12599 molecules 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 (e.g., a 59079 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, anti-59079 and anti-12599 antibodies may be employed in an immune-based detection system for a 59079 or 12599 protein marker, or 59079- or 12599-specific radiolabeled probes may be used to detect a 59079 or 12599 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.

[0302] The 59079 and 12599 molecules of the invention are also useful as pharmacogenomic markers. As used herein, a "pharmacogenomic marker" is an objective biochemical marker which correlates with a specific clinical drug response or susceptibility in a subject (see, e.g., McLeod et al. (1999) Eur. J. Cancer 35:1650-1652). The presence or quantity of the pharmacogenomic marker is related to the predicted response of the subject to a specific drug or class of drugs prior to administration of the drug. By assessing the presence or quantity of one or more pharmacogenomic markers in a subject, a drug therapy which is most appropriate for the subject, 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 (e.g., 59079 and 12599 protein or RNA) for specific tumor markers in a subject, 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 subject. Similarly, the presence or absence of a specific sequence mutation in 59079 or 12599 DNA may correlate 59079 or 12599 drug response. The use of pharmacogenomic markers therefore permits the application of the most appropriate treatment for each subject without having to administer the therapy.

[0303] Pharmaceutical Compositions

[0304] The nucleic acid and polypeptides, fragments thereof, as well as anti-59079 and anti-12599 antibodies and small molecule modulators of 59079 and 12599 molecules (also referred to herein as "active compounds") of the invention can be incorporated into pharmaceutical compositions. Such compositions typically include the nucleic acid molecule, protein, or antibody and a pharmaceutically acceptable carrier. As used herein, a "pharmaceutically acceptable carrier" includes solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Supplementary active compounds can also be incorporated into the compositions.

[0305] A pharmaceutical composition 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 ethylenediaminetetraacetic 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 ampoules, disposable syringes or multiple dose vials made of glass or plastic.

[0306] 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 dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL.TM. (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 should 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 polyetheylene 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 manitol, sorbitol, 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. Sterile injectable solutions can be prepared by incorporating the active compound 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 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.

[0307] Oral compositions generally include an inert diluent or an edible carrier. 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, e.g., gelatin capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash. 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.

[0308] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

[0309] 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.

[0310] 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.

[0311] 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 (Palo Alto Calif.) and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) 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.

[0312] It is 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.

[0313] Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD.sub.50 (the dose lethal to 50% of the population) and the ED.sub.50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD.sub.50/ED.sub.50. Compounds which exhibit high therapeutic indices are preferred. While compounds that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to uninfected cells and, thereby, reduce side effects.

[0314] The data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED.sub.50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any compound used in the method of the invention, the therapeutically effective dose can be estimated initially from cell culture assays. A dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC.sub.50 (i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma may be measured, for example, by high performance liquid chromatography.

[0315] As defined herein, a therapeutically effective amount of protein or polypeptide (i.e., an effective dosage) ranges from about 0.001 to 30 mg/kg body weight, preferably about 0.01 to 25 mg/kg body weight, more preferably about 0.1 to 20 mg/kg body weight, and even more preferably about 1 to 10 mg/kg, 2 to 9 mg/kg, 3 to 8 mg/kg, 4 to 7 mg/kg, or 5 to 6 mg/kg body weight. The protein or polypeptide can be administered one time per week for between about 1 to 10 weeks, preferably between 2 to 8 weeks, more preferably between about 3 to 7 weeks, and even more preferably for about 4, 5, or 6 weeks. The skilled artisan will appreciate that certain factors may influence the dosage and timing required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of a protein, polypeptide, or antibody can include a single treatment or, preferably, can include a series of treatments.

[0316] For antibodies, the preferred dosage is 0.1 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 (e.g., into the brain). A method for lipidation of antibodies is described by Cruikshank et al. ((1997) J. Acquired Immune Deficiency Syndromes and Human Retrovirology 14:193).

[0317] The present invention encompasses agents which modulate expression or activity. An agent may, for example, be a small molecule. For example, such small molecules include, but are not limited to, peptides, peptidomimetics (e.g., peptoids), amino acids, amino acid analogs, polynucleotides, polynucleotide analogs, nucleotides, nucleotide analogs, organic or inorganic compounds (i.e., including heteroorganic and organometallic compounds) having a molecular weight less than about 10,000 grams per mole, organic or inorganic compounds having a molecular weight less than about 5,000 grams per mole, organic or inorganic compounds having a molecular weight less than about 1,000 grams per mole, organic or inorganic compounds having a molecular weight less than about 500 grams per mole, and salts, esters, and other pharmaceutically acceptable forms of such compounds.

[0318] Exemplary doses include milligram or microgram amounts of the small molecule 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. It is furthermore understood that appropriate doses of a small molecule depend upon the potency of the small molecule with respect to the expression or activity to be modulated. When one or more of these small molecules 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 may, 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 compound 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.

[0319] An antibody (or fragment thereof) may be 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).

[0320] The conjugates of the invention can be used for modifying a given biological response, 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 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.

[0321] Alternatively, an antibody can be conjugated to a second antibody to form an antibody heteroconjugate as described by Segal in U.S. Pat. No. 4,676,980.

[0322] The nucleic acid molecules of the invention 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 (see 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.

[0323] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0324] Methods of Treatment

[0325] The present invention provides for both prophylactic and therapeutic methods of treating a subject at risk of (or susceptible to) a disorder or having a disorder associated with aberrant or undesirable 59079 or 12599 expression or activity. With regard to both prophylactic and therapeutic methods of treatment, such treatments may be specifically tailored or modified, based on knowledge obtained from the field of pharmacogenomics. "Pharmacogenomics", as used herein, refers to the application of genomics technologies such as gene sequencing, statistical genetics, and gene expression analysis to drugs in clinical development and commercially available. More specifically, the term refers the study of how a patient's genes determine his or her response to a drug (e.g., a patient's "drug response phenotype", or "drug response genotype".) Thus, another aspect of the invention provides methods for tailoring an individual's prophylactic or therapeutic treatment with either the 59079 or 12599 molecules of the present invention or 59079 or 12599 modulators according to that individual's drug response genotype. Pharmacogenomics allows a clinician or physician to target prophylactic or therapeutic treatments to patients who will most benefit from the treatment and to identify patients who will experience toxic drug-related side effects.

[0326] "Treatment", as used herein, is defined as the application or administration of a therapeutic agent to a patient, or application or administration of a therapeutic agent to an isolated tissue or cell line from a patient, who has a disease, a symptom of disease or a predisposition toward a disease, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, palliate, improve or affect the disease, the symptoms of disease or the predisposition toward disease. A therapeutic agent includes, but is not limited to, small molecules, peptides, antibodies, ribozymes and antisense oligonucleotides.

[0327] In one aspect, the invention provides a method for preventing in a subject, a disease or condition associated with an aberrant or undesirable 59079 or 12599 expression or activity, by administering to the subject a 59079 or 12599 molecule or an agent which modulates 59079 or 12599 expression or at least one 59079 or 12599 activity. Subjects at risk for a disease which is caused or contributed to by aberrant or undesirable 59079 or 12599 expression or activity can be identified by, for example, any or a combination of diagnostic or prognostic assays as described herein. Administration of a prophylactic agent can occur prior to the manifestation of symptoms characteristic of the 59079 or 12599 aberrance, such that a disease or disorder is prevented or, alternatively, delayed in its progression. Depending on the type of 59079 or 12599 aberrance, for example, a 59079 or 12599 molecule (e.g., a 59079 or 12599 nucleic acid molecule or a 59079 or 12599 protein or polypeptide, or a fragment thereof, as described herein), or 59079 or 12599 agonist or 59079 or 12599 antagonist agent can be used for treating the subject. The appropriate agent can be determined based on screening assays described herein.

[0328] It is possible that some 59079 and 12599 disorders can be caused, at least in part, by an abnormal level of gene product, or by the presence of a gene product exhibiting abnormal activity. As such, the reduction in the level and/or activity of such gene products would bring about the amelioration of disorder symptoms.

[0329] As discussed, successful treatment of 59079 and 12599 disorders can be brought about by techniques that serve to inhibit the expression or activity of 59079 or 12599 target gene products. For example, compounds, e.g., an agent identified using an assays described above, that proves to exhibit negative modulatory activity, can be used in accordance with the invention to prevent and/or ameliorate symptoms of 59079 or 12599 disorders. Such molecules can include, but are not limited to peptides, phosphopeptides, small organic or inorganic molecules, or antibodies (including, for example, polyclonal, monoclonal, humanized, anti-idiotypic, chimeric or single chain antibodies, and Fab, F(ab').sub.2 and Fab expression library fragments, scFV molecules, and epitope-binding fragments thereof).

[0330] Further, antisense and ribozyme molecules that inhibit expression of the target gene can also be used in accordance with the invention to reduce the level of target gene expression, thus effectively reducing the level of target gene activity. Still further, triple helix molecules can be utilized in reducing the level of target gene activity. Antisense, ribozyme and triple helix molecules are discussed above.

[0331] It is possible that the use of antisense, ribozyme, and/or triple helix molecules to reduce or inhibit mutant gene expression can also reduce or inhibit the transcription (triple helix) and/or translation (antisense, ribozyme) of mRNA produced by normal target gene alleles, such that the concentration of normal target gene product present can be lower than is necessary for a normal phenotype. In such cases, nucleic acid molecules that encode and express target gene polypeptides exhibiting normal target gene activity can be introduced into cells via gene therapy method. Alternatively, in instances in that the target gene encodes an extracellular protein, it can be preferable to co-administer normal target gene protein into the cell or tissue in order to maintain the requisite level of cellular or tissue target gene activity.

[0332] Another method by which nucleic acid molecules may be utilized in treating or preventing a disease characterized by undesirable 59079 or 12599 expression is through the use of aptamer molecules specific for 59079 or 12599 protein. Aptamers are nucleic acid molecules having a tertiary structure which permits them to specifically bind to protein ligands (see, e.g., Osborne, et al., Curr. Opin. Chem. Biol. 1997, 1:5-9; and Patel, D. J., Curr. Opin. Chem. Biol. 1997 June; 1:32-46). Since nucleic acid molecules may in many cases be more conveniently introduced into target cells than therapeutic protein molecules may be, aptamers offer a method by which 59079 protein activity may be specifically decreased without the introduction of drugs or other molecules which may have pluripotent effects.

[0333] Antibodies can be generated that are both specific for target gene product and that reduce target gene product activity. Such antibodies may, therefore, by administered in instances whereby negative modulatory techniques are appropriate for the treatment of 59079 or 12599 disorders. For a description of antibodies, see the Antibody section above.

[0334] In circumstances wherein injection of an animal or a human subject with a 59079 or 12599 protein or epitope for stimulating antibody production is harmful to the subject, it is possible to generate an immune response against 59079 or 12599 through the use of anti-idiotypic antibodies (see, for example, Herlyn, D., Ann. Med. 1999; 31:66-78; and Bhattacharya-Chatterjee, M., and Foon, K. A. (1998) Cancer Treat. Res. 94:51-68). If an anti-idiotypic antibody is introduced into a mammal or human subject, it should stimulate the production of anti-anti-idiotypic antibodies, which should be specific to the 59079 or 12599 protein. Vaccines directed to a disease characterized by 59079 or 12599 expression may also be generated in this fashion.

[0335] In instances where the target antigen is intracellular and whole antibodies are used, internalizing antibodies may be preferred. Lipofectin or liposomes can be used to deliver the antibody or a fragment of the Fab region that binds to the target antigen into cells. Where fragments of the antibody are used, the smallest inhibitory fragment that binds to the target antigen is preferred. For example, peptides having an amino acid sequence corresponding to the Fv region of the antibody can be used. Alternatively, single chain neutralizing antibodies that bind to intracellular target antigens can also be administered. Such single chain antibodies can be administered, for example, by expressing nucleotide sequences encoding single-chain antibodies within the target cell population (see e.g., Marasco et al., (1993, Proc. Natl. Acad. Sci. USA 90:7889-7893).

[0336] The identified compounds that inhibit target gene expression, synthesis and/or activity can be administered to a patient at therapeutically effective doses to prevent, treat or ameliorate 59079 and 12599 disorders. A therapeutically effective dose refers to that amount of the compound sufficient to result in amelioration of symptoms of the disorders.

[0337] Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD.sub.50 (the dose lethal to 50% of the population) and the ED.sub.50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD.sub.50/ED.sub.50. Compounds that exhibit large therapeutic indices are preferred. While compounds that exhibit toxic side effects can be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to uninfected cells and, thereby, reduce side effects.

[0338] The data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED.sub.50 with little or no toxicity. The dosage can vary within this range depending upon the dosage form employed and the route of administration utilized. For any compound used in the method of the invention, the therapeutically effective dose can be estimated initially from cell culture assays. A dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC.sub.50 (i.e., the concentration of the test compound that achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma can be measured, for example, by high performance liquid chromatography.

[0339] Another measurement which can be used to determine the effective dose for an individual is to directly assay levels of "free" and "bound" compound in the serum of the test subject. Such assays may utilize antibody mimics and/or "biosensors" that have been created through molecular imprinting techniques. The compound which is able to modulate 59079 activity is used as a template, or "imprinting molecule", to spatially organize polymerizable monomers prior to their polymerization with catalytic reagents. The subsequent removal of the imprinted molecule leaves a polymer matrix which contains a repeated "negative image" of the compound and is able to selectively rebind the molecule under biological assay conditions. A detailed review of this technique is found in Ansell, R. J. et al., (1996) Current Opinion in Biotechnology 7:89-94 and in Shea, K. J., (1994) Trends in Polymer Science 2:166-173. Such "imprinted" affinity matrixes are amenable to ligand-binding assays, whereby the immobilized monoclonal antibody component is replaced by an appropriately imprinted matrix. An example of the use of such matrices in this way can be seen in Vlatakis, G. et al., (1993) Nature 361:645-647. Through the use of isotope-labeling, the "free" concentration of compound which modulates the expression or activity of 59079 can be readily monitored and used in calculations of IC.sub.50.

[0340] Such "imprinted" affinity matrices can also be designed to include fluorescent groups whose photon-emitting properties measurably change upon local and selective binding of target compound. These changes can be readily assayed in real time using appropriate fiberoptic devices, in turn allowing the dose in a test subject to be quickly optimized based on its individual IC.sub.50. A rudimentary example of such a "biosensor" is discussed in Kriz, D. et al., (1995) Analytical Chemistry 67:2142-2144.

[0341] Another aspect of the invention pertains to methods of modulating 59079 expression or activity for therapeutic purposes. Accordingly, in an exemplary embodiment, the modulatory method of the invention involves contacting a cell with a 59079 molecule (e.g., a 59079 or 12599 nucleic acid molecule or 59079 or 12599 protein or polypeptide, or a fragment thereof, as described herein) or an agent that modulates one or more of the activities of the 59079 or 12599 protein activity associated with the cell. An agent that modulates 59079 or 12599 protein activity can be an agent as described herein, such as a nucleic acid or a protein, a naturally-occurring target molecule of a 59079 or 12599 protein (e.g., a 59079 or 12599 substrate, ligand, or receptor), an anti-59079 or anti-12599 antibody, a 59079 or 12599 agonist or antagonist, a peptidomimetic of a 59079 or 12599 agonist or antagonist, or other small molecule.

[0342] In one embodiment, the agent stimulates one or more 59079 or 12599 activities. Examples of such stimulatory agents include active 59079 and 12599 proteins and nucleic acid molecules encoding a 59079 or 12599 protein or polypeptide, or a fragment thereof. In another embodiment, the agent inhibits one or more 59079 or 12599 activities. Examples of such inhibitory agents include antisense 59079 and 12599 nucleic acid molecules, anti-59079 and anti-12599 antibodies, and 59079 and 12599 inhibitors. These modulatory methods can be performed in vitro (e.g., by culturing the cell with the agent) or, alternatively, in vivo (e.g., by administering the agent to a subject), or in situ. As such, the present invention provides methods of treating an individual afflicted with a disease or disorder characterized by aberrant or unwanted expression or activity of a 59079 or 12599 protein or nucleic acid molecule. In one embodiment, the method involves administering an agent (e.g., an agent identified by a screening assay described herein), or combination of agents that modulates (e.g., upregulates or downregulates) 59079 or 12599 expression or activity. In another embodiment, the method involves administering a 59079 or 12599 protein or nucleic acid molecule as therapy to compensate for reduced, aberrant, or undesirable 59079 or 12599 expression or activity.

[0343] Stimulation of 59079 or 12599 expression or activity is desirable in situations in which 59079 or 12599 expression or activity is abnormally downregulated and/or in which increased 59079 or 12599 expression or activity is likely to have a beneficial effect. Likewise, inhibition of 59079 or 12599 expression or activity is desirable in situations in which 59079 or 12599 expression or activity is abnormally upregulated and/or in which decreased 59079 or 12599 expression or activity is likely to have a beneficial effect.

[0344] The 59079 and 12599 molecules can act as novel diagnostic targets and therapeutic agents for controlling one or more of cellular proliferative and/or differentiative disorders, hormonal disorders, immune and inflammatory disorders, neurological disorders, cardiovascular disorders, blood vessel disorders, and platelet disorders, as described above, as well as disorders associated with bone metabolism, hepatic disorders, viral diseases, and pain and metabolic or pain disorders.

[0345] Aberrant expression and/or activity of 59079 or 12599 molecules may mediate disorders associated with bone metabolism. "Bone metabolism" refers to direct or indirect effects in the formation or degeneration of bone structures, e.g., bone formation, bone resorption, etc., which may ultimately affect the concentrations in serum of calcium and phosphate. This term also includes activities mediated by 59079 or 12599 molecules effects in bone cells, e.g. osteoclasts and osteoblasts, that may in turn result in bone formation and degeneration. For example, 59079 or 12599 molecules may support different activities of bone resorbing osteoclasts such as the stimulation of differentiation of monocytes and mononuclear phagocytes into osteoclasts. Accordingly, 59079 and 12599 molecules that modulate the production of bone cells can influence bone formation and degeneration, and thus may be used to treat bone disorders. Examples of such disorders include, but are not limited to, osteoporosis, osteodystrophy, osteomalacia, rickets, osteitis fibrosa cystica, renal osteodystrophy, osteosclerosis, anti-convulsant treatment, osteopenia, fibrogenesis-imperfecta ossium, secondary hyperparathyrodism, hypoparathyroidism, hyperparathyroidism, cirrhosis, obstructive jaundice, drug induced metabolism, medullary carcinoma, chronic renal disease, rickets, sarcoidosis, glucocorticoid antagonism, malabsorption syndrome, steatorrhea, tropical sprue, idiopathic hypercalcemia and milk fever.

[0346] Hepatic disorders which can be treated or diagnosed by methods described herein include, but are not limited to, disorders associated with an accumulation in the liver of fibrous tissue, such as that resulting from an imbalance between production and degradation of the extracellular matrix accompanied by the collapse and condensation of preexisting fibers. The methods described herein can be used to diagnose or treat hepatocellular necrosis or injury induced by a wide variety of agents including processes which disturb homeostasis, such as an inflammatory process, tissue damage resulting from toxic injury or altered hepatic blood flow, and infections (e.g., bacterial, viral and parasitic). For example, the methods can be used for the early detection of hepatic injury, such as portal hypertension or hepatic fibrosis. In addition, the methods can be employed to detect liver fibrosis attributed to inborn errors of metabolsim, for example, fibrosis resulting from a storage disorder such as Gaucher's disease (lipid abnormalities) or a glycogen storage disease, A1-antitrypsin deficiency; a disorder mediating the accumulation (e.g., storage) of an exogenous substance, for example, hemochromatosis (iron-overload syndrome) and copper storage diseases (Wilson's disease), disorders resulting in the accumulation of a toxic metabolite (e.g., tyrosinemia, fructosemia and galactosemia) and peroxisomal disorders (e.g., Zellweger syndrome). Additionally, the methods described herein may be useful for the early detection and treatment of liver injury associated with the administration of various chemicals or drugs, such as for example, methotrexate, isonizaid, oxyphenisatin, methyldopa, chlorpromazine, tolbutamide or alcohol, or which represents a hepatic manifestation of a vascular disorder such as obstruction of either the intrahepatic or extrahepatic bile flow or an alteration in hepatic circulation resulting, for example, from chronic heart failure, veno-occlusive disease, portal vein thrombosis or Budd-Chiari syndrome.

[0347] Additionally, 59079 and 12599 molecules may play an important role in the etiology of certain viral diseases, including but not limited to, Hepatitis B, Hepatitis C and Herpes Simplex Virus (HSV). Modulators of 59079 activity can be used to control viral diseases. The modulators can be used in the treatment and/or diagnosis of viral infected tissue or virus-associated tissue fibrosis, especially liver and liver fibrosis. Also, 59079 modulators can be used in the treatment and/or diagnosis of virus-associated carcinomas, especially hepatocellular cancers.

[0348] Additionally, 59079 and 12599 may play an important role in the regulation of metabolism or pain disorders. Diseases of metabolic imbalance include, but are not limited to, obesity, anorexia nervosa, bullemia, cachexia, lipid disorders, and diabetes. Examples of pain disorders include, but are not limited to, pain response elicited during various forms of tissue injury, e.g., inflammation, infection, and ischemia, usually referred to as hyperalgesia (described in, for example, Fields, H. L., (1987) Pain, New York: McGraw-Hill); pain associated with muscoloskeletal disorders, e.g., joint pain; tooth pain; headaches; pain associated with surgery; pain related to irritable bowel syndrome; and chest pain.

[0349] Pharmacogenomics

[0350] The 59079 and 12599 molecules of the present invention, as well as agents, and modulators which have a stimulatory or inhibitory effect on a 59079 or 12599 activity (e.g., 59079 or 12599 gene expression) as identified by a screening assay described herein can be administered to individuals to treat (prophylactically or therapeutically) 59079 and 12599 associated disorders (e.g., cellular proliferative and/or differentiative disorders, hormonal disorders, immune and inflammatory disorders, neurological disorders, cardiovascular disorders, blood vessel disorders, and platelet disorders) associated with aberrant or undesirable 59079 or 12599 activity. In conjunction with such treatment, pharmacogenomics (i.e., the study of the relationship between an individual's genotype and that individual's response to a foreign compound or drug) may be considered. Differences in metabolism of therapeutics can lead to severe toxicity or therapeutic failure by altering the relation between dose and blood concentration of the pharmacologically active drug. Thus, a physician or clinician may consider applying knowledge obtained in relevant pharmacogenomics studies in determining whether to administer a 59079 or 12599 molecule or 59079 or 12599 modulator as well as tailoring the dosage and/or therapeutic regimen of treatment with a 59079 or 12599 molecule or 59079 or 12599 modulator.

[0351] Pharmacogenomics deals with clinically significant hereditary variations in the response to drugs due to altered drug disposition and abnormal action in affected persons. See, for example, Eichelbaum, M. et al. (1996) Clin. Exp. Pharmacol. Physiol. 23:983-985 and Linder, M. W. et al. (1997) Clin. Chem. 43:254-266. In general, two types of pharmacogenetic conditions can be differentiated. Genetic conditions transmitted as a single factor altering the way drugs act on the body (altered drug action) or genetic conditions transmitted as single factors altering the way the body acts on drugs (altered drug metabolism). These pharmacogenetic conditions can occur either as rare genetic defects or as naturally-occurring polymorphisms. For example, glucose-6-phosphate dehydrogenase deficiency (G6PD) is a common inherited enzymopathy in which the main clinical complication is haemolysis after ingestion of oxidant drugs (anti-malarials, sulfonamides, analgesics, nitrofurans) and consumption of fava beans.

[0352] One pharmacogenomics approach to identifying genes that predict drug response, known as "a genome-wide association", relies primarily on a high-resolution map of the human genome consisting of already known gene-related markers (e.g., a "bi-allelic" gene marker map which consists of 60,000-100,000 polymorphic or variable sites on the human genome, each of which has two variants.) Such a high-resolution genetic map can be compared to a map of the genome of each of a statistically significant number of patients taking part in a Phase II/III drug trial to identify markers associated with a particular observed drug response or side effect. Alternatively, such a high resolution map can be generated from a combination of some ten-million known single nucleotide polymorphisms (SNPs) in the human genome. As used herein, a "SNP" is a common alteration that occurs in a single nucleotide base in a stretch of DNA. For example, a SNP may occur once per every 1000 bases of DNA. A SNP may be involved in a disease process, however, the vast majority may not be disease-associated. Given a genetic map based on the occurrence of such SNPs, individuals can be grouped into genetic categories depending on a particular pattern of SNPs in their individual genome. In such a manner, treatment regimens can be tailored to groups of genetically similar individuals, taking into account traits that may be common among such genetically similar individuals.

[0353] Alternatively, a method termed the "candidate gene approach", can be utilized to identify genes that predict drug response. According to this method, if a gene that encodes a drug's target is known (e.g., a 59079 or 12599 protein of the present invention), all common variants of that gene can be fairly easily identified in the population and it can be determined if having one version of the gene versus another is associated with a particular drug response.

[0354] Alternatively, a method termed the "gene expression profiling", can be utilized to identify genes that predict drug response. For example, the gene expression of an animal dosed with a drug (e.g., a 59079 or 12599 molecule or 59079 or 12599 modulator of the present invention) can give an indication whether gene pathways related to toxicity have been turned on.

[0355] Information generated from more than one of the above pharmacogenomics approaches can be used to determine appropriate dosage and treatment regimens for prophylactic or therapeutic treatment of an individual. 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 59079 or 12599 molecule or 59079 or 12599 modulator, such as a modulator identified by one of the exemplary screening assays described herein.

[0356] The present invention further provides methods for identifying new agents, or combinations, that are based on identifying agents that modulate the activity of one or more of the gene products encoded by one or more of the 59079 and 12599 genes of the present invention, wherein these products may be associated with resistance of the cells to a therapeutic agent. Specifically, the activity of the proteins encoded by the 59079 and 12599 genes of the present invention can be used as a basis for identifying agents for overcoming agent resistance. By blocking the activity of one or more of the resistance proteins, target cells, e.g., human cells, will become sensitive to treatment with an agent that the unmodified target cells were resistant to.

[0357] Monitoring the influence of agents (e.g., drugs) on the expression or activity of a 59079 or 12599 protein can be applied in clinical trials. For example, the effectiveness of an agent determined by a screening assay as described herein to increase 59079 or 12599 gene expression or protein levels, or upregulate 59079 or 12599 activity, can be monitored in clinical trials of subjects exhibiting decreased 59079 or 12599 gene expression or protein levels, or downregulated 59079 or 12599 activity. Alternatively, the effectiveness of an agent determined by a screening assay to decrease 59079 or 12599 gene expression or protein levels, or downregulate 59079 or 12599 activity, can be monitored in clinical trials of subjects exhibiting increased 59079 or 12599 gene expression or protein levels, or upregulated 59079 or 12599 activity. In such clinical trials, the expression or activity of a 59079 or 12599 gene, and preferably, other genes that have been implicated in, for example, a protein kinase associated disorder can be used as a "read out" or markers of the phenotype of a particular cell.

Other Embodiments

[0358] In another aspect, the invention features a method of analyzing a plurality of capture probes. The method is useful, e.g., to analyze gene expression. The method includes: providing a two dimensional array having a plurality of addresses, each address of the plurality being positionally distinguishable from each other address of the plurality, and each address of the plurality having a unique capture probe, e.g., a nucleic acid or peptide sequence, wherein the capture probes are from a cell or subject which expresses 59079 or 12599 or from a cell or subject in which a 59079- or 12599-mediated response has been elicited; contacting the array with a 59079 nucleic acid (preferably purified), a 59079 or 12599 polypeptide (preferably purified), or an anti-59079 or anti-12599 antibody, and thereby evaluating the plurality of capture probes. Binding, e.g., in the case of a nucleic acid, hybridization with a capture probe at an address of the plurality, is detected, e.g., by a signal generated from a label attached to the 59079 or 12599 nucleic acid, polypeptide, or antibody.

[0359] The capture probes can be a set of nucleic acids from a selected sample, e.g., a sample of nucleic acids derived from a control or non-stimulated tissue or cell.

[0360] The method can include contacting the 59079 or 12599 nucleic acid, polypeptide, or antibody with a first array having a plurality of capture probes and a second array having a different plurality of capture probes. The results of each hybridization can be compared, e.g., to analyze differences in expression between a first and second sample. The first plurality of capture probes can be from a control sample, e.g., a wild type, normal, or non-diseased, non-stimulated, sample, e.g., a biological fluid, tissue, or cell sample. The second plurality of capture probes can be from an experimental sample, e.g., a mutant type, at risk, disease-state or disorder-state, or stimulated, sample, e.g., a biological fluid, tissue, or cell sample.

[0361] The plurality of capture probes can be a plurality of nucleic acid probes each of which specifically hybridizes, with an allele of 59079 or 12599. Such methods can be used to diagnose a subject, e.g., to evaluate risk for a disease or disorder, to evaluate suitability of a selected treatment for a subject, to evaluate whether a subject has a disease or disorder.

[0362] The method can be used to detect SNPs, as described above.

[0363] In another aspect, the invention features, a method of analyzing 59079 or 12599, e.g., analyzing structure, function, or relatedness to other nucleic acid or amino acid sequences. The method includes: providing a 59079 or 12599 nucleic acid or amino acid sequence; comparing the 59079 or 12599 sequence with one or more preferably a plurality of sequences from a collection of sequences, e.g., a nucleic acid or protein sequence database; to thereby analyze 59079 or 12599.

[0364] The method can include evaluating the sequence identity between a 59079 or 12599 sequence and a database sequence. The method can be performed by accessing the database at a second site, e.g., over the internet. Preferred databases include GenBank.TM. and SwissProt.

[0365] In another aspect, the invention features, a set of oligonucleotides, useful, e.g., for identifying SNP's, or identifying specific alleles of 59079 or 12599. The set includes a plurality of oligonucleotides, each of which has a different nucleotide at an interrogation position, e.g., an SNP or the site of a mutation. In a preferred embodiment, the oligonucleotides of the plurality identical in sequence with one another (except for differences in length). The oligonucleotides can be provided with differential labels, such that an oligonucleotides which hybridizes to one allele provides a signal that is distinguishable from an oligonucleotides which hybridizes to a second allele.

[0366] The sequence of a 59079 or 12599 molecule is provided in a variety of mediums to facilitate use thereof. A sequence can be provided as a manufacture, other than an isolated nucleic acid or amino acid molecule, which contains a 59079 or 12599 molecule. Such a manufacture can provide a nucleotide or amino acid sequence, e.g., an open reading frame, in a form which allows examination of the manufacture using means not directly applicable to examining the nucleotide or amino acid sequences, or a subset thereof, as they exists in nature or in purified form.

[0367] A 59079 or 12599 nucleotide or amino acid sequence can be recorded on computer readable media. As used herein, "computer readable media" refers to any medium that can be read and accessed directly by a computer. Such media 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 and CD-ROM; electrical storage media such as RAM, ROM, EPROM, EEPROM, and the like; and general hard disks and hybrids of these categories such as magnetic/optical storage media. The medium is adapted or configured for having thereon 59079 sequence information of the present invention.

[0368] As used herein, the term "electronic apparatus" is intended to include any suitable computing or processing apparatus of 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 personal digital assistants (PDAs), cellular phones, pagers, and the like; and local and distributed processing systems.

[0369] 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 59079 or 12599 sequence information.

[0370] A variety of data storage structures are available to a skilled artisan for creating a computer readable medium having recorded thereon a nucleotide or amino acid sequence of the present invention. The choice of the data storage structure will generally be based on the means chosen to access the stored information. In addition, a variety of data processor programs and formats can be used to store the nucleotide sequence information of the present invention on computer readable medium. The sequence information 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. The skilled artisan can readily adapt any number of data processor structuring formats (e.g., text file or database) in order to obtain computer readable medium having recorded thereon the nucleotide sequence information of the present invention.

[0371] By providing the nucleotide or amino acid sequences of the invention in computer readable form, the skilled artisan can routinely access the sequence information for a variety of purposes. For example, one skilled in the art can use the nucleotide or amino acid sequences of the invention in computer readable form to compare a target sequence or target structural motif with the sequence information stored within the data storage means. A search is used to identify fragments or regions of the sequences of the invention which match a particular target sequence or target motif.

[0372] The present invention therefore provides a medium for holding instructions for performing a method for determining whether a subject has a protein kinase associated disease or disorder or a pre-disposition to a protein kinase associated disease or disorder, wherein the method comprises the steps of determining 59079 or 12599 sequence information associated with the subject and based on the 59079 or 12599 sequence information, determining whether the subject has a protein kinase associated disease or disorder and/or recommending a particular treatment for the disease, disorder, or pre-disease condition.

[0373] The present invention further provides in an electronic system and/or in a network, a method for determining whether a subject has a protein kinase associated disease or disorder or a pre-disposition to a disease associated with 59079 or 12599, wherein the method comprises the steps of determining 59079 or 12599 sequence information associated with the subject, and based on the 59079 or 12599 sequence information, determining whether the subject has a protein kinase associated disease or disorder or a pre-disposition to a protein kinase associated disease or disorder, and/or recommending a particular treatment for the disease, disorder, or pre-disease 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.

[0374] The present invention also provides in a network, a method for determining whether a subject has a protein kinase associated disease or disorder or a pre-disposition to a protein kinase associated disease or disorder, said method comprising the steps of receiving 59079 or 12599 sequence information from the subject and/or information related thereto, receiving phenotypic information associated with the subject, acquiring information from the network corresponding to 59079 or 12599 and/or corresponding to a protein kinase associated disease or disorder, and based on one or more of the phenotypic information, the 59079 or 12599 information (e.g., sequence information and/or information related thereto), and the acquired information, determining whether the subject has a protein kinase associated disease or disorder or a pre-disposition to a protein kinase associated disease or disorder. The method may further comprise the step of recommending a particular treatment for the disease, disorder, or pre-disease condition.

[0375] The present invention also provides a business method for determining whether a subject has a protein kinase associated disease or disorder or a pre-disposition to a protein kinase associated disease or disorder, said method comprising the steps of receiving information related to 59079 (e.g., sequence information and/or information related thereto), receiving phenotypic information associated with the subject, acquiring information from the network related to 59079 or 12599 and/or related to a protein kinase associated disease or disorder, and based on one or more of the phenotypic information, the 59079 or 12599 information, and the acquired information, determining whether the subject has a protein kinase associated disease or disorder or a pre-disposition to a protein kinase associated disease or disorder. The method may further comprise the step of recommending a particular treatment for the disease, disorder, or pre-disease condition.

[0376] The invention also includes an array comprising a 59079 or 12599 sequence 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, which can include 59079 and/or 12599. This allows a profile to be developed showing a battery of genes specifically expressed in one or more tissues.

[0377] In addition to such qualitative information, 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 if 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 in that tissue. 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. 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.

[0378] 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 a protein kinase associated disease or disorder, progression of protein kinase associated disease or disorder, and processes, such a cellular transformation associated with the protein kinase associated disease or disorder.

[0379] 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 (e.g., ascertaining the effect of 59079 or 12599 expression on the expression of other genes). This provides, for example, for a selection of alternate molecular targets for therapeutic intervention if the ultimate or downstream target cannot be regulated.

[0380] 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 (e.g., including 59079) that could serve as a molecular target for diagnosis or therapeutic intervention.

[0381] As used herein, a "target sequence" can be any DNA or amino acid sequence of six or more nucleotides or two or more amino acids. A skilled artisan can readily recognize that the longer a target sequence is, the less likely a target sequence will be present as a random occurrence in the database. Typical sequence lengths of a target sequence are from about 10 to 100 amino acids or from about 30 to 300 nucleotide residues. However, it is well recognized that commercially important fragments, such as sequence fragments involved in gene expression and protein processing, may be of shorter length.

[0382] Computer software is publicly available which allows a skilled artisan to access sequence information provided in a computer readable medium for analysis and comparison to other sequences. A variety of known algorithms are disclosed publicly and a variety of commercially available software for conducting search means are and can be used in the computer-based systems of the present invention. Examples of such software include, but are not limited to, MacPattern (EMBL), BLASTN and BLASTX (NCBI).

[0383] Thus, the invention features a method of making a computer readable record of a sequence of a 59079 or 12599 sequence which includes recording the sequence on a computer readable matrix. In a preferred embodiment the record includes one or more of the following: identification of an ORF; identification of a domain, region, or site; identification of the start of transcription; identification of the transcription terminator; the full length amino acid sequence of the protein, or a mature form thereof; the 5' end of the translated region.

[0384] In another aspect, the invention features, a method of analyzing a sequence. The method includes: providing a 59079 or 12599 sequence, or record, in computer readable form; comparing a second sequence to the 59079 or 12599 sequence; thereby analyzing a sequence. Comparison can include comparing to sequences for sequence identity or determining if one sequence is included within the other, e.g., determining if the 59079 or 12599 sequence includes a sequence being compared. In a preferred embodiment the 59079 or second sequence is stored on a first computer, e.g., at a first site and the comparison is performed, read, or recorded on a second computer, e.g., at a second site. For example, the 59079 or 12599 or second sequence can be stored in a public or proprietary database in one computer, and the results of the comparison performed, read, or recorded on a second computer. In a preferred embodiment the record includes one or more of the following: identification of an ORF; identification of a domain, region, or site; identification of the start of transcription; identification of the transcription terminator; the full length amino acid sequence of the protein, or a mature form thereof; the 5' end of the translated region.

[0385] This invention is further illustrated by the following exemplification, which should not be construed as limiting.

Exemplification

[0386] 59079 Gene Expression Analysis

[0387] Total RNA was prepared from various human tissues by a single step extraction method using RNA STAT-60 according to the manufacturer's instructions (TelTest, Inc). 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. 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 SUPERSCRIPT.TM. Choice System following the manufacturer's instructions (GibcoBRL). A negative control of RNA without reverse transcriptase was mock reverse transcribed for each RNA sample.

[0388] Human 59079 expression was measured by TaqMan.RTM. quantitative PCR (Perkin Elmer Applied Biosystems) in cDNA prepared from a variety of normal and diseased (e.g., cancerous) human tissues or cell lines.

[0389] Probes were designed by PrimerExpress software (PE Biosystems) based on the sequence of the human 59079 gene. Each human 59079 gene probe was labeled using FAM (6-carboxyfluorescein), and the .beta.2-microglobulin 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. Forward and reverse primers and the probes for both .beta.2-microglobulin and target gene were added to the TaqMan.RTM. Universal PCR Master Mix (PE Applied Biosystems). Although the final concentration of primer and probe could vary, each was internally consistent within a given experiment. A typical experiment contained 200 nM of forward and reverse primers plus 100 nM probe for .beta.-2 microglobulin and 600 nM forward and reverse primers plus 200 nM probe for the target gene. TaqMan matrix experiments were carried out on an ABI PRISM 7700 Sequence Detection System (PE 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.

[0390] The following method was used to quantitatively calculate human 59079 gene expression in the various tissues relative to .alpha.-2 microglobulin 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 human 59079 gene is normalized by subtracting the Ct value of the .alpha.-2 microglobulin gene to obtain a .sub..DELTA.Ct value using the following formula: .sub..DELTA.Ct=Ct.sub.human 59914 and 59921-Ct.sub..beta.-2 microglobulin. Expression is then calibrated against a cDNA sample showing a comparatively low level of expression of the human 59079 gene. The .sub..DELTA.Ct value for the calibrator sample is then subtracted from .sub..DELTA.Ct for each tissue sample according to the following formula: .sub..DELTA..DELTA.Ct=.sub..DELTA.Ct-.sub.sample-.sub..DELTA.Ct-- .sub.calibrator. Relative expression is then calculated using the arithmetic formula given by 2.sup.-.DELTA..DELTA.Ct. Expression of the target human 59079 gene in each of the tissues tested is then graphically represented as discussed in more detail below.

[0391] The results indicate significant 59079 expression in normal heart and upregulated expression in diseased heart. Significant expression was also seen in skeletal muscle.

[0392] The contents of all references, patents and published patent applications cited throughout this application are incorporated herein by reference.

[0393] Equivalents

[0394] 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.

Sequence CWU 1

1

9 1 8106 DNA Homo sapiens 5'UTR (1)...(71) CDS (72)...(7964) 3'UTR (7965)...(8106) 1 tgcacaccct ggagatcatc tccgtcaccc gggaggactc tggccagtat gcagcctata 60 tcagcaatgc c atg ggt gct gcc tac tcg tct gcc cgg ctg ctg gtt cga 110 Met Gly Ala Ala Tyr Ser Ser Ala Arg Leu Leu Val Arg 1 5 10 ggc cct gat gag cca gaa gag aag cct gca tca gat gtg cat gag cag 158 Gly Pro Asp Glu Pro Glu Glu Lys Pro Ala Ser Asp Val His Glu Gln 15 20 25 ctg gtg ccg ccc cga atg ctg gag agg ttc acc ccc aag aaa gtg aag 206 Leu Val Pro Pro Arg Met Leu Glu Arg Phe Thr Pro Lys Lys Val Lys 30 35 40 45 aaa ggc tcc agc atc acc ttc tct gtg aag gta gaa gga cgc ccg gtg 254 Lys Gly Ser Ser Ile Thr Phe Ser Val Lys Val Glu Gly Arg Pro Val 50 55 60 ccc acc gtg cac tgg ctc agg gag gag gct gag aga ggc gtg ctg tgg 302 Pro Thr Val His Trp Leu Arg Glu Glu Ala Glu Arg Gly Val Leu Trp 65 70 75 att ggc cct gac aca ccg ggc tac acc gtg gcc agc tct gcg cag cag 350 Ile Gly Pro Asp Thr Pro Gly Tyr Thr Val Ala Ser Ser Ala Gln Gln 80 85 90 cac agc ctg gtc ctg ctg gac gtg ggc cgg cag cac cag ggc acc tac 398 His Ser Leu Val Leu Leu Asp Val Gly Arg Gln His Gln Gly Thr Tyr 95 100 105 aca tgc att gcc agc aac gct gcc ggc cag gcc ctc tgc tcc gcc agc 446 Thr Cys Ile Ala Ser Asn Ala Ala Gly Gln Ala Leu Cys Ser Ala Ser 110 115 120 125 ctg cac gtc tcg ggc ctg cct aag gtg gag gag cag gag aaa gtg aag 494 Leu His Val Ser Gly Leu Pro Lys Val Glu Glu Gln Glu Lys Val Lys 130 135 140 gaa gcg ctg att tcc act ttc ctg cag ggg acc aca caa gcc atc tca 542 Glu Ala Leu Ile Ser Thr Phe Leu Gln Gly Thr Thr Gln Ala Ile Ser 145 150 155 gca cag ggg ttg gaa act gcg agt ttt gct gac ctt ggt ggg cag agg 590 Ala Gln Gly Leu Glu Thr Ala Ser Phe Ala Asp Leu Gly Gly Gln Arg 160 165 170 aaa gaa gag cct ctg gct gcc aag gag gcc ctc ggc cac ctg tcc ctc 638 Lys Glu Glu Pro Leu Ala Ala Lys Glu Ala Leu Gly His Leu Ser Leu 175 180 185 gct gag gtg ggc aca gag gag ttc ctg cag aaa ctg acc tcc cag atc 686 Ala Glu Val Gly Thr Glu Glu Phe Leu Gln Lys Leu Thr Ser Gln Ile 190 195 200 205 act gag atg gta tcg gcc aag atc acg cag gcc aag ctg cag gtg ccc 734 Thr Glu Met Val Ser Ala Lys Ile Thr Gln Ala Lys Leu Gln Val Pro 210 215 220 gga ggt gac agt gat gag gac tcc aag aca cca tct gca tcc ccc cgc 782 Gly Gly Asp Ser Asp Glu Asp Ser Lys Thr Pro Ser Ala Ser Pro Arg 225 230 235 cat ggc cga tca cgg cca tcc tcc agc atc cag gag tct tcc tca gag 830 His Gly Arg Ser Arg Pro Ser Ser Ser Ile Gln Glu Ser Ser Ser Glu 240 245 250 tca gag gac ggc gat gcc cga ggc gag atc ttt gac atc tac gtg gtc 878 Ser Glu Asp Gly Asp Ala Arg Gly Glu Ile Phe Asp Ile Tyr Val Val 255 260 265 acc gct gac tac ctg ccc cta ggg gct gag cag gat gcc atc acg ctg 926 Thr Ala Asp Tyr Leu Pro Leu Gly Ala Glu Gln Asp Ala Ile Thr Leu 270 275 280 285 cgg gaa ggc cag tat gtg gag gtc ctg gat gca gcc cac cca ctg cgc 974 Arg Glu Gly Gln Tyr Val Glu Val Leu Asp Ala Ala His Pro Leu Arg 290 295 300 tgg ctt gtc cgc acc aag ccc acc aag tcc agc ccc tca cgg cag ggc 1022 Trp Leu Val Arg Thr Lys Pro Thr Lys Ser Ser Pro Ser Arg Gln Gly 305 310 315 tgg gtg tca cca gcc tac ctg gac agg agg ctc aag ctg tca cct gag 1070 Trp Val Ser Pro Ala Tyr Leu Asp Arg Arg Leu Lys Leu Ser Pro Glu 320 325 330 tgg ggg gcc gct gag gcc cct gag ttc cct ggg gag gct gtg tct gaa 1118 Trp Gly Ala Ala Glu Ala Pro Glu Phe Pro Gly Glu Ala Val Ser Glu 335 340 345 gac gaa tac aag gca agg ctg agc tct gtg atc cag gag ctg ctg agt 1166 Asp Glu Tyr Lys Ala Arg Leu Ser Ser Val Ile Gln Glu Leu Leu Ser 350 355 360 365 tct gag cag gcc ttc gtg gag gag ctg cag ttc ctg cag agc cac cac 1214 Ser Glu Gln Ala Phe Val Glu Glu Leu Gln Phe Leu Gln Ser His His 370 375 380 ctg cag cac ctg gag cgc tgc ccc cac gtg ccc ata gcc gtg gcc ggc 1262 Leu Gln His Leu Glu Arg Cys Pro His Val Pro Ile Ala Val Ala Gly 385 390 395 cag aag gca gtc atc ttc cgc aat gtg cgg gac atc ggc cgc ttc cac 1310 Gln Lys Ala Val Ile Phe Arg Asn Val Arg Asp Ile Gly Arg Phe His 400 405 410 agc agc ttc ctg cag gag ttg cag cag tgc gac acg gac gac gac gtg 1358 Ser Ser Phe Leu Gln Glu Leu Gln Gln Cys Asp Thr Asp Asp Asp Val 415 420 425 gcc atg tgc ttc atc aag aac cag gcg gcc ttt gag cag tac ctg gag 1406 Ala Met Cys Phe Ile Lys Asn Gln Ala Ala Phe Glu Gln Tyr Leu Glu 430 435 440 445 ttc ctg gtg ggg cgt gtg cag gct gag tcg gtg gtc gtc agc acg gcc 1454 Phe Leu Val Gly Arg Val Gln Ala Glu Ser Val Val Val Ser Thr Ala 450 455 460 atc cag gag ttc tac aag aaa tac gcg gag gag gcc ctg ttg gca ggg 1502 Ile Gln Glu Phe Tyr Lys Lys Tyr Ala Glu Glu Ala Leu Leu Ala Gly 465 470 475 gac ccc tct cag ccc ccg cca cca cct ctg cag cac tac ctg gag cag 1550 Asp Pro Ser Gln Pro Pro Pro Pro Pro Leu Gln His Tyr Leu Glu Gln 480 485 490 cca gtg gag cgg gtg cag cgc tac cag gcc ttg ctg aag gag ttg atc 1598 Pro Val Glu Arg Val Gln Arg Tyr Gln Ala Leu Leu Lys Glu Leu Ile 495 500 505 cgc aac aag gcg cgg aac aga cag aac tgc gcg ctg ctg gag cag gcc 1646 Arg Asn Lys Ala Arg Asn Arg Gln Asn Cys Ala Leu Leu Glu Gln Ala 510 515 520 525 tat gcc gtg gtg tct gcc ctg cca cag cgc gct gag aac aag ctg cac 1694 Tyr Ala Val Val Ser Ala Leu Pro Gln Arg Ala Glu Asn Lys Leu His 530 535 540 gtg tcc ctc atg gag aac tac cca ggc acc ctg gag gcc ctg ggc gag 1742 Val Ser Leu Met Glu Asn Tyr Pro Gly Thr Leu Glu Ala Leu Gly Glu 545 550 555 ccc atc cgc cag ggc cac ttc atc gtg tgg gag ggt gca ccg ggg gcc 1790 Pro Ile Arg Gln Gly His Phe Ile Val Trp Glu Gly Ala Pro Gly Ala 560 565 570 cgc atg ccc tgg aag ggc cac aac cgt cac gtg ttc ctc ttc cgc aac 1838 Arg Met Pro Trp Lys Gly His Asn Arg His Val Phe Leu Phe Arg Asn 575 580 585 cac ctg gta atc tgc aag ccc cgg cga gac tcc cgc acc gat acc gtc 1886 His Leu Val Ile Cys Lys Pro Arg Arg Asp Ser Arg Thr Asp Thr Val 590 595 600 605 agc tac gtg ttc cgg aac atg atg aag ctg agc agc atc gac ctg aac 1934 Ser Tyr Val Phe Arg Asn Met Met Lys Leu Ser Ser Ile Asp Leu Asn 610 615 620 gac cag gtg gag ggg gat gac cgc gcc ttc gag gtg tgg cag gag cgg 1982 Asp Gln Val Glu Gly Asp Asp Arg Ala Phe Glu Val Trp Gln Glu Arg 625 630 635 gag gac tcg gtg cgc aag tac ctg ctg cag gca cgg aca gcc att atc 2030 Glu Asp Ser Val Arg Lys Tyr Leu Leu Gln Ala Arg Thr Ala Ile Ile 640 645 650 aag agc tcg tgg gtg aag gag atc tgt ggc atc cag cag cgt ctg gcc 2078 Lys Ser Ser Trp Val Lys Glu Ile Cys Gly Ile Gln Gln Arg Leu Ala 655 660 665 ctg cct gtg tgg cgg ccc ccg gac ttt gaa gag gag ctg gcc gac tgc 2126 Leu Pro Val Trp Arg Pro Pro Asp Phe Glu Glu Glu Leu Ala Asp Cys 670 675 680 685 aca gcc gag ctg ggt gag aca gtc aag ctg gcc tgc cgc gtg acg ggc 2174 Thr Ala Glu Leu Gly Glu Thr Val Lys Leu Ala Cys Arg Val Thr Gly 690 695 700 aca ccc aag cct gtc atc agc tgg tac aaa gat ggg aaa gca gtg cag 2222 Thr Pro Lys Pro Val Ile Ser Trp Tyr Lys Asp Gly Lys Ala Val Gln 705 710 715 gtg gac ccc cac cac atc ctc att gaa gac cct gat ggc tcg tgt gca 2270 Val Asp Pro His His Ile Leu Ile Glu Asp Pro Asp Gly Ser Cys Ala 720 725 730 ctc atc ctg gac agc ctg acc ggt gtg gac tct ggc cag tac atg tgc 2318 Leu Ile Leu Asp Ser Leu Thr Gly Val Asp Ser Gly Gln Tyr Met Cys 735 740 745 ttc gcg gcc agc gcc gct ggc aac tgc agt acc ctg ggc aag atc ctg 2366 Phe Ala Ala Ser Ala Ala Gly Asn Cys Ser Thr Leu Gly Lys Ile Leu 750 755 760 765 gtg caa gtc cca cca cgg ttc gtg aac aag gtc cgg gcc tca ccc ttt 2414 Val Gln Val Pro Pro Arg Phe Val Asn Lys Val Arg Ala Ser Pro Phe 770 775 780 gtg gag gga gag gac gcc cag ttc acc tgc acc atc gaa ggc gcc ccg 2462 Val Glu Gly Glu Asp Ala Gln Phe Thr Cys Thr Ile Glu Gly Ala Pro 785 790 795 tac ccg cag atc agg tgg tac aag gac ggg gcc ctg ctg acc act ggc 2510 Tyr Pro Gln Ile Arg Trp Tyr Lys Asp Gly Ala Leu Leu Thr Thr Gly 800 805 810 aac aag ttc cag aca ctg agt gag cct cgc agc ggc ctg cta gtg ctg 2558 Asn Lys Phe Gln Thr Leu Ser Glu Pro Arg Ser Gly Leu Leu Val Leu 815 820 825 gtg atc cgg gcg gcc agc aag gag gac ctg ggg ctc tac gag tgt gag 2606 Val Ile Arg Ala Ala Ser Lys Glu Asp Leu Gly Leu Tyr Glu Cys Glu 830 835 840 845 ctg gtg aac cgg ctg ggc tcc gcg cgg gct agt gcg gag ctg cgc att 2654 Leu Val Asn Arg Leu Gly Ser Ala Arg Ala Ser Ala Glu Leu Arg Ile 850 855 860 cag agc ccc atg ctg cag gcc cag gag cag tgt cac agg gag cag ctc 2702 Gln Ser Pro Met Leu Gln Ala Gln Glu Gln Cys His Arg Glu Gln Leu 865 870 875 gtg gct gca gtg gaa gac acc acc ctg gag cga gcg gac cag gag gtc 2750 Val Ala Ala Val Glu Asp Thr Thr Leu Glu Arg Ala Asp Gln Glu Val 880 885 890 aca tct gtc ctg aag aga ctg ctg ggc ccc aag gcg cca ggc ccc tcc 2798 Thr Ser Val Leu Lys Arg Leu Leu Gly Pro Lys Ala Pro Gly Pro Ser 895 900 905 aca ggg gac ctc act ggc cct ggc ccc tgc ccc agg ggg gca ccc gca 2846 Thr Gly Asp Leu Thr Gly Pro Gly Pro Cys Pro Arg Gly Ala Pro Ala 910 915 920 925 ctc cag gaa acc ggc tcc cag ccc cca gtc acc gga act tcg gag gca 2894 Leu Gln Glu Thr Gly Ser Gln Pro Pro Val Thr Gly Thr Ser Glu Ala 930 935 940 cct gcc gtg ccc ccg agg gtg cca cag ccc ctc ctc cac gaa ggc cca 2942 Pro Ala Val Pro Pro Arg Val Pro Gln Pro Leu Leu His Glu Gly Pro 945 950 955 gag cag gag ccg gag gcc att gcc aga gcc cag gaa tgg act gtg ccc 2990 Glu Gln Glu Pro Glu Ala Ile Ala Arg Ala Gln Glu Trp Thr Val Pro 960 965 970 att cgg atg gag ggt gca gcc tgg ccc ggg gca ggc aca ggg gag ctg 3038 Ile Arg Met Glu Gly Ala Ala Trp Pro Gly Ala Gly Thr Gly Glu Leu 975 980 985 ctc tgg gac gtc cac agc cac gtg gtc aga gag acc aca cag agg acc 3086 Leu Trp Asp Val His Ser His Val Val Arg Glu Thr Thr Gln Arg Thr 990 995 1000 1005 tac aca tac cag gcc atc gac acg cac acc gca cgg ccc cca tcc atg 3134 Tyr Thr Tyr Gln Ala Ile Asp Thr His Thr Ala Arg Pro Pro Ser Met 1010 1015 1020 cag gta acc atc gag gat gtg cag gca cag aca ggc gga acg gcc caa 3182 Gln Val Thr Ile Glu Asp Val Gln Ala Gln Thr Gly Gly Thr Ala Gln 1025 1030 1035 ttc gag gct atc att gag ggc gac cca cag ccc tcg gtg acc tgg tac 3230 Phe Glu Ala Ile Ile Glu Gly Asp Pro Gln Pro Ser Val Thr Trp Tyr 1040 1045 1050 aag gac agc gtc cag ctg gtg gac agc acc cgg ctt agc cag cag caa 3278 Lys Asp Ser Val Gln Leu Val Asp Ser Thr Arg Leu Ser Gln Gln Gln 1055 1060 1065 gaa ggc acc aca tac tcc ctg gtg ctg agg cat gtg gcc tcg aag gat 3326 Glu Gly Thr Thr Tyr Ser Leu Val Leu Arg His Val Ala Ser Lys Asp 1070 1075 1080 1085 gcc ggc gtt tac acc tgc ctg gcc caa aac act ggt ggc cag gtg ctc 3374 Ala Gly Val Tyr Thr Cys Leu Ala Gln Asn Thr Gly Gly Gln Val Leu 1090 1095 1100 tgc aag gca gag ctg ctg gtg ctt ggg ggg gac aat gag ccg gac tca 3422 Cys Lys Ala Glu Leu Leu Val Leu Gly Gly Asp Asn Glu Pro Asp Ser 1105 1110 1115 gag aag caa agc cac cgg agg aag ctg cac tcc ttc tat gag gtc aag 3470 Glu Lys Gln Ser His Arg Arg Lys Leu His Ser Phe Tyr Glu Val Lys 1120 1125 1130 gag gag att gga agg ggc gtg ttt ggc ttc gta aaa aga gtg cag cac 3518 Glu Glu Ile Gly Arg Gly Val Phe Gly Phe Val Lys Arg Val Gln His 1135 1140 1145 aaa gga aac aag atc ttg tgc gct gcc aag ttc atc ccc cta cgg agc 3566 Lys Gly Asn Lys Ile Leu Cys Ala Ala Lys Phe Ile Pro Leu Arg Ser 1150 1155 1160 1165 aga act cgg gcc cag gca tac agg gag cga gac atc ctg gcc gcg ctg 3614 Arg Thr Arg Ala Gln Ala Tyr Arg Glu Arg Asp Ile Leu Ala Ala Leu 1170 1175 1180 agc cac ccg ctg gtc acg ggg ctg ctg gac cag ttt gag acc cgc aag 3662 Ser His Pro Leu Val Thr Gly Leu Leu Asp Gln Phe Glu Thr Arg Lys 1185 1190 1195 acc ctc atc ctc atc ctg gag ctg tgc tca tcc gag gag ctg ctg gac 3710 Thr Leu Ile Leu Ile Leu Glu Leu Cys Ser Ser Glu Glu Leu Leu Asp 1200 1205 1210 cgc ctg tac agg aag ggc gtg gtg acg gag gcc gag gtc aag gtc tac 3758 Arg Leu Tyr Arg Lys Gly Val Val Thr Glu Ala Glu Val Lys Val Tyr 1215 1220 1225 atc cag cag ctg gtg gag ggg ctg cac tac ctg cac agc cat ggc gtt 3806 Ile Gln Gln Leu Val Glu Gly Leu His Tyr Leu His Ser His Gly Val 1230 1235 1240 1245 ctc cac ctg gac ata aag ccc tct aac atc ctg atg gtg cat cct gcc 3854 Leu His Leu Asp Ile Lys Pro Ser Asn Ile Leu Met Val His Pro Ala 1250 1255 1260 cgg gaa gac att aaa atc tgc gac ttt ggc ttt gcc cag aac atc acc 3902 Arg Glu Asp Ile Lys Ile Cys Asp Phe Gly Phe Ala Gln Asn Ile Thr 1265 1270 1275 cca gca gag ctg cag ttc agc cag tac ggc tcc cct gag ttc gtc tcc 3950 Pro Ala Glu Leu Gln Phe Ser Gln Tyr Gly Ser Pro Glu Phe Val Ser 1280 1285 1290 ccc gag atc atc cag cag aac cct gtg agc gaa gcc tcc gac att tgg 3998 Pro Glu Ile Ile Gln Gln Asn Pro Val Ser Glu Ala Ser Asp Ile Trp 1295 1300 1305 gcc atg ggt gtc atc tcc tac ctc agc ctg acc tgc tca tcc cca ttt 4046 Ala Met Gly Val Ile Ser Tyr Leu Ser Leu Thr Cys Ser Ser Pro Phe 1310 1315 1320 1325 gcc ggc gag agt gac cgt gcc acc ctc ctg aac gtc ctg gag ggg cgc 4094 Ala Gly Glu Ser Asp Arg Ala Thr Leu Leu Asn Val Leu Glu Gly Arg 1330 1335 1340 gtg tca tgg agc agc ccc atg gct gcc cac ctc agc gaa gac gcc aaa 4142 Val Ser Trp Ser Ser Pro Met Ala Ala His Leu Ser Glu Asp Ala Lys 1345 1350 1355 gac ttc atc aag gct acg ctg cag aga gcc cct cag gcc cgg cct agt 4190 Asp Phe Ile Lys Ala Thr Leu Gln Arg Ala Pro Gln Ala Arg Pro Ser 1360 1365 1370 gcg gcc cag tgc ctc tcc cac ccc tgg ttc ctg aaa tcc atg cct gcg 4238 Ala Ala Gln Cys Leu Ser His Pro Trp Phe Leu Lys Ser Met Pro Ala 1375 1380 1385 gag gag gcc cac ttc atc aac acc aag cag ctc aag ttc ctc ctg gcc 4286 Glu Glu Ala His Phe Ile Asn Thr Lys Gln Leu Lys Phe Leu Leu Ala 1390 1395 1400 1405 cga agt cgc tgg cag cgt tcc ctg atg agc tac aag tcc atc ctg gtg 4334 Arg Ser Arg Trp Gln Arg Ser Leu Met Ser Tyr Lys Ser Ile Leu Val 1410 1415 1420 atg cgc tcc atc cct gag ctg ctg cgg ggc cca ccc gac agc ccc tcc 4382 Met Arg Ser Ile Pro Glu Leu Leu Arg Gly Pro Pro Asp Ser Pro Ser 1425 1430 1435 ctc ggc gta gcc cgg cac ctc tgc agg gac act ggt ggc tcc tcc agt 4430 Leu Gly Val Ala Arg His Leu Cys Arg Asp Thr Gly Gly Ser Ser Ser 1440 1445 1450 tcc tcc tcc tcc tct gac aac gag ctc gcc cca ttt gcc cgg gct aag 4478 Ser Ser Ser Ser Ser Asp Asn Glu Leu Ala Pro Phe Ala Arg Ala Lys 1455 1460 1465 tca ctg cca ccc tcc ccg gtg aca cac tca cca ctg ctg cac ccc cgg 4526 Ser Leu Pro Pro Ser Pro Val Thr His Ser Pro Leu Leu His Pro Arg 1470 1475 1480 1485 ggc ttc ctg cgg ccc tcg gcc agc ctg cct gag gaa gcc gag gcc agt 4574 Gly Phe Leu Arg Pro Ser Ala Ser Leu Pro Glu Glu Ala Glu Ala Ser 1490 1495

1500 gag cgc tcc acc gag gcc cca gct ccg cct gca tct ccc gag ggt gcc 4622 Glu Arg Ser Thr Glu Ala Pro Ala Pro Pro Ala Ser Pro Glu Gly Ala 1505 1510 1515 ggg cca ccg gcc gcc cag ggc tgc gtg ccc cgg cac agc gtc atc cgc 4670 Gly Pro Pro Ala Ala Gln Gly Cys Val Pro Arg His Ser Val Ile Arg 1520 1525 1530 agc ctg ttc tac cac cag gcg ggt gag agc cct gag cac ggg gcc ctg 4718 Ser Leu Phe Tyr His Gln Ala Gly Glu Ser Pro Glu His Gly Ala Leu 1535 1540 1545 gcc ccg ggg agc agg cgg cac ccg gcc cgg cgg cgg cac ctg ctg aag 4766 Ala Pro Gly Ser Arg Arg His Pro Ala Arg Arg Arg His Leu Leu Lys 1550 1555 1560 1565 ggc ggg tac att gcg ggg gcg ctg cca ggc ctg cgc gag cca ctg atg 4814 Gly Gly Tyr Ile Ala Gly Ala Leu Pro Gly Leu Arg Glu Pro Leu Met 1570 1575 1580 gag cac cgc gtg ctg gag gag gag gcc gcc agg gag gag cag gcc acc 4862 Glu His Arg Val Leu Glu Glu Glu Ala Ala Arg Glu Glu Gln Ala Thr 1585 1590 1595 ctc ctg gcc aaa gcc ccc tca ttc gag act gcc ctc cgg ctg cct gcc 4910 Leu Leu Ala Lys Ala Pro Ser Phe Glu Thr Ala Leu Arg Leu Pro Ala 1600 1605 1610 tct ggc acc cac ttg gcc cct ggc cac agc cac tcc ctg gaa cat gac 4958 Ser Gly Thr His Leu Ala Pro Gly His Ser His Ser Leu Glu His Asp 1615 1620 1625 tct ccg agc acc ccc cgc ccc tcc tcg gag gcc tgc ggt gag gca cag 5006 Ser Pro Ser Thr Pro Arg Pro Ser Ser Glu Ala Cys Gly Glu Ala Gln 1630 1635 1640 1645 cga ctg cct tca gcc ccc tcc ggg ggg gcc cct atc agg gac atg ggg 5054 Arg Leu Pro Ser Ala Pro Ser Gly Gly Ala Pro Ile Arg Asp Met Gly 1650 1655 1660 cac cct cag ggc tcc aag cag ctt cca tcc act ggt ggc cac cca ggc 5102 His Pro Gln Gly Ser Lys Gln Leu Pro Ser Thr Gly Gly His Pro Gly 1665 1670 1675 act gct cag cca gag agg cca tcc ccg gac agc cct tgg ggg cag cca 5150 Thr Ala Gln Pro Glu Arg Pro Ser Pro Asp Ser Pro Trp Gly Gln Pro 1680 1685 1690 gcc cct ttc tgc cac ccc aag cag ggt tct gcc ccc cag gag ggc tgc 5198 Ala Pro Phe Cys His Pro Lys Gln Gly Ser Ala Pro Gln Glu Gly Cys 1695 1700 1705 agc ccc cac cca gca gtt gcc cca tgc cct cct ggc tcc ttc cct cca 5246 Ser Pro His Pro Ala Val Ala Pro Cys Pro Pro Gly Ser Phe Pro Pro 1710 1715 1720 1725 gga tct tgc aaa gag gcc ccc tta gta ccc tca agc ccc ttc ttg gga 5294 Gly Ser Cys Lys Glu Ala Pro Leu Val Pro Ser Ser Pro Phe Leu Gly 1730 1735 1740 cag ccc cag gca ccc cct gcc cct gcc aaa gca agc ccc cca ttg gac 5342 Gln Pro Gln Ala Pro Pro Ala Pro Ala Lys Ala Ser Pro Pro Leu Asp 1745 1750 1755 tct aag atg ggg cct gga gac atc tct ctt cct ggg agg cca aaa ccc 5390 Ser Lys Met Gly Pro Gly Asp Ile Ser Leu Pro Gly Arg Pro Lys Pro 1760 1765 1770 ggc ccc tgc agt tcc cca ggg tca gcc tcc cag gcg agc tct tcc caa 5438 Gly Pro Cys Ser Ser Pro Gly Ser Ala Ser Gln Ala Ser Ser Ser Gln 1775 1780 1785 gtg agc tcc ctc agg gtg ggc tcc tcc cag gtg ggc aca gag cct ggc 5486 Val Ser Ser Leu Arg Val Gly Ser Ser Gln Val Gly Thr Glu Pro Gly 1790 1795 1800 1805 ccc tcc ctg gat gcg gag ggc tgg acc cag gag gct gag gat ctg tcc 5534 Pro Ser Leu Asp Ala Glu Gly Trp Thr Gln Glu Ala Glu Asp Leu Ser 1810 1815 1820 gac tcc aca ccc acc ttg cag cgg cct cag gaa cag gcg acc atg cgc 5582 Asp Ser Thr Pro Thr Leu Gln Arg Pro Gln Glu Gln Ala Thr Met Arg 1825 1830 1835 aag ttc tcc ctg ggt ggt cgc ggg ggc tac gca ggc gtg gct ggc tat 5630 Lys Phe Ser Leu Gly Gly Arg Gly Gly Tyr Ala Gly Val Ala Gly Tyr 1840 1845 1850 ggc acc ttt gcc ttt ggt gga gat gca ggg ggc atg ctg ggg cag ggg 5678 Gly Thr Phe Ala Phe Gly Gly Asp Ala Gly Gly Met Leu Gly Gln Gly 1855 1860 1865 ccc atg tgg gcc agg ata gcc tgg gct gtg tcc cag tcg gag gag gag 5726 Pro Met Trp Ala Arg Ile Ala Trp Ala Val Ser Gln Ser Glu Glu Glu 1870 1875 1880 1885 gag cag gag gag gcc agg gct gag tcc cag tcg gag gag cag cag gag 5774 Glu Gln Glu Glu Ala Arg Ala Glu Ser Gln Ser Glu Glu Gln Gln Glu 1890 1895 1900 gcc agg gct gag agc cca ctg ccc cag gtc agt gca agg cct gtg cct 5822 Ala Arg Ala Glu Ser Pro Leu Pro Gln Val Ser Ala Arg Pro Val Pro 1905 1910 1915 gag gtc ggc agg gct ccc acc agg agc tct cca gag ccc acc cca tgg 5870 Glu Val Gly Arg Ala Pro Thr Arg Ser Ser Pro Glu Pro Thr Pro Trp 1920 1925 1930 gag gac atc ggg cag gtc tcc ctg gtg cag atc cgg gac ctg tca ggt 5918 Glu Asp Ile Gly Gln Val Ser Leu Val Gln Ile Arg Asp Leu Ser Gly 1935 1940 1945 gat gcg gag gcg gcc gac aca ata tcc ctg gac att tcc gag gtg gac 5966 Asp Ala Glu Ala Ala Asp Thr Ile Ser Leu Asp Ile Ser Glu Val Asp 1950 1955 1960 1965 ccc gcc tac ctc aac ctc tca gac ctg tac gat atc aag tac ctc cca 6014 Pro Ala Tyr Leu Asn Leu Ser Asp Leu Tyr Asp Ile Lys Tyr Leu Pro 1970 1975 1980 ttc gag ttt atg atc ttc agg aaa gtc ccc aag tcc gct cag cca gag 6062 Phe Glu Phe Met Ile Phe Arg Lys Val Pro Lys Ser Ala Gln Pro Glu 1985 1990 1995 ccg ccc tcc ccc atg gct gag gag gag ctg gcc gag ttc ccg gag ccc 6110 Pro Pro Ser Pro Met Ala Glu Glu Glu Leu Ala Glu Phe Pro Glu Pro 2000 2005 2010 acg tgg ccc tgg cca ggt gaa ctg ggc ccc cac gca ggc ctg gag atc 6158 Thr Trp Pro Trp Pro Gly Glu Leu Gly Pro His Ala Gly Leu Glu Ile 2015 2020 2025 aca gag gag tca gag gat gtg gac gcg ctg ctg gca gag gct gcc gtg 6206 Thr Glu Glu Ser Glu Asp Val Asp Ala Leu Leu Ala Glu Ala Ala Val 2030 2035 2040 2045 ggc agg aag cgc aag tgg tcc tcg ccg tca cgc agc ctc ttc cac ttc 6254 Gly Arg Lys Arg Lys Trp Ser Ser Pro Ser Arg Ser Leu Phe His Phe 2050 2055 2060 cct ggg agg cac ctg ccg ctg gat gag cct gca gag ctg ggg ctg cgt 6302 Pro Gly Arg His Leu Pro Leu Asp Glu Pro Ala Glu Leu Gly Leu Arg 2065 2070 2075 gag aga gtg aag gcc tcc gtg gag cac atc tcc cgg atc ctg aag ggc 6350 Glu Arg Val Lys Ala Ser Val Glu His Ile Ser Arg Ile Leu Lys Gly 2080 2085 2090 agg ccg gaa ggt ctg gag aag gag ggg ccc ccc agg aag aag cca ggc 6398 Arg Pro Glu Gly Leu Glu Lys Glu Gly Pro Pro Arg Lys Lys Pro Gly 2095 2100 2105 ctt gct tcc ttc cgg ctc tca ggt ctg aag agc tgg gac cga gcg ccg 6446 Leu Ala Ser Phe Arg Leu Ser Gly Leu Lys Ser Trp Asp Arg Ala Pro 2110 2115 2120 2125 aca ttc cta agg gag ctc tca gat gag act gtg gtc ctg ggc cag tca 6494 Thr Phe Leu Arg Glu Leu Ser Asp Glu Thr Val Val Leu Gly Gln Ser 2130 2135 2140 gtg aca ctg gcc tgc cag gtg tca gcc cag cca gct gcc cag gcc acc 6542 Val Thr Leu Ala Cys Gln Val Ser Ala Gln Pro Ala Ala Gln Ala Thr 2145 2150 2155 tgg agc aaa gac gga gcc ccc ctg gag agc agc agc cgt gtc ctc atc 6590 Trp Ser Lys Asp Gly Ala Pro Leu Glu Ser Ser Ser Arg Val Leu Ile 2160 2165 2170 tct gcc acc ctc aag aac ttc cag ctt ctg acc atc ctg gtg gtg gtg 6638 Ser Ala Thr Leu Lys Asn Phe Gln Leu Leu Thr Ile Leu Val Val Val 2175 2180 2185 gct gag gac ctg ggt gtg tac acc tgc agc gtg agc aat gcg ctg ggg 6686 Ala Glu Asp Leu Gly Val Tyr Thr Cys Ser Val Ser Asn Ala Leu Gly 2190 2195 2200 2205 aca gtg acc acc acg ggc gtc ctc cgg aag gca gag cgc ccc tca tct 6734 Thr Val Thr Thr Thr Gly Val Leu Arg Lys Ala Glu Arg Pro Ser Ser 2210 2215 2220 tcg cca tgc ccg gat atc ggg gag gtg tac gcg gat ggg gtg ctg ctg 6782 Ser Pro Cys Pro Asp Ile Gly Glu Val Tyr Ala Asp Gly Val Leu Leu 2225 2230 2235 gtc tgg aag ccc gtg gaa tcc tac ggc cct gtg acc tac att gtg cag 6830 Val Trp Lys Pro Val Glu Ser Tyr Gly Pro Val Thr Tyr Ile Val Gln 2240 2245 2250 tgc agc cta gaa ggc ggc agc tgg acc aca ctg gcc tcc gac atc ttt 6878 Cys Ser Leu Glu Gly Gly Ser Trp Thr Thr Leu Ala Ser Asp Ile Phe 2255 2260 2265 gac tgc tgc tac ctg acc agc aag ctc tcc cgg ggt ggc acc tac acc 6926 Asp Cys Cys Tyr Leu Thr Ser Lys Leu Ser Arg Gly Gly Thr Tyr Thr 2270 2275 2280 2285 ttc cgc acg gca tgt gtc agc aag gca gga atg ggt ccc tac agc agc 6974 Phe Arg Thr Ala Cys Val Ser Lys Ala Gly Met Gly Pro Tyr Ser Ser 2290 2295 2300 ccc tcg gag caa gtc ctc ctg gga ggg ccc agc cac ctg gcc tct gag 7022 Pro Ser Glu Gln Val Leu Leu Gly Gly Pro Ser His Leu Ala Ser Glu 2305 2310 2315 gag gag agc cag ggg cgg tca gcc caa ccc ctg ccc agc aca aag acc 7070 Glu Glu Ser Gln Gly Arg Ser Ala Gln Pro Leu Pro Ser Thr Lys Thr 2320 2325 2330 ttc gca ttc cag aca cag atc cag agg ggc cgc ttc agc gtg gtg cgg 7118 Phe Ala Phe Gln Thr Gln Ile Gln Arg Gly Arg Phe Ser Val Val Arg 2335 2340 2345 caa tgc tgg gag aag gcc agc ggg cgg gcg ctg gcc gcc aag atc atc 7166 Gln Cys Trp Glu Lys Ala Ser Gly Arg Ala Leu Ala Ala Lys Ile Ile 2350 2355 2360 2365 ccc tac cac ccc aag gac aag aca gca gtg ctg cgc gaa tac gag gcc 7214 Pro Tyr His Pro Lys Asp Lys Thr Ala Val Leu Arg Glu Tyr Glu Ala 2370 2375 2380 ctc aag ggc ctg cgc cac ccg cac ctg gcc cag ctg cac gca gcc tac 7262 Leu Lys Gly Leu Arg His Pro His Leu Ala Gln Leu His Ala Ala Tyr 2385 2390 2395 ctc agc ccc cgg cac ctg gtg ctc atc ttg gag ctg tgc tct ggg ccc 7310 Leu Ser Pro Arg His Leu Val Leu Ile Leu Glu Leu Cys Ser Gly Pro 2400 2405 2410 gag ctg ctc ccc tgc ctg gcc gag agg gcc tcc tac tca gaa tcc gag 7358 Glu Leu Leu Pro Cys Leu Ala Glu Arg Ala Ser Tyr Ser Glu Ser Glu 2415 2420 2425 gtg aag gac tac ctg tgg cag atg ttg agt gcc acc cag tac ctg cac 7406 Val Lys Asp Tyr Leu Trp Gln Met Leu Ser Ala Thr Gln Tyr Leu His 2430 2435 2440 2445 aac cag cac atc ctg cac ctg gac ctg agg tcc gag aac atg atc atc 7454 Asn Gln His Ile Leu His Leu Asp Leu Arg Ser Glu Asn Met Ile Ile 2450 2455 2460 acc gaa tac aac ctg ctc aag gtc gtg gac ctg ggc aat gca cag agc 7502 Thr Glu Tyr Asn Leu Leu Lys Val Val Asp Leu Gly Asn Ala Gln Ser 2465 2470 2475 ctc agc cag gag aag gtg ctg ccc tca gac aag ttc aag gac tac cta 7550 Leu Ser Gln Glu Lys Val Leu Pro Ser Asp Lys Phe Lys Asp Tyr Leu 2480 2485 2490 gag acc atg gct cca gag ctc ctg gag ggc cag ggg gct gtt cca cag 7598 Glu Thr Met Ala Pro Glu Leu Leu Glu Gly Gln Gly Ala Val Pro Gln 2495 2500 2505 aca gac atc tgg gcc atc ggt gtg aca gcc ttc atc atg ctg agc gcc 7646 Thr Asp Ile Trp Ala Ile Gly Val Thr Ala Phe Ile Met Leu Ser Ala 2510 2515 2520 2525 gag tac ccg gtg agc agc gag ggt gca cgc gac ctg cag aga gga ctg 7694 Glu Tyr Pro Val Ser Ser Glu Gly Ala Arg Asp Leu Gln Arg Gly Leu 2530 2535 2540 cgc aag ggg ctg gtc cgg ctg agc cgc tgc tac gcg ggg ctg tcc ggg 7742 Arg Lys Gly Leu Val Arg Leu Ser Arg Cys Tyr Ala Gly Leu Ser Gly 2545 2550 2555 ggc gcc gtg gcc ttc ctg cgc agc act ctg tgc gcc cag ccc tgg ggc 7790 Gly Ala Val Ala Phe Leu Arg Ser Thr Leu Cys Ala Gln Pro Trp Gly 2560 2565 2570 cgg ccc tgc gcg tcc agc tgc ctg cag tgc ccg tgg cta aca gag gag 7838 Arg Pro Cys Ala Ser Ser Cys Leu Gln Cys Pro Trp Leu Thr Glu Glu 2575 2580 2585 ggc ccg gcc tgt tcg cgg ccc gcg ccc gtg acc ttc cct acc gcg cgg 7886 Gly Pro Ala Cys Ser Arg Pro Ala Pro Val Thr Phe Pro Thr Ala Arg 2590 2595 2600 2605 ctg cgc gtc ttc gtg cgc aat cgc gag aag aga cgc gcg ctg ctg tac 7934 Leu Arg Val Phe Val Arg Asn Arg Glu Lys Arg Arg Ala Leu Leu Tyr 2610 2615 2620 aag agg cac aac ctg gcc cag gtg cgc tga gggtcgcccc ggccacaccc 7984 Lys Arg His Asn Leu Ala Gln Val Arg * 2625 2630 ttggtctccc cgctgggggt cgctgcagac gcgccaataa aaacgcccag ccgggcgaga 8044 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaag gcggccgcta aaaaagtcta 8104 ga 8106 2 2630 PRT Homo sapiens 2 Met Gly Ala Ala Tyr Ser Ser Ala Arg Leu Leu Val Arg Gly Pro Asp 1 5 10 15 Glu Pro Glu Glu Lys Pro Ala Ser Asp Val His Glu Gln Leu Val Pro 20 25 30 Pro Arg Met Leu Glu Arg Phe Thr Pro Lys Lys Val Lys Lys Gly Ser 35 40 45 Ser Ile Thr Phe Ser Val Lys Val Glu Gly Arg Pro Val Pro Thr Val 50 55 60 His Trp Leu Arg Glu Glu Ala Glu Arg Gly Val Leu Trp Ile Gly Pro 65 70 75 80 Asp Thr Pro Gly Tyr Thr Val Ala Ser Ser Ala Gln Gln His Ser Leu 85 90 95 Val Leu Leu Asp Val Gly Arg Gln His Gln Gly Thr Tyr Thr Cys Ile 100 105 110 Ala Ser Asn Ala Ala Gly Gln Ala Leu Cys Ser Ala Ser Leu His Val 115 120 125 Ser Gly Leu Pro Lys Val Glu Glu Gln Glu Lys Val Lys Glu Ala Leu 130 135 140 Ile Ser Thr Phe Leu Gln Gly Thr Thr Gln Ala Ile Ser Ala Gln Gly 145 150 155 160 Leu Glu Thr Ala Ser Phe Ala Asp Leu Gly Gly Gln Arg Lys Glu Glu 165 170 175 Pro Leu Ala Ala Lys Glu Ala Leu Gly His Leu Ser Leu Ala Glu Val 180 185 190 Gly Thr Glu Glu Phe Leu Gln Lys Leu Thr Ser Gln Ile Thr Glu Met 195 200 205 Val Ser Ala Lys Ile Thr Gln Ala Lys Leu Gln Val Pro Gly Gly Asp 210 215 220 Ser Asp Glu Asp Ser Lys Thr Pro Ser Ala Ser Pro Arg His Gly Arg 225 230 235 240 Ser Arg Pro Ser Ser Ser Ile Gln Glu Ser Ser Ser Glu Ser Glu Asp 245 250 255 Gly Asp Ala Arg Gly Glu Ile Phe Asp Ile Tyr Val Val Thr Ala Asp 260 265 270 Tyr Leu Pro Leu Gly Ala Glu Gln Asp Ala Ile Thr Leu Arg Glu Gly 275 280 285 Gln Tyr Val Glu Val Leu Asp Ala Ala His Pro Leu Arg Trp Leu Val 290 295 300 Arg Thr Lys Pro Thr Lys Ser Ser Pro Ser Arg Gln Gly Trp Val Ser 305 310 315 320 Pro Ala Tyr Leu Asp Arg Arg Leu Lys Leu Ser Pro Glu Trp Gly Ala 325 330 335 Ala Glu Ala Pro Glu Phe Pro Gly Glu Ala Val Ser Glu Asp Glu Tyr 340 345 350 Lys Ala Arg Leu Ser Ser Val Ile Gln Glu Leu Leu Ser Ser Glu Gln 355 360 365 Ala Phe Val Glu Glu Leu Gln Phe Leu Gln Ser His His Leu Gln His 370 375 380 Leu Glu Arg Cys Pro His Val Pro Ile Ala Val Ala Gly Gln Lys Ala 385 390 395 400 Val Ile Phe Arg Asn Val Arg Asp Ile Gly Arg Phe His Ser Ser Phe 405 410 415 Leu Gln Glu Leu Gln Gln Cys Asp Thr Asp Asp Asp Val Ala Met Cys 420 425 430 Phe Ile Lys Asn Gln Ala Ala Phe Glu Gln Tyr Leu Glu Phe Leu Val 435 440 445 Gly Arg Val Gln Ala Glu Ser Val Val Val Ser Thr Ala Ile Gln Glu 450 455 460 Phe Tyr Lys Lys Tyr Ala Glu Glu Ala Leu Leu Ala Gly Asp Pro Ser 465 470 475 480 Gln Pro Pro Pro Pro Pro Leu Gln His Tyr Leu Glu Gln Pro Val Glu 485 490 495 Arg Val Gln Arg Tyr Gln Ala Leu Leu Lys Glu Leu Ile Arg Asn Lys 500 505 510 Ala Arg Asn Arg Gln Asn Cys Ala Leu Leu Glu Gln Ala Tyr Ala Val 515 520 525 Val Ser Ala Leu Pro Gln Arg Ala Glu Asn Lys Leu His Val Ser Leu 530 535 540 Met Glu Asn Tyr Pro Gly Thr Leu Glu Ala Leu Gly Glu Pro Ile Arg 545 550 555 560 Gln Gly His Phe Ile Val Trp Glu Gly Ala Pro Gly Ala Arg Met Pro 565

570 575 Trp Lys Gly His Asn Arg His Val Phe Leu Phe Arg Asn His Leu Val 580 585 590 Ile Cys Lys Pro Arg Arg Asp Ser Arg Thr Asp Thr Val Ser Tyr Val 595 600 605 Phe Arg Asn Met Met Lys Leu Ser Ser Ile Asp Leu Asn Asp Gln Val 610 615 620 Glu Gly Asp Asp Arg Ala Phe Glu Val Trp Gln Glu Arg Glu Asp Ser 625 630 635 640 Val Arg Lys Tyr Leu Leu Gln Ala Arg Thr Ala Ile Ile Lys Ser Ser 645 650 655 Trp Val Lys Glu Ile Cys Gly Ile Gln Gln Arg Leu Ala Leu Pro Val 660 665 670 Trp Arg Pro Pro Asp Phe Glu Glu Glu Leu Ala Asp Cys Thr Ala Glu 675 680 685 Leu Gly Glu Thr Val Lys Leu Ala Cys Arg Val Thr Gly Thr Pro Lys 690 695 700 Pro Val Ile Ser Trp Tyr Lys Asp Gly Lys Ala Val Gln Val Asp Pro 705 710 715 720 His His Ile Leu Ile Glu Asp Pro Asp Gly Ser Cys Ala Leu Ile Leu 725 730 735 Asp Ser Leu Thr Gly Val Asp Ser Gly Gln Tyr Met Cys Phe Ala Ala 740 745 750 Ser Ala Ala Gly Asn Cys Ser Thr Leu Gly Lys Ile Leu Val Gln Val 755 760 765 Pro Pro Arg Phe Val Asn Lys Val Arg Ala Ser Pro Phe Val Glu Gly 770 775 780 Glu Asp Ala Gln Phe Thr Cys Thr Ile Glu Gly Ala Pro Tyr Pro Gln 785 790 795 800 Ile Arg Trp Tyr Lys Asp Gly Ala Leu Leu Thr Thr Gly Asn Lys Phe 805 810 815 Gln Thr Leu Ser Glu Pro Arg Ser Gly Leu Leu Val Leu Val Ile Arg 820 825 830 Ala Ala Ser Lys Glu Asp Leu Gly Leu Tyr Glu Cys Glu Leu Val Asn 835 840 845 Arg Leu Gly Ser Ala Arg Ala Ser Ala Glu Leu Arg Ile Gln Ser Pro 850 855 860 Met Leu Gln Ala Gln Glu Gln Cys His Arg Glu Gln Leu Val Ala Ala 865 870 875 880 Val Glu Asp Thr Thr Leu Glu Arg Ala Asp Gln Glu Val Thr Ser Val 885 890 895 Leu Lys Arg Leu Leu Gly Pro Lys Ala Pro Gly Pro Ser Thr Gly Asp 900 905 910 Leu Thr Gly Pro Gly Pro Cys Pro Arg Gly Ala Pro Ala Leu Gln Glu 915 920 925 Thr Gly Ser Gln Pro Pro Val Thr Gly Thr Ser Glu Ala Pro Ala Val 930 935 940 Pro Pro Arg Val Pro Gln Pro Leu Leu His Glu Gly Pro Glu Gln Glu 945 950 955 960 Pro Glu Ala Ile Ala Arg Ala Gln Glu Trp Thr Val Pro Ile Arg Met 965 970 975 Glu Gly Ala Ala Trp Pro Gly Ala Gly Thr Gly Glu Leu Leu Trp Asp 980 985 990 Val His Ser His Val Val Arg Glu Thr Thr Gln Arg Thr Tyr Thr Tyr 995 1000 1005 Gln Ala Ile Asp Thr His Thr Ala Arg Pro Pro Ser Met Gln Val Thr 1010 1015 1020 Ile Glu Asp Val Gln Ala Gln Thr Gly Gly Thr Ala Gln Phe Glu Ala 1025 1030 1035 1040 Ile Ile Glu Gly Asp Pro Gln Pro Ser Val Thr Trp Tyr Lys Asp Ser 1045 1050 1055 Val Gln Leu Val Asp Ser Thr Arg Leu Ser Gln Gln Gln Glu Gly Thr 1060 1065 1070 Thr Tyr Ser Leu Val Leu Arg His Val Ala Ser Lys Asp Ala Gly Val 1075 1080 1085 Tyr Thr Cys Leu Ala Gln Asn Thr Gly Gly Gln Val Leu Cys Lys Ala 1090 1095 1100 Glu Leu Leu Val Leu Gly Gly Asp Asn Glu Pro Asp Ser Glu Lys Gln 1105 1110 1115 1120 Ser His Arg Arg Lys Leu His Ser Phe Tyr Glu Val Lys Glu Glu Ile 1125 1130 1135 Gly Arg Gly Val Phe Gly Phe Val Lys Arg Val Gln His Lys Gly Asn 1140 1145 1150 Lys Ile Leu Cys Ala Ala Lys Phe Ile Pro Leu Arg Ser Arg Thr Arg 1155 1160 1165 Ala Gln Ala Tyr Arg Glu Arg Asp Ile Leu Ala Ala Leu Ser His Pro 1170 1175 1180 Leu Val Thr Gly Leu Leu Asp Gln Phe Glu Thr Arg Lys Thr Leu Ile 1185 1190 1195 1200 Leu Ile Leu Glu Leu Cys Ser Ser Glu Glu Leu Leu Asp Arg Leu Tyr 1205 1210 1215 Arg Lys Gly Val Val Thr Glu Ala Glu Val Lys Val Tyr Ile Gln Gln 1220 1225 1230 Leu Val Glu Gly Leu His Tyr Leu His Ser His Gly Val Leu His Leu 1235 1240 1245 Asp Ile Lys Pro Ser Asn Ile Leu Met Val His Pro Ala Arg Glu Asp 1250 1255 1260 Ile Lys Ile Cys Asp Phe Gly Phe Ala Gln Asn Ile Thr Pro Ala Glu 1265 1270 1275 1280 Leu Gln Phe Ser Gln Tyr Gly Ser Pro Glu Phe Val Ser Pro Glu Ile 1285 1290 1295 Ile Gln Gln Asn Pro Val Ser Glu Ala Ser Asp Ile Trp Ala Met Gly 1300 1305 1310 Val Ile Ser Tyr Leu Ser Leu Thr Cys Ser Ser Pro Phe Ala Gly Glu 1315 1320 1325 Ser Asp Arg Ala Thr Leu Leu Asn Val Leu Glu Gly Arg Val Ser Trp 1330 1335 1340 Ser Ser Pro Met Ala Ala His Leu Ser Glu Asp Ala Lys Asp Phe Ile 1345 1350 1355 1360 Lys Ala Thr Leu Gln Arg Ala Pro Gln Ala Arg Pro Ser Ala Ala Gln 1365 1370 1375 Cys Leu Ser His Pro Trp Phe Leu Lys Ser Met Pro Ala Glu Glu Ala 1380 1385 1390 His Phe Ile Asn Thr Lys Gln Leu Lys Phe Leu Leu Ala Arg Ser Arg 1395 1400 1405 Trp Gln Arg Ser Leu Met Ser Tyr Lys Ser Ile Leu Val Met Arg Ser 1410 1415 1420 Ile Pro Glu Leu Leu Arg Gly Pro Pro Asp Ser Pro Ser Leu Gly Val 1425 1430 1435 1440 Ala Arg His Leu Cys Arg Asp Thr Gly Gly Ser Ser Ser Ser Ser Ser 1445 1450 1455 Ser Ser Asp Asn Glu Leu Ala Pro Phe Ala Arg Ala Lys Ser Leu Pro 1460 1465 1470 Pro Ser Pro Val Thr His Ser Pro Leu Leu His Pro Arg Gly Phe Leu 1475 1480 1485 Arg Pro Ser Ala Ser Leu Pro Glu Glu Ala Glu Ala Ser Glu Arg Ser 1490 1495 1500 Thr Glu Ala Pro Ala Pro Pro Ala Ser Pro Glu Gly Ala Gly Pro Pro 1505 1510 1515 1520 Ala Ala Gln Gly Cys Val Pro Arg His Ser Val Ile Arg Ser Leu Phe 1525 1530 1535 Tyr His Gln Ala Gly Glu Ser Pro Glu His Gly Ala Leu Ala Pro Gly 1540 1545 1550 Ser Arg Arg His Pro Ala Arg Arg Arg His Leu Leu Lys Gly Gly Tyr 1555 1560 1565 Ile Ala Gly Ala Leu Pro Gly Leu Arg Glu Pro Leu Met Glu His Arg 1570 1575 1580 Val Leu Glu Glu Glu Ala Ala Arg Glu Glu Gln Ala Thr Leu Leu Ala 1585 1590 1595 1600 Lys Ala Pro Ser Phe Glu Thr Ala Leu Arg Leu Pro Ala Ser Gly Thr 1605 1610 1615 His Leu Ala Pro Gly His Ser His Ser Leu Glu His Asp Ser Pro Ser 1620 1625 1630 Thr Pro Arg Pro Ser Ser Glu Ala Cys Gly Glu Ala Gln Arg Leu Pro 1635 1640 1645 Ser Ala Pro Ser Gly Gly Ala Pro Ile Arg Asp Met Gly His Pro Gln 1650 1655 1660 Gly Ser Lys Gln Leu Pro Ser Thr Gly Gly His Pro Gly Thr Ala Gln 1665 1670 1675 1680 Pro Glu Arg Pro Ser Pro Asp Ser Pro Trp Gly Gln Pro Ala Pro Phe 1685 1690 1695 Cys His Pro Lys Gln Gly Ser Ala Pro Gln Glu Gly Cys Ser Pro His 1700 1705 1710 Pro Ala Val Ala Pro Cys Pro Pro Gly Ser Phe Pro Pro Gly Ser Cys 1715 1720 1725 Lys Glu Ala Pro Leu Val Pro Ser Ser Pro Phe Leu Gly Gln Pro Gln 1730 1735 1740 Ala Pro Pro Ala Pro Ala Lys Ala Ser Pro Pro Leu Asp Ser Lys Met 1745 1750 1755 1760 Gly Pro Gly Asp Ile Ser Leu Pro Gly Arg Pro Lys Pro Gly Pro Cys 1765 1770 1775 Ser Ser Pro Gly Ser Ala Ser Gln Ala Ser Ser Ser Gln Val Ser Ser 1780 1785 1790 Leu Arg Val Gly Ser Ser Gln Val Gly Thr Glu Pro Gly Pro Ser Leu 1795 1800 1805 Asp Ala Glu Gly Trp Thr Gln Glu Ala Glu Asp Leu Ser Asp Ser Thr 1810 1815 1820 Pro Thr Leu Gln Arg Pro Gln Glu Gln Ala Thr Met Arg Lys Phe Ser 1825 1830 1835 1840 Leu Gly Gly Arg Gly Gly Tyr Ala Gly Val Ala Gly Tyr Gly Thr Phe 1845 1850 1855 Ala Phe Gly Gly Asp Ala Gly Gly Met Leu Gly Gln Gly Pro Met Trp 1860 1865 1870 Ala Arg Ile Ala Trp Ala Val Ser Gln Ser Glu Glu Glu Glu Gln Glu 1875 1880 1885 Glu Ala Arg Ala Glu Ser Gln Ser Glu Glu Gln Gln Glu Ala Arg Ala 1890 1895 1900 Glu Ser Pro Leu Pro Gln Val Ser Ala Arg Pro Val Pro Glu Val Gly 1905 1910 1915 1920 Arg Ala Pro Thr Arg Ser Ser Pro Glu Pro Thr Pro Trp Glu Asp Ile 1925 1930 1935 Gly Gln Val Ser Leu Val Gln Ile Arg Asp Leu Ser Gly Asp Ala Glu 1940 1945 1950 Ala Ala Asp Thr Ile Ser Leu Asp Ile Ser Glu Val Asp Pro Ala Tyr 1955 1960 1965 Leu Asn Leu Ser Asp Leu Tyr Asp Ile Lys Tyr Leu Pro Phe Glu Phe 1970 1975 1980 Met Ile Phe Arg Lys Val Pro Lys Ser Ala Gln Pro Glu Pro Pro Ser 1985 1990 1995 2000 Pro Met Ala Glu Glu Glu Leu Ala Glu Phe Pro Glu Pro Thr Trp Pro 2005 2010 2015 Trp Pro Gly Glu Leu Gly Pro His Ala Gly Leu Glu Ile Thr Glu Glu 2020 2025 2030 Ser Glu Asp Val Asp Ala Leu Leu Ala Glu Ala Ala Val Gly Arg Lys 2035 2040 2045 Arg Lys Trp Ser Ser Pro Ser Arg Ser Leu Phe His Phe Pro Gly Arg 2050 2055 2060 His Leu Pro Leu Asp Glu Pro Ala Glu Leu Gly Leu Arg Glu Arg Val 2065 2070 2075 2080 Lys Ala Ser Val Glu His Ile Ser Arg Ile Leu Lys Gly Arg Pro Glu 2085 2090 2095 Gly Leu Glu Lys Glu Gly Pro Pro Arg Lys Lys Pro Gly Leu Ala Ser 2100 2105 2110 Phe Arg Leu Ser Gly Leu Lys Ser Trp Asp Arg Ala Pro Thr Phe Leu 2115 2120 2125 Arg Glu Leu Ser Asp Glu Thr Val Val Leu Gly Gln Ser Val Thr Leu 2130 2135 2140 Ala Cys Gln Val Ser Ala Gln Pro Ala Ala Gln Ala Thr Trp Ser Lys 2145 2150 2155 2160 Asp Gly Ala Pro Leu Glu Ser Ser Ser Arg Val Leu Ile Ser Ala Thr 2165 2170 2175 Leu Lys Asn Phe Gln Leu Leu Thr Ile Leu Val Val Val Ala Glu Asp 2180 2185 2190 Leu Gly Val Tyr Thr Cys Ser Val Ser Asn Ala Leu Gly Thr Val Thr 2195 2200 2205 Thr Thr Gly Val Leu Arg Lys Ala Glu Arg Pro Ser Ser Ser Pro Cys 2210 2215 2220 Pro Asp Ile Gly Glu Val Tyr Ala Asp Gly Val Leu Leu Val Trp Lys 2225 2230 2235 2240 Pro Val Glu Ser Tyr Gly Pro Val Thr Tyr Ile Val Gln Cys Ser Leu 2245 2250 2255 Glu Gly Gly Ser Trp Thr Thr Leu Ala Ser Asp Ile Phe Asp Cys Cys 2260 2265 2270 Tyr Leu Thr Ser Lys Leu Ser Arg Gly Gly Thr Tyr Thr Phe Arg Thr 2275 2280 2285 Ala Cys Val Ser Lys Ala Gly Met Gly Pro Tyr Ser Ser Pro Ser Glu 2290 2295 2300 Gln Val Leu Leu Gly Gly Pro Ser His Leu Ala Ser Glu Glu Glu Ser 2305 2310 2315 2320 Gln Gly Arg Ser Ala Gln Pro Leu Pro Ser Thr Lys Thr Phe Ala Phe 2325 2330 2335 Gln Thr Gln Ile Gln Arg Gly Arg Phe Ser Val Val Arg Gln Cys Trp 2340 2345 2350 Glu Lys Ala Ser Gly Arg Ala Leu Ala Ala Lys Ile Ile Pro Tyr His 2355 2360 2365 Pro Lys Asp Lys Thr Ala Val Leu Arg Glu Tyr Glu Ala Leu Lys Gly 2370 2375 2380 Leu Arg His Pro His Leu Ala Gln Leu His Ala Ala Tyr Leu Ser Pro 2385 2390 2395 2400 Arg His Leu Val Leu Ile Leu Glu Leu Cys Ser Gly Pro Glu Leu Leu 2405 2410 2415 Pro Cys Leu Ala Glu Arg Ala Ser Tyr Ser Glu Ser Glu Val Lys Asp 2420 2425 2430 Tyr Leu Trp Gln Met Leu Ser Ala Thr Gln Tyr Leu His Asn Gln His 2435 2440 2445 Ile Leu His Leu Asp Leu Arg Ser Glu Asn Met Ile Ile Thr Glu Tyr 2450 2455 2460 Asn Leu Leu Lys Val Val Asp Leu Gly Asn Ala Gln Ser Leu Ser Gln 2465 2470 2475 2480 Glu Lys Val Leu Pro Ser Asp Lys Phe Lys Asp Tyr Leu Glu Thr Met 2485 2490 2495 Ala Pro Glu Leu Leu Glu Gly Gln Gly Ala Val Pro Gln Thr Asp Ile 2500 2505 2510 Trp Ala Ile Gly Val Thr Ala Phe Ile Met Leu Ser Ala Glu Tyr Pro 2515 2520 2525 Val Ser Ser Glu Gly Ala Arg Asp Leu Gln Arg Gly Leu Arg Lys Gly 2530 2535 2540 Leu Val Arg Leu Ser Arg Cys Tyr Ala Gly Leu Ser Gly Gly Ala Val 2545 2550 2555 2560 Ala Phe Leu Arg Ser Thr Leu Cys Ala Gln Pro Trp Gly Arg Pro Cys 2565 2570 2575 Ala Ser Ser Cys Leu Gln Cys Pro Trp Leu Thr Glu Glu Gly Pro Ala 2580 2585 2590 Cys Ser Arg Pro Ala Pro Val Thr Phe Pro Thr Ala Arg Leu Arg Val 2595 2600 2605 Phe Val Arg Asn Arg Glu Lys Arg Arg Ala Leu Leu Tyr Lys Arg His 2610 2615 2620 Asn Leu Ala Gln Val Arg 2625 2630 3 7893 DNA Homo sapiens 3 atgggtgctg cctactcgtc tgcccggctg ctggttcgag gccctgatga gccagaagag 60 aagcctgcat cagatgtgca tgagcagctg gtgccgcccc gaatgctgga gaggttcacc 120 cccaagaaag tgaagaaagg ctccagcatc accttctctg tgaaggtaga aggacgcccg 180 gtgcccaccg tgcactggct cagggaggag gctgagagag gcgtgctgtg gattggccct 240 gacacaccgg gctacaccgt ggccagctct gcgcagcagc acagcctggt cctgctggac 300 gtgggccggc agcaccaggg cacctacaca tgcattgcca gcaacgctgc cggccaggcc 360 ctctgctccg ccagcctgca cgtctcgggc ctgcctaagg tggaggagca ggagaaagtg 420 aaggaagcgc tgatttccac tttcctgcag gggaccacac aagccatctc agcacagggg 480 ttggaaactg cgagttttgc tgaccttggt gggcagagga aagaagagcc tctggctgcc 540 aaggaggccc tcggccacct gtccctcgct gaggtgggca cagaggagtt cctgcagaaa 600 ctgacctccc agatcactga gatggtatcg gccaagatca cgcaggccaa gctgcaggtg 660 cccggaggtg acagtgatga ggactccaag acaccatctg catccccccg ccatggccga 720 tcacggccat cctccagcat ccaggagtct tcctcagagt cagaggacgg cgatgcccga 780 ggcgagatct ttgacatcta cgtggtcacc gctgactacc tgcccctagg ggctgagcag 840 gatgccatca cgctgcggga aggccagtat gtggaggtcc tggatgcagc ccacccactg 900 cgctggcttg tccgcaccaa gcccaccaag tccagcccct cacggcaggg ctgggtgtca 960 ccagcctacc tggacaggag gctcaagctg tcacctgagt ggggggccgc tgaggcccct 1020 gagttccctg gggaggctgt gtctgaagac gaatacaagg caaggctgag ctctgtgatc 1080 caggagctgc tgagttctga gcaggccttc gtggaggagc tgcagttcct gcagagccac 1140 cacctgcagc acctggagcg ctgcccccac gtgcccatag ccgtggccgg ccagaaggca 1200 gtcatcttcc gcaatgtgcg ggacatcggc cgcttccaca gcagcttcct gcaggagttg 1260 cagcagtgcg acacggacga cgacgtggcc atgtgcttca tcaagaacca ggcggccttt 1320 gagcagtacc tggagttcct ggtggggcgt gtgcaggctg agtcggtggt cgtcagcacg 1380 gccatccagg agttctacaa gaaatacgcg gaggaggccc tgttggcagg ggacccctct 1440 cagcccccgc caccacctct gcagcactac ctggagcagc cagtggagcg ggtgcagcgc 1500 taccaggcct tgctgaagga gttgatccgc aacaaggcgc ggaacagaca gaactgcgcg 1560 ctgctggagc aggcctatgc cgtggtgtct gccctgccac agcgcgctga gaacaagctg 1620 cacgtgtccc tcatggagaa ctacccaggc accctggagg ccctgggcga gcccatccgc 1680 cagggccact tcatcgtgtg ggagggtgca ccgggggccc gcatgccctg gaagggccac 1740 aaccgtcacg tgttcctctt ccgcaaccac ctggtaatct gcaagccccg gcgagactcc 1800 cgcaccgata ccgtcagcta cgtgttccgg aacatgatga agctgagcag catcgacctg 1860 aacgaccagg tggaggggga tgaccgcgcc ttcgaggtgt ggcaggagcg ggaggactcg 1920 gtgcgcaagt acctgctgca ggcacggaca gccattatca agagctcgtg ggtgaaggag 1980 atctgtggca tccagcagcg tctggccctg cctgtgtggc ggcccccgga ctttgaagag 2040 gagctggccg actgcacagc cgagctgggt gagacagtca agctggcctg ccgcgtgacg 2100 ggcacaccca agcctgtcat cagctggtac aaagatggga aagcagtgca ggtggacccc 2160 caccacatcc tcattgaaga ccctgatggc tcgtgtgcac tcatcctgga cagcctgacc 2220

ggtgtggact ctggccagta catgtgcttc gcggccagcg ccgctggcaa ctgcagtacc 2280 ctgggcaaga tcctggtgca agtcccacca cggttcgtga acaaggtccg ggcctcaccc 2340 tttgtggagg gagaggacgc ccagttcacc tgcaccatcg aaggcgcccc gtacccgcag 2400 atcaggtggt acaaggacgg ggccctgctg accactggca acaagttcca gacactgagt 2460 gagcctcgca gcggcctgct agtgctggtg atccgggcgg ccagcaagga ggacctgggg 2520 ctctacgagt gtgagctggt gaaccggctg ggctccgcgc gggctagtgc ggagctgcgc 2580 attcagagcc ccatgctgca ggcccaggag cagtgtcaca gggagcagct cgtggctgca 2640 gtggaagaca ccaccctgga gcgagcggac caggaggtca catctgtcct gaagagactg 2700 ctgggcccca aggcgccagg cccctccaca ggggacctca ctggccctgg cccctgcccc 2760 aggggggcac ccgcactcca ggaaaccggc tcccagcccc cagtcaccgg aacttcggag 2820 gcacctgccg tgcccccgag ggtgccacag cccctcctcc acgaaggccc agagcaggag 2880 ccggaggcca ttgccagagc ccaggaatgg actgtgccca ttcggatgga gggtgcagcc 2940 tggcccgggg caggcacagg ggagctgctc tgggacgtcc acagccacgt ggtcagagag 3000 accacacaga ggacctacac ataccaggcc atcgacacgc acaccgcacg gcccccatcc 3060 atgcaggtaa ccatcgagga tgtgcaggca cagacaggcg gaacggccca attcgaggct 3120 atcattgagg gcgacccaca gccctcggtg acctggtaca aggacagcgt ccagctggtg 3180 gacagcaccc ggcttagcca gcagcaagaa ggcaccacat actccctggt gctgaggcat 3240 gtggcctcga aggatgccgg cgtttacacc tgcctggccc aaaacactgg tggccaggtg 3300 ctctgcaagg cagagctgct ggtgcttggg ggggacaatg agccggactc agagaagcaa 3360 agccaccgga ggaagctgca ctccttctat gaggtcaagg aggagattgg aaggggcgtg 3420 tttggcttcg taaaaagagt gcagcacaaa ggaaacaaga tcttgtgcgc tgccaagttc 3480 atccccctac ggagcagaac tcgggcccag gcatacaggg agcgagacat cctggccgcg 3540 ctgagccacc cgctggtcac ggggctgctg gaccagtttg agacccgcaa gaccctcatc 3600 ctcatcctgg agctgtgctc atccgaggag ctgctggacc gcctgtacag gaagggcgtg 3660 gtgacggagg ccgaggtcaa ggtctacatc cagcagctgg tggaggggct gcactacctg 3720 cacagccatg gcgttctcca cctggacata aagccctcta acatcctgat ggtgcatcct 3780 gcccgggaag acattaaaat ctgcgacttt ggctttgccc agaacatcac cccagcagag 3840 ctgcagttca gccagtacgg ctcccctgag ttcgtctccc ccgagatcat ccagcagaac 3900 cctgtgagcg aagcctccga catttgggcc atgggtgtca tctcctacct cagcctgacc 3960 tgctcatccc catttgccgg cgagagtgac cgtgccaccc tcctgaacgt cctggagggg 4020 cgcgtgtcat ggagcagccc catggctgcc cacctcagcg aagacgccaa agacttcatc 4080 aaggctacgc tgcagagagc ccctcaggcc cggcctagtg cggcccagtg cctctcccac 4140 ccctggttcc tgaaatccat gcctgcggag gaggcccact tcatcaacac caagcagctc 4200 aagttcctcc tggcccgaag tcgctggcag cgttccctga tgagctacaa gtccatcctg 4260 gtgatgcgct ccatccctga gctgctgcgg ggcccacccg acagcccctc cctcggcgta 4320 gcccggcacc tctgcaggga cactggtggc tcctccagtt cctcctcctc ctctgacaac 4380 gagctcgccc catttgcccg ggctaagtca ctgccaccct ccccggtgac acactcacca 4440 ctgctgcacc cccggggctt cctgcggccc tcggccagcc tgcctgagga agccgaggcc 4500 agtgagcgct ccaccgaggc cccagctccg cctgcatctc ccgagggtgc cgggccaccg 4560 gccgcccagg gctgcgtgcc ccggcacagc gtcatccgca gcctgttcta ccaccaggcg 4620 ggtgagagcc ctgagcacgg ggccctggcc ccggggagca ggcggcaccc ggcccggcgg 4680 cggcacctgc tgaagggcgg gtacattgcg ggggcgctgc caggcctgcg cgagccactg 4740 atggagcacc gcgtgctgga ggaggaggcc gccagggagg agcaggccac cctcctggcc 4800 aaagccccct cattcgagac tgccctccgg ctgcctgcct ctggcaccca cttggcccct 4860 ggccacagcc actccctgga acatgactct ccgagcaccc cccgcccctc ctcggaggcc 4920 tgcggtgagg cacagcgact gccttcagcc ccctccgggg gggcccctat cagggacatg 4980 gggcaccctc agggctccaa gcagcttcca tccactggtg gccacccagg cactgctcag 5040 ccagagaggc catccccgga cagcccttgg gggcagccag cccctttctg ccaccccaag 5100 cagggttctg ccccccagga gggctgcagc ccccacccag cagttgcccc atgccctcct 5160 ggctccttcc ctccaggatc ttgcaaagag gcccccttag taccctcaag ccccttcttg 5220 ggacagcccc aggcaccccc tgcccctgcc aaagcaagcc ccccattgga ctctaagatg 5280 gggcctggag acatctctct tcctgggagg ccaaaacccg gcccctgcag ttccccaggg 5340 tcagcctccc aggcgagctc ttcccaagtg agctccctca gggtgggctc ctcccaggtg 5400 ggcacagagc ctggcccctc cctggatgcg gagggctgga cccaggaggc tgaggatctg 5460 tccgactcca cacccacctt gcagcggcct caggaacagg cgaccatgcg caagttctcc 5520 ctgggtggtc gcgggggcta cgcaggcgtg gctggctatg gcacctttgc ctttggtgga 5580 gatgcagggg gcatgctggg gcaggggccc atgtgggcca ggatagcctg ggctgtgtcc 5640 cagtcggagg aggaggagca ggaggaggcc agggctgagt cccagtcgga ggagcagcag 5700 gaggccaggg ctgagagccc actgccccag gtcagtgcaa ggcctgtgcc tgaggtcggc 5760 agggctccca ccaggagctc tccagagccc accccatggg aggacatcgg gcaggtctcc 5820 ctggtgcaga tccgggacct gtcaggtgat gcggaggcgg ccgacacaat atccctggac 5880 atttccgagg tggaccccgc ctacctcaac ctctcagacc tgtacgatat caagtacctc 5940 ccattcgagt ttatgatctt caggaaagtc cccaagtccg ctcagccaga gccgccctcc 6000 cccatggctg aggaggagct ggccgagttc ccggagccca cgtggccctg gccaggtgaa 6060 ctgggccccc acgcaggcct ggagatcaca gaggagtcag aggatgtgga cgcgctgctg 6120 gcagaggctg ccgtgggcag gaagcgcaag tggtcctcgc cgtcacgcag cctcttccac 6180 ttccctggga ggcacctgcc gctggatgag cctgcagagc tggggctgcg tgagagagtg 6240 aaggcctccg tggagcacat ctcccggatc ctgaagggca ggccggaagg tctggagaag 6300 gaggggcccc ccaggaagaa gccaggcctt gcttccttcc ggctctcagg tctgaagagc 6360 tgggaccgag cgccgacatt cctaagggag ctctcagatg agactgtggt cctgggccag 6420 tcagtgacac tggcctgcca ggtgtcagcc cagccagctg cccaggccac ctggagcaaa 6480 gacggagccc ccctggagag cagcagccgt gtcctcatct ctgccaccct caagaacttc 6540 cagcttctga ccatcctggt ggtggtggct gaggacctgg gtgtgtacac ctgcagcgtg 6600 agcaatgcgc tggggacagt gaccaccacg ggcgtcctcc ggaaggcaga gcgcccctca 6660 tcttcgccat gcccggatat cggggaggtg tacgcggatg gggtgctgct ggtctggaag 6720 cccgtggaat cctacggccc tgtgacctac attgtgcagt gcagcctaga aggcggcagc 6780 tggaccacac tggcctccga catctttgac tgctgctacc tgaccagcaa gctctcccgg 6840 ggtggcacct acaccttccg cacggcatgt gtcagcaagg caggaatggg tccctacagc 6900 agcccctcgg agcaagtcct cctgggaggg cccagccacc tggcctctga ggaggagagc 6960 caggggcggt cagcccaacc cctgcccagc acaaagacct tcgcattcca gacacagatc 7020 cagaggggcc gcttcagcgt ggtgcggcaa tgctgggaga aggccagcgg gcgggcgctg 7080 gccgccaaga tcatccccta ccaccccaag gacaagacag cagtgctgcg cgaatacgag 7140 gccctcaagg gcctgcgcca cccgcacctg gcccagctgc acgcagccta cctcagcccc 7200 cggcacctgg tgctcatctt ggagctgtgc tctgggcccg agctgctccc ctgcctggcc 7260 gagagggcct cctactcaga atccgaggtg aaggactacc tgtggcagat gttgagtgcc 7320 acccagtacc tgcacaacca gcacatcctg cacctggacc tgaggtccga gaacatgatc 7380 atcaccgaat acaacctgct caaggtcgtg gacctgggca atgcacagag cctcagccag 7440 gagaaggtgc tgccctcaga caagttcaag gactacctag agaccatggc tccagagctc 7500 ctggagggcc agggggctgt tccacagaca gacatctggg ccatcggtgt gacagccttc 7560 atcatgctga gcgccgagta cccggtgagc agcgagggtg cacgcgacct gcagagagga 7620 ctgcgcaagg ggctggtccg gctgagccgc tgctacgcgg ggctgtccgg gggcgccgtg 7680 gccttcctgc gcagcactct gtgcgcccag ccctggggcc ggccctgcgc gtccagctgc 7740 ctgcagtgcc cgtggctaac agaggagggc ccggcctgtt cgcggcccgc gcccgtgacc 7800 ttccctaccg cgcggctgcg cgtcttcgtg cgcaatcgcg agaagagacg cgcgctgctg 7860 tacaagaggc acaacctggc ccaggtgcgc tga 7893 4 24120 DNA Homo sapiens 5'UTR (1)...(71) CDS (72)...(23978) 3'UTR (23979)...(24120) 4 tgcctaccag cagcccacac tccggccgct gcccagagcc cccatagaga gaggtccccg 60 ccgccaccgt c atg gat cag cca cag ttc agc ggg gcg ccc cgc ttt ctc 110 Met Asp Gln Pro Gln Phe Ser Gly Ala Pro Arg Phe Leu 1 5 10 acc cgg ccc aag gcc ttc gtg gtg tcg gtg ggc aag gac gcc acc ctc 158 Thr Arg Pro Lys Ala Phe Val Val Ser Val Gly Lys Asp Ala Thr Leu 15 20 25 agc tgc cag atc gtg ggt aat ccc acg cca cag gtg agc tgg gag aag 206 Ser Cys Gln Ile Val Gly Asn Pro Thr Pro Gln Val Ser Trp Glu Lys 30 35 40 45 gac cag cag ccg gtg acg gcc ggc gcg cgc ttc cgt ctg gcc cag gac 254 Asp Gln Gln Pro Val Thr Ala Gly Ala Arg Phe Arg Leu Ala Gln Asp 50 55 60 ggc gac ctc tac cgc ctc act atc ctg gac ctg gcg ctg ggc gac agt 302 Gly Asp Leu Tyr Arg Leu Thr Ile Leu Asp Leu Ala Leu Gly Asp Ser 65 70 75 ggg caa tac gtg tgc cgc gcg cgc aat gcc ata ggc gag gcc ttc gct 350 Gly Gln Tyr Val Cys Arg Ala Arg Asn Ala Ile Gly Glu Ala Phe Ala 80 85 90 gcc gtg ggc ctg cag gtg gac gcg gag gcc gcg tgc gcc gag cag gcg 398 Ala Val Gly Leu Gln Val Asp Ala Glu Ala Ala Cys Ala Glu Gln Ala 95 100 105 ccg cac ttc ctg ctg cgg ccc acg tcc atc cgc gtg cgc gag ggc tca 446 Pro His Phe Leu Leu Arg Pro Thr Ser Ile Arg Val Arg Glu Gly Ser 110 115 120 125 gag gcc acc ttc cgc tgc cgc gtg ggt ggc tcc ccg agg ccg gca gtg 494 Glu Ala Thr Phe Arg Cys Arg Val Gly Gly Ser Pro Arg Pro Ala Val 130 135 140 agc tgg tcc aag gac ggg cgg cgc ctg ggt gag ccc gac ggc ccc cgc 542 Ser Trp Ser Lys Asp Gly Arg Arg Leu Gly Glu Pro Asp Gly Pro Arg 145 150 155 gtg cgc gtg gag gag ctc ggc gag gca agt gcg ctg cgc att cgg gcg 590 Val Arg Val Glu Glu Leu Gly Glu Ala Ser Ala Leu Arg Ile Arg Ala 160 165 170 gcg cgg ccg cgc gac ggc ggc act tac gag gtc cgc gcc gag aac ccg 638 Ala Arg Pro Arg Asp Gly Gly Thr Tyr Glu Val Arg Ala Glu Asn Pro 175 180 185 ctg ggc gct gcc agc gcc gcc gcg gcg cta gtg gtg gac tcg gac gcc 686 Leu Gly Ala Ala Ser Ala Ala Ala Ala Leu Val Val Asp Ser Asp Ala 190 195 200 205 gcg gac acg gcc agc cgg ccc ggg acc tcc acg gcc gcg ctc ctg gcg 734 Ala Asp Thr Ala Ser Arg Pro Gly Thr Ser Thr Ala Ala Leu Leu Ala 210 215 220 cac ctg cag cgg cgg cgc gag gct atg cgc gcc gag ggc gcc ccc gcc 782 His Leu Gln Arg Arg Arg Glu Ala Met Arg Ala Glu Gly Ala Pro Ala 225 230 235 tca ccg ccc agc acc ggc acg cgc acc tgc acg gtg act gaa ggc aag 830 Ser Pro Pro Ser Thr Gly Thr Arg Thr Cys Thr Val Thr Glu Gly Lys 240 245 250 cac gcg cgc ctc agc tgc tac gtg acc ggc gag ccc aag ccc gag acg 878 His Ala Arg Leu Ser Cys Tyr Val Thr Gly Glu Pro Lys Pro Glu Thr 255 260 265 gtg tgg aag aag gac ggc cag ctg gtg acc gag ggc cgg cgc cac gtg 926 Val Trp Lys Lys Asp Gly Gln Leu Val Thr Glu Gly Arg Arg His Val 270 275 280 285 gtg tac gag gac gcg cag gag aac ttc gtg ctc aag atc ctc ttc tgc 974 Val Tyr Glu Asp Ala Gln Glu Asn Phe Val Leu Lys Ile Leu Phe Cys 290 295 300 aag cag tcg gac cgc ggc ctc tac acc tgc acg gcg tcc aac ctc gtg 1022 Lys Gln Ser Asp Arg Gly Leu Tyr Thr Cys Thr Ala Ser Asn Leu Val 305 310 315 ggc cag acc tac agc tct gtg ctg gtc gta gtg cgc gag ccc gcg gtt 1070 Gly Gln Thr Tyr Ser Ser Val Leu Val Val Val Arg Glu Pro Ala Val 320 325 330 ccc ttc aaa aag cgg ctg caa gat ctg gag gtg cgg gag aag gag tcg 1118 Pro Phe Lys Lys Arg Leu Gln Asp Leu Glu Val Arg Glu Lys Glu Ser 335 340 345 gct acg ttc cta tgt gag gtg ccc cag ccg tcc act gag gcc gcg tgg 1166 Ala Thr Phe Leu Cys Glu Val Pro Gln Pro Ser Thr Glu Ala Ala Trp 350 355 360 365 ttc aag gag gag acg cgg ttg tgg gcg agc gcc aag tac ggc atc gag 1214 Phe Lys Glu Glu Thr Arg Leu Trp Ala Ser Ala Lys Tyr Gly Ile Glu 370 375 380 gag gag ggc acc gag cgc cgc ctg acc gtg cgc aat gtc tcg gcc gac 1262 Glu Glu Gly Thr Glu Arg Arg Leu Thr Val Arg Asn Val Ser Ala Asp 385 390 395 gac gac gcg gtg tac atc tgc gag acg cca gag ggc agc cgc acg gtg 1310 Asp Asp Ala Val Tyr Ile Cys Glu Thr Pro Glu Gly Ser Arg Thr Val 400 405 410 gcg gag ctc gca gtc caa gga aac ctc ctc cga aag ctc cct cgg aag 1358 Ala Glu Leu Ala Val Gln Gly Asn Leu Leu Arg Lys Leu Pro Arg Lys 415 420 425 acg gcg gtg cgc gtg ggc gac acg gct atg ttt tgc gtg gag ctg gcg 1406 Thr Ala Val Arg Val Gly Asp Thr Ala Met Phe Cys Val Glu Leu Ala 430 435 440 445 gtc ccg gtg ggc ccc gtc cac tgg ctg cgg aac cag gag gaa gtg gtg 1454 Val Pro Val Gly Pro Val His Trp Leu Arg Asn Gln Glu Glu Val Val 450 455 460 gcg ggg ggc cgc gtg gcc atc tcc gcg gag ggc acg cgc cac aca ctg 1502 Ala Gly Gly Arg Val Ala Ile Ser Ala Glu Gly Thr Arg His Thr Leu 465 470 475 acc atc tcc cag tgc tgc ctg gag gat gtg ggc cag gtg gcc ttt atg 1550 Thr Ile Ser Gln Cys Cys Leu Glu Asp Val Gly Gln Val Ala Phe Met 480 485 490 gct ggc gac tgc cag acg tcc acc cgg ttc tgc gtg tcg gcc ccc agg 1598 Ala Gly Asp Cys Gln Thr Ser Thr Arg Phe Cys Val Ser Ala Pro Arg 495 500 505 aag cct ccc ctg caa ccc cct gtg gat cct gtg gta aag gcc agg atg 1646 Lys Pro Pro Leu Gln Pro Pro Val Asp Pro Val Val Lys Ala Arg Met 510 515 520 525 gag agt tcc gtg att ctc agc tgg tcc cca cca ccc cat ggg gaa cgc 1694 Glu Ser Ser Val Ile Leu Ser Trp Ser Pro Pro Pro His Gly Glu Arg 530 535 540 cct gtc act atc gac ggc tac ctg gta gag aag aag aag ctt ggc acc 1742 Pro Val Thr Ile Asp Gly Tyr Leu Val Glu Lys Lys Lys Leu Gly Thr 545 550 555 tac acc tgg atc agg tgc cac gag gct gaa tgg gtg gct aca cct gag 1790 Tyr Thr Trp Ile Arg Cys His Glu Ala Glu Trp Val Ala Thr Pro Glu 560 565 570 ctg acc gtg gct gat gtg gcg gag gag ggg aac ttc cag ttc cga gtg 1838 Leu Thr Val Ala Asp Val Ala Glu Glu Gly Asn Phe Gln Phe Arg Val 575 580 585 tcc gct ctc aac agc ttt ggt cag agt ccc tac ctc gag ttc ccg ggg 1886 Ser Ala Leu Asn Ser Phe Gly Gln Ser Pro Tyr Leu Glu Phe Pro Gly 590 595 600 605 act gtc cac ctg gcc ccc aag ctg gcc gtg agg aca ccg ctg aag gcg 1934 Thr Val His Leu Ala Pro Lys Leu Ala Val Arg Thr Pro Leu Lys Ala 610 615 620 gtg cag gcg gta gag ggt ggc gag gtc act ttc tcc gtg gac ctc acg 1982 Val Gln Ala Val Glu Gly Gly Glu Val Thr Phe Ser Val Asp Leu Thr 625 630 635 gtg gcc tca gcg ggt gag tgg ttc ctg gat ggg cag gcc ctg aag gcc 2030 Val Ala Ser Ala Gly Glu Trp Phe Leu Asp Gly Gln Ala Leu Lys Ala 640 645 650 agc agt gtg tat gag atc cac tgt gat cgc acc cgg cac acg ctc acc 2078 Ser Ser Val Tyr Glu Ile His Cys Asp Arg Thr Arg His Thr Leu Thr 655 660 665 atc cgg gag gtg ccc gcc agc ctg cac ggg gcg cag ctg aag ttc gtg 2126 Ile Arg Glu Val Pro Ala Ser Leu His Gly Ala Gln Leu Lys Phe Val 670 675 680 685 gcc aac ggc att gag agc agc atc cgg atg gag gtc cgg gcg gcc cca 2174 Ala Asn Gly Ile Glu Ser Ser Ile Arg Met Glu Val Arg Ala Ala Pro 690 695 700 ggg ctg act gcc aac aag ccg cca gcc gca gct gcc cgg gag gtg ctg 2222 Gly Leu Thr Ala Asn Lys Pro Pro Ala Ala Ala Ala Arg Glu Val Leu 705 710 715 gct cgg ctg cac gag gag gcg cag ctg ctg gct gag ctg tca gat cag 2270 Ala Arg Leu His Glu Glu Ala Gln Leu Leu Ala Glu Leu Ser Asp Gln 720 725 730 gct gcg gct gtg acg tgg ctg aag gat ggt cgc aca ctg tcc cca ggc 2318 Ala Ala Ala Val Thr Trp Leu Lys Asp Gly Arg Thr Leu Ser Pro Gly 735 740 745 ccc aag tat gag gtg cag gca tcg gcc ggg cgg cgg gtg ctc ctt gtg 2366 Pro Lys Tyr Glu Val Gln Ala Ser Ala Gly Arg Arg Val Leu Leu Val 750 755 760 765 cga gat gtg gcc cgg gac gat gca ggc ctc tac gag tgc gtc agc cgc 2414 Arg Asp Val Ala Arg Asp Asp Ala Gly Leu Tyr Glu Cys Val Ser Arg 770 775 780 ggg ggc cgc atc gcc tac cag ctc tcc gtg caa ggc ctc gcg cgc ttt 2462 Gly Gly Arg Ile Ala Tyr Gln Leu Ser Val Gln Gly Leu Ala Arg Phe 785 790 795 ctg cac aag gac atg gcg ggc agc tgt gtg gat gcc gtg gct ggg ggc 2510 Leu His Lys Asp Met Ala Gly Ser Cys Val Asp Ala Val Ala Gly Gly 800 805 810 ccg gcg cag ttt gag tgt gag acc tcc gaa gcc cac gtc cac gtg cac 2558 Pro Ala Gln Phe Glu Cys Glu Thr Ser Glu Ala His Val His Val His 815 820 825 tgg tac aag gat ggc atg gag ctg ggc cac tcc ggt gag cgc ttc ttg 2606 Trp Tyr Lys Asp Gly Met Glu Leu Gly His Ser Gly Glu Arg Phe Leu 830 835 840 845 cag gag gat gtg ggg acg cgg cac cgg ctg gtg gca gcc aca gtc acc 2654 Gln Glu Asp Val Gly Thr Arg His Arg Leu Val Ala Ala Thr Val Thr 850 855 860 agg cag gat gaa ggc acc tac tcc tgc cgc gtg ggc gag gac tct gtg 2702 Arg Gln Asp Glu Gly Thr Tyr Ser Cys Arg Val Gly Glu Asp Ser Val 865 870 875 gac ttc cgg ctc cgc gtc tct gag ccc aag gtg gtg ttt gct aag gag 2750 Asp Phe Arg Leu Arg Val Ser Glu Pro Lys Val Val Phe Ala Lys Glu 880 885 890 cag ctg gca cgc agg aag ctg cag gca gag gca gga gcc agt gcc aca 2798 Gln Leu Ala Arg Arg Lys Leu Gln Ala Glu Ala Gly Ala Ser Ala Thr 895 900 905 ctg agc tgc gag gtg gcc cag gcc cag acg gag gtg acg tgg tac aag 2846 Leu Ser Cys Glu Val Ala Gln Ala Gln Thr Glu Val Thr Trp Tyr Lys 910 915 920 925 gat ggg aag aag ctg agc tcc agc tcg aaa

gtg tgc atg gag gcc aca 2894 Asp Gly Lys Lys Leu Ser Ser Ser Ser Lys Val Cys Met Glu Ala Thr 930 935 940 ggc tgc acg cgc agg ctg gtt gtg cag cag gca ggc cag gcg gat gcc 2942 Gly Cys Thr Arg Arg Leu Val Val Gln Gln Ala Gly Gln Ala Asp Ala 945 950 955 ggg gag tat agc tgc gag gct ggg ggc cag cgg ctc tcc ttc cat ctg 2990 Gly Glu Tyr Ser Cys Glu Ala Gly Gly Gln Arg Leu Ser Phe His Leu 960 965 970 gat gtc aaa gag ccc aag gtg gtg ttt gcc aag gac cag gtg gca cac 3038 Asp Val Lys Glu Pro Lys Val Val Phe Ala Lys Asp Gln Val Ala His 975 980 985 agt gag gtg cag gct gag gca ggg gcc aat gcc acg ctg agc tgc gag 3086 Ser Glu Val Gln Ala Glu Ala Gly Ala Asn Ala Thr Leu Ser Cys Glu 990 995 1000 1005 gtg gcc cag gcc cag gcg gag gtg atg tgg tac aaa gat ggg aag aag 3134 Val Ala Gln Ala Gln Ala Glu Val Met Trp Tyr Lys Asp Gly Lys Lys 1010 1015 1020 ctg agc tcc agc ttg aaa gtg cat gta gag gcc aaa ggc tgc aga cgg 3182 Leu Ser Ser Ser Leu Lys Val His Val Glu Ala Lys Gly Cys Arg Arg 1025 1030 1035 agg ctg gtg gtg cag cag gca ggc aag acg gat gcc ggg gac tac agc 3230 Arg Leu Val Val Gln Gln Ala Gly Lys Thr Asp Ala Gly Asp Tyr Ser 1040 1045 1050 tgc gag gcc agg ggc cag agg gtc tcc ttc cgc ctg cac atc aca gag 3278 Cys Glu Ala Arg Gly Gln Arg Val Ser Phe Arg Leu His Ile Thr Glu 1055 1060 1065 ccc aag atg atg ttt gca aag gag cag tca gtg cat aat gag gtg cag 3326 Pro Lys Met Met Phe Ala Lys Glu Gln Ser Val His Asn Glu Val Gln 1070 1075 1080 1085 gct gag gcg ggg gcc agt gcc atg ctg agc tgt gag gtg gcc cag gcc 3374 Ala Glu Ala Gly Ala Ser Ala Met Leu Ser Cys Glu Val Ala Gln Ala 1090 1095 1100 cag acg gag gtg acg tgg tac aag gat ggg aag aag ctg agc tcc agc 3422 Gln Thr Glu Val Thr Trp Tyr Lys Asp Gly Lys Lys Leu Ser Ser Ser 1105 1110 1115 tca aaa gtg ggc atg gag gtc aaa ggg tgc aca cgg agg ctg gtg ctg 3470 Ser Lys Val Gly Met Glu Val Lys Gly Cys Thr Arg Arg Leu Val Leu 1120 1125 1130 cca cag gcg ggc aaa gca gat gct ggg gag tac agc tgt gag gct ggg 3518 Pro Gln Ala Gly Lys Ala Asp Ala Gly Glu Tyr Ser Cys Glu Ala Gly 1135 1140 1145 ggc cag aga gtc tcc ttc cac ctg cac atc aca gag ccc aag ggg gtg 3566 Gly Gln Arg Val Ser Phe His Leu His Ile Thr Glu Pro Lys Gly Val 1150 1155 1160 1165 ttt gcg aag gag cag tca gtg cat aat gag gtg cag gct gag gcg ggg 3614 Phe Ala Lys Glu Gln Ser Val His Asn Glu Val Gln Ala Glu Ala Gly 1170 1175 1180 acc act gcc atg ctg agc tgt gag gtg gcc cag ccc cag acg gag gtg 3662 Thr Thr Ala Met Leu Ser Cys Glu Val Ala Gln Pro Gln Thr Glu Val 1185 1190 1195 acg tgg tac aag gac ggg aag aag ctg agc tcc agc tca aaa gta cgc 3710 Thr Trp Tyr Lys Asp Gly Lys Lys Leu Ser Ser Ser Ser Lys Val Arg 1200 1205 1210 atg gag gtc aag ggc tgc aca cga agg ctg gta gtg cag cag gtg ggc 3758 Met Glu Val Lys Gly Cys Thr Arg Arg Leu Val Val Gln Gln Val Gly 1215 1220 1225 aaa gca gat gct ggg gag tac agc tgc gag gct ggg ggc cag aga gtc 3806 Lys Ala Asp Ala Gly Glu Tyr Ser Cys Glu Ala Gly Gly Gln Arg Val 1230 1235 1240 1245 tcc ttt caa ctg cac atc aca gag ccc aag gca gtg ttt gcc aag gag 3854 Ser Phe Gln Leu His Ile Thr Glu Pro Lys Ala Val Phe Ala Lys Glu 1250 1255 1260 cag ttg gtg cat aat gag gtg cgg act gag gca ggg gcc agt gcc aca 3902 Gln Leu Val His Asn Glu Val Arg Thr Glu Ala Gly Ala Ser Ala Thr 1265 1270 1275 ctg agc tgt gag gtg gcc cag gcc cag aca gag gtg acg tgg tac aag 3950 Leu Ser Cys Glu Val Ala Gln Ala Gln Thr Glu Val Thr Trp Tyr Lys 1280 1285 1290 gat ggg aag aag ctg agc tcc agt tcg aaa gtg cgc ata gag gct gcg 3998 Asp Gly Lys Lys Leu Ser Ser Ser Ser Lys Val Arg Ile Glu Ala Ala 1295 1300 1305 ggc tgc atg cgg cag ctg gtg gtg cag cag gca ggc cag gca gat gct 4046 Gly Cys Met Arg Gln Leu Val Val Gln Gln Ala Gly Gln Ala Asp Ala 1310 1315 1320 1325 ggg gag tac acc tgt gag gct ggg ggc cag cgg ctc tcc ttc cac ctg 4094 Gly Glu Tyr Thr Cys Glu Ala Gly Gly Gln Arg Leu Ser Phe His Leu 1330 1335 1340 gat gtt tca gag ccc aag gcg gtg ttt gca aag gag cag ctg gca cac 4142 Asp Val Ser Glu Pro Lys Ala Val Phe Ala Lys Glu Gln Leu Ala His 1345 1350 1355 agg aag gtg cag gcc gag gcg ggg gcc att gcc acg ctg agc tgc gag 4190 Arg Lys Val Gln Ala Glu Ala Gly Ala Ile Ala Thr Leu Ser Cys Glu 1360 1365 1370 gtg gcc cag gcc cag aca gag gtg acg tgg tac aag gac ggg aag aag 4238 Val Ala Gln Ala Gln Thr Glu Val Thr Trp Tyr Lys Asp Gly Lys Lys 1375 1380 1385 ctg agc tcc agc tcg aaa gtt cga atg gag gct gtg ggc tgc aca cgg 4286 Leu Ser Ser Ser Ser Lys Val Arg Met Glu Ala Val Gly Cys Thr Arg 1390 1395 1400 1405 agg ctg gtg gtg cag cag gca tgc cag gcg gac acc ggg gag tat agc 4334 Arg Leu Val Val Gln Gln Ala Cys Gln Ala Asp Thr Gly Glu Tyr Ser 1410 1415 1420 tgc gag gcc ggg ggc cag cgg ctc tcc ttc agc ctg gac gtg gca gag 4382 Cys Glu Ala Gly Gly Gln Arg Leu Ser Phe Ser Leu Asp Val Ala Glu 1425 1430 1435 ccc aag gtg gtg ttt gcc aag gag cag cca gtg cac agg gag gtg cag 4430 Pro Lys Val Val Phe Ala Lys Glu Gln Pro Val His Arg Glu Val Gln 1440 1445 1450 gcc cag gcg ggg gcc agc acc aca ctc agc tgc gag gtg gct cag gcc 4478 Ala Gln Ala Gly Ala Ser Thr Thr Leu Ser Cys Glu Val Ala Gln Ala 1455 1460 1465 cag acg gag gtg atg tgg tac aag gac ggg aag aag ctg agc ttc agc 4526 Gln Thr Glu Val Met Trp Tyr Lys Asp Gly Lys Lys Leu Ser Phe Ser 1470 1475 1480 1485 tcg aaa gtg cgc atg gag gct gtg ggc tgc aca cgg agg ctg gtg gtg 4574 Ser Lys Val Arg Met Glu Ala Val Gly Cys Thr Arg Arg Leu Val Val 1490 1495 1500 cag cag gcg ggc cag gcg gac gcc ggg gag tac agc tgc gag gcg ggg 4622 Gln Gln Ala Gly Gln Ala Asp Ala Gly Glu Tyr Ser Cys Glu Ala Gly 1505 1510 1515 agc cag cgg ctc tcc ttc cac ctg cac gtg gca gag ccc aag gcg gtg 4670 Ser Gln Arg Leu Ser Phe His Leu His Val Ala Glu Pro Lys Ala Val 1520 1525 1530 ttt gcc aag gag cag cca gcg agc agg gag gtg cag gct gag gcg ggg 4718 Phe Ala Lys Glu Gln Pro Ala Ser Arg Glu Val Gln Ala Glu Ala Gly 1535 1540 1545 acc agt gcc acg ctg agc tgc gag gtg gcc cag gcc cag aca gag gtg 4766 Thr Ser Ala Thr Leu Ser Cys Glu Val Ala Gln Ala Gln Thr Glu Val 1550 1555 1560 1565 acg tgg tac aag gac ggg aag aaa ctg agc tcc agc tcg aaa gtg cga 4814 Thr Trp Tyr Lys Asp Gly Lys Lys Leu Ser Ser Ser Ser Lys Val Arg 1570 1575 1580 atg gag gcc gtg ggc tgc aca cgg agg ctg gtg gtg cag gag gca ggc 4862 Met Glu Ala Val Gly Cys Thr Arg Arg Leu Val Val Gln Glu Ala Gly 1585 1590 1595 cag gcg gac gcc ggg gag tac agc tgc aag gcc ggg gat cag cgg ctg 4910 Gln Ala Asp Ala Gly Glu Tyr Ser Cys Lys Ala Gly Asp Gln Arg Leu 1600 1605 1610 tcc ttc cac ctg cac gtg gca gag ccc aag gtg gtg ttt gcc aag gag 4958 Ser Phe His Leu His Val Ala Glu Pro Lys Val Val Phe Ala Lys Glu 1615 1620 1625 cag cca gca cac agg gag gtg cag gct gag gcg ggg gcc agt gcc acg 5006 Gln Pro Ala His Arg Glu Val Gln Ala Glu Ala Gly Ala Ser Ala Thr 1630 1635 1640 1645 ctg agc tgc gag gtg gcc cag gcc cag aca gag gtg acg tgg tac aag 5054 Leu Ser Cys Glu Val Ala Gln Ala Gln Thr Glu Val Thr Trp Tyr Lys 1650 1655 1660 gat ggg aag aag ctg agt tcc agc tcg aaa gtg cgc gtg gag gcc gtg 5102 Asp Gly Lys Lys Leu Ser Ser Ser Ser Lys Val Arg Val Glu Ala Val 1665 1670 1675 ggc tgc aca cgg agg ctg gtg gtg cag cag gcg ggc cag gcg gat gct 5150 Gly Cys Thr Arg Arg Leu Val Val Gln Gln Ala Gly Gln Ala Asp Ala 1680 1685 1690 ggg gag tac agc tgt gag gcg ggg ggc caa cgg ctg tcc ttc cgc ctg 5198 Gly Glu Tyr Ser Cys Glu Ala Gly Gly Gln Arg Leu Ser Phe Arg Leu 1695 1700 1705 cac gtg gca gag ctg gag ccc caa att tca gag aga ccc tgc cgc agg 5246 His Val Ala Glu Leu Glu Pro Gln Ile Ser Glu Arg Pro Cys Arg Arg 1710 1715 1720 1725 gag cct ctg gtg gtc aag gag cat gaa gac atc atc ctg acc gcc aca 5294 Glu Pro Leu Val Val Lys Glu His Glu Asp Ile Ile Leu Thr Ala Thr 1730 1735 1740 ctg gcc aca ccc tct gcg gcc acg gtg acc tgg ctc aag gat ggt gtg 5342 Leu Ala Thr Pro Ser Ala Ala Thr Val Thr Trp Leu Lys Asp Gly Val 1745 1750 1755 gag att cgc cgc agc aag cgg cat gag aca gcc agc cag ggg gac acc 5390 Glu Ile Arg Arg Ser Lys Arg His Glu Thr Ala Ser Gln Gly Asp Thr 1760 1765 1770 cac acc ctg acc gtg cat ggc gcc cag gtt ctg gac agc gcc atc tac 5438 His Thr Leu Thr Val His Gly Ala Gln Val Leu Asp Ser Ala Ile Tyr 1775 1780 1785 agc tgc cgt gtg ggc gca gag ggg cag gac ttc cca gtg cag gtg gaa 5486 Ser Cys Arg Val Gly Ala Glu Gly Gln Asp Phe Pro Val Gln Val Glu 1790 1795 1800 1805 gag gtg gcc gcc aag ttc tgc cgg ctg ctg gag cct gtg tgc ggc gag 5534 Glu Val Ala Ala Lys Phe Cys Arg Leu Leu Glu Pro Val Cys Gly Glu 1810 1815 1820 ctg ggt ggc acg gtg aca ctg gcc tgc gag cta agc cca gcg tgt gca 5582 Leu Gly Gly Thr Val Thr Leu Ala Cys Glu Leu Ser Pro Ala Cys Ala 1825 1830 1835 gag gtg gtg tgg cgc tgc ggc aac acg cag cct cgg gtg ggc aag cgc 5630 Glu Val Val Trp Arg Cys Gly Asn Thr Gln Pro Arg Val Gly Lys Arg 1840 1845 1850 ttc cag atg gtg gcc gag ggg ccc gtg cgc tca ctc act gtg ttg ggg 5678 Phe Gln Met Val Ala Glu Gly Pro Val Arg Ser Leu Thr Val Leu Gly 1855 1860 1865 ctg cgc gca gag gac gca ggg gag tac gtg tgt gag agc cgt gat gac 5726 Leu Arg Ala Glu Asp Ala Gly Glu Tyr Val Cys Glu Ser Arg Asp Asp 1870 1875 1880 1885 cac acc agt gcg cag ctc acc gtc agt gtg ccc cga gtg gtg aag ttt 5774 His Thr Ser Ala Gln Leu Thr Val Ser Val Pro Arg Val Val Lys Phe 1890 1895 1900 atg tct ggg ctg agc acc gtg gtc gca gag gag ggc ggc gag gcc acc 5822 Met Ser Gly Leu Ser Thr Val Val Ala Glu Glu Gly Gly Glu Ala Thr 1905 1910 1915 ttc cag tgc gtg gtg tcc ccc agt gat gtg gca gtc gtg tgg ttc cgg 5870 Phe Gln Cys Val Val Ser Pro Ser Asp Val Ala Val Val Trp Phe Arg 1920 1925 1930 gac ggt gcc ctg ctt cag ccc agc gag aag ttt gcc ata tca cag agt 5918 Asp Gly Ala Leu Leu Gln Pro Ser Glu Lys Phe Ala Ile Ser Gln Ser 1935 1940 1945 ggc gcc agc cac agc ctg acc atc tca gac ctg gtg ctg gag gac gcg 5966 Gly Ala Ser His Ser Leu Thr Ile Ser Asp Leu Val Leu Glu Asp Ala 1950 1955 1960 1965 ggc cag atc acc gtg gag gct gag ggc gcc tca tcc tct gct gcc ctg 6014 Gly Gln Ile Thr Val Glu Ala Glu Gly Ala Ser Ser Ser Ala Ala Leu 1970 1975 1980 agg gtc cga gag gcg cct gtg ctg ttc aaa aag aag ctg gag ccg cag 6062 Arg Val Arg Glu Ala Pro Val Leu Phe Lys Lys Lys Leu Glu Pro Gln 1985 1990 1995 acg gtg gag gag cgg agc tcg gtg acc ctg gag gtg gag ctg acg cgg 6110 Thr Val Glu Glu Arg Ser Ser Val Thr Leu Glu Val Glu Leu Thr Arg 2000 2005 2010 ccg tgg ccg gag ctg agg tgg aca cgg aac gcg acg gcc ctg gcg ccg 6158 Pro Trp Pro Glu Leu Arg Trp Thr Arg Asn Ala Thr Ala Leu Ala Pro 2015 2020 2025 gga aag aac gtg gag atc cac gcc gag ggc gcc cgc cac cgc ctg gtt 6206 Gly Lys Asn Val Glu Ile His Ala Glu Gly Ala Arg His Arg Leu Val 2030 2035 2040 2045 ctg cac aac gta ggt ttt gcc gac cgt ggc ttc ttt ggc tgc gag acg 6254 Leu His Asn Val Gly Phe Ala Asp Arg Gly Phe Phe Gly Cys Glu Thr 2050 2055 2060 ccg gat gac aag aca cag gcc aaa ctc acc gtg gag atg cgc cag gta 6302 Pro Asp Asp Lys Thr Gln Ala Lys Leu Thr Val Glu Met Arg Gln Val 2065 2070 2075 cgg ctc gta cgg ggc ctg cag gca gtg gag gca cgg gag cag ggc acg 6350 Arg Leu Val Arg Gly Leu Gln Ala Val Glu Ala Arg Glu Gln Gly Thr 2080 2085 2090 gct acc atg gag gtg cag ctg tcg cat gcg gac gtg gat ggc agc tgg 6398 Ala Thr Met Glu Val Gln Leu Ser His Ala Asp Val Asp Gly Ser Trp 2095 2100 2105 act cgt gac ggt ctg cgg ttc cag cag ggg ccc acg tgc cac ctg gct 6446 Thr Arg Asp Gly Leu Arg Phe Gln Gln Gly Pro Thr Cys His Leu Ala 2110 2115 2120 2125 gtg cgg ggc ccc atg cac acc ctc aca ctc tcg ggg ctg cgg cca gag 6494 Val Arg Gly Pro Met His Thr Leu Thr Leu Ser Gly Leu Arg Pro Glu 2130 2135 2140 gat agt ggc ctt atg gtc ttc aag gcc gaa gga gtg cac acg tcg gcg 6542 Asp Ser Gly Leu Met Val Phe Lys Ala Glu Gly Val His Thr Ser Ala 2145 2150 2155 cgg ctc gtg gtc acc gag ctt ccc gtg agc ttc agc cgc ccg ctg cag 6590 Arg Leu Val Val Thr Glu Leu Pro Val Ser Phe Ser Arg Pro Leu Gln 2160 2165 2170 gac gtg gtg acc act gag aag gag aag gtt acc ctg gag tgc gag ctg 6638 Asp Val Val Thr Thr Glu Lys Glu Lys Val Thr Leu Glu Cys Glu Leu 2175 2180 2185 tcg cgt cct aat gtg gat gtg cgc tgg ctg aag gac ggt gtg gag ctg 6686 Ser Arg Pro Asn Val Asp Val Arg Trp Leu Lys Asp Gly Val Glu Leu 2190 2195 2200 2205 cgg gca ggc aag acg atg gcc atc gca gcc cag ggc gcc tgc agg agc 6734 Arg Ala Gly Lys Thr Met Ala Ile Ala Ala Gln Gly Ala Cys Arg Ser 2210 2215 2220 ctc acc att tac cgg tgc gag ttc gcg gat cag gga gtg tat gtg tgt 6782 Leu Thr Ile Tyr Arg Cys Glu Phe Ala Asp Gln Gly Val Tyr Val Cys 2225 2230 2235 gat gcc cat gat gcc cag agc tct gcc tcc gtg aag gta caa gga agg 6830 Asp Ala His Asp Ala Gln Ser Ser Ala Ser Val Lys Val Gln Gly Arg 2240 2245 2250 aca tac act ctc atc tac cgg aga gtc ctg gcg gaa gat gca gga gag 6878 Thr Tyr Thr Leu Ile Tyr Arg Arg Val Leu Ala Glu Asp Ala Gly Glu 2255 2260 2265 atc caa ttt gta gcc gaa aat gca gaa tcg cga gcc cag ctc cga gtg 6926 Ile Gln Phe Val Ala Glu Asn Ala Glu Ser Arg Ala Gln Leu Arg Val 2270 2275 2280 2285 aag gag ctg cca gtg acc ctc gtg cgc ccg ctg cgg gac aag att gcc 6974 Lys Glu Leu Pro Val Thr Leu Val Arg Pro Leu Arg Asp Lys Ile Ala 2290 2295 2300 atg gag aag cac cgc ggt gtg ctg gag tgt cag gtg tcc cgg gcc agc 7022 Met Glu Lys His Arg Gly Val Leu Glu Cys Gln Val Ser Arg Ala Ser 2305 2310 2315 gcc cag gtg cgg tgg ttc aag ggc agt cag gag ctg cag ccc ggg ccc 7070 Ala Gln Val Arg Trp Phe Lys Gly Ser Gln Glu Leu Gln Pro Gly Pro 2320 2325 2330 aag tac gag ctg gtc agt gat ggc ctc tac cgc aag ctg atc atc agt 7118 Lys Tyr Glu Leu Val Ser Asp Gly Leu Tyr Arg Lys Leu Ile Ile Ser 2335 2340 2345 gat gtc cac gca gag gac gag gac acc tac acc tgt gac gcc ggt gat 7166 Asp Val His Ala Glu Asp Glu Asp Thr Tyr Thr Cys Asp Ala Gly Asp 2350 2355 2360 2365 gtc aag acc agt gca cag ttc ttc gtg gaa gag caa tcc atc acc att 7214 Val Lys Thr Ser Ala Gln Phe Phe Val Glu Glu Gln Ser Ile Thr Ile 2370 2375 2380 gtg cgg ggt ctg cag gac gtg aca gtg atg gag ccc gct cct gcc tgg 7262 Val Arg Gly Leu Gln Asp Val Thr Val Met Glu Pro Ala Pro Ala Trp 2385 2390 2395 ttt gag tgt gag acc tcc atc ccc tca gtg cgg cca cct aag tgg ctc 7310 Phe Glu Cys Glu Thr Ser Ile Pro Ser Val Arg Pro Pro Lys Trp Leu 2400 2405 2410 ctg ggg aag acg gtg ttg cag gct ggg ggg aac gtg ggc ctg gag cag 7358 Leu Gly Lys Thr Val Leu Gln Ala Gly Gly Asn Val Gly Leu Glu Gln 2415 2420 2425 gag ggc acg gtg cac cgg ctg atg ctg cgg cgg acc tgc tcc acc atg 7406 Glu Gly

Thr Val His Arg Leu Met Leu Arg Arg Thr Cys Ser Thr Met 2430 2435 2440 2445 acc ggg ccc gtg cac ttc acc gtt ggc aag tcg cgc tcc tct gcc cgc 7454 Thr Gly Pro Val His Phe Thr Val Gly Lys Ser Arg Ser Ser Ala Arg 2450 2455 2460 ctg gtg gtc tca gac atc ccc gta gtc ctc aca cgg ccg ttg gag ccc 7502 Leu Val Val Ser Asp Ile Pro Val Val Leu Thr Arg Pro Leu Glu Pro 2465 2470 2475 aag aca ggg cgt gag ctg cag tca gtg gtc ctg tcc tgc gac ttc cgg 7550 Lys Thr Gly Arg Glu Leu Gln Ser Val Val Leu Ser Cys Asp Phe Arg 2480 2485 2490 cca gcc ccc aag gct gtg cag tgg tac aag gat gac acg ccc ctg tct 7598 Pro Ala Pro Lys Ala Val Gln Trp Tyr Lys Asp Asp Thr Pro Leu Ser 2495 2500 2505 ccc tct gag aag ttt aag atg agc ctg gag ggt cag atg gct gag ctg 7646 Pro Ser Glu Lys Phe Lys Met Ser Leu Glu Gly Gln Met Ala Glu Leu 2510 2515 2520 2525 cgc atc ctc cgg ctc atg cct gct gat gct ggt gtc tac cgg tgc cag 7694 Arg Ile Leu Arg Leu Met Pro Ala Asp Ala Gly Val Tyr Arg Cys Gln 2530 2535 2540 gcg ggc agt gcc cac agc agc act gag gtc act gtg gaa gcg cgg gag 7742 Ala Gly Ser Ala His Ser Ser Thr Glu Val Thr Val Glu Ala Arg Glu 2545 2550 2555 gtg aca gtg aca ggg ccg cta cag gat gca gag gcc acg gag gag ggc 7790 Val Thr Val Thr Gly Pro Leu Gln Asp Ala Glu Ala Thr Glu Glu Gly 2560 2565 2570 tgg gcc agc ttc tcc tgt gag ctg tcc cac gag gat gag gag gtc gag 7838 Trp Ala Ser Phe Ser Cys Glu Leu Ser His Glu Asp Glu Glu Val Glu 2575 2580 2585 tgg tcg ctc aac ggg atg ccc ctg tac aac gac agc ttc cat gag atc 7886 Trp Ser Leu Asn Gly Met Pro Leu Tyr Asn Asp Ser Phe His Glu Ile 2590 2595 2600 2605 tca cac aag ggc cgg cgc cac acg ctg gta ctg aag agc atc cag cgg 7934 Ser His Lys Gly Arg Arg His Thr Leu Val Leu Lys Ser Ile Gln Arg 2610 2615 2620 gct gat gcg ggc ata gta cgc gcc tcc tcc ctg aag gtg tcg acc tct 7982 Ala Asp Ala Gly Ile Val Arg Ala Ser Ser Leu Lys Val Ser Thr Ser 2625 2630 2635 gcc cgc ctg gag gtc cga gtg aag ccg gtg gtg ttc ctg aag gcg ctg 8030 Ala Arg Leu Glu Val Arg Val Lys Pro Val Val Phe Leu Lys Ala Leu 2640 2645 2650 gat gac ctg tcc gca gag gag cgc ggc acc ctg gcc ctg cag tgt gaa 8078 Asp Asp Leu Ser Ala Glu Glu Arg Gly Thr Leu Ala Leu Gln Cys Glu 2655 2660 2665 gtc tct gac ccc gag gcc cat gtg gtg tgg cgc aaa gat ggc gtg cag 8126 Val Ser Asp Pro Glu Ala His Val Val Trp Arg Lys Asp Gly Val Gln 2670 2675 2680 2685 ctg ggc ccc agt gac aag tat gac ttc ctg cac acg gcg ggc acg cgg 8174 Leu Gly Pro Ser Asp Lys Tyr Asp Phe Leu His Thr Ala Gly Thr Arg 2690 2695 2700 ggg ctc gtg gtg cat gac gtg agc cct gaa gac gcc ggc ctg tac acc 8222 Gly Leu Val Val His Asp Val Ser Pro Glu Asp Ala Gly Leu Tyr Thr 2705 2710 2715 tgc cac gtg ggc tcc gag gag acc cgg gcc cgg gtc cgc gtg cac gat 8270 Cys His Val Gly Ser Glu Glu Thr Arg Ala Arg Val Arg Val His Asp 2720 2725 2730 ctg cac gtg ggc atc acc aag agg ctg aag aca atg gag gtg ctg gaa 8318 Leu His Val Gly Ile Thr Lys Arg Leu Lys Thr Met Glu Val Leu Glu 2735 2740 2745 ggg gaa agc tgc agc ttt gag tgc gtc ctg tcc cac gag agt gcc agc 8366 Gly Glu Ser Cys Ser Phe Glu Cys Val Leu Ser His Glu Ser Ala Ser 2750 2755 2760 2765 gac ccg gcc atg tgg aca gtc ggt ggg aag aca gtg ggc agc tcc agc 8414 Asp Pro Ala Met Trp Thr Val Gly Gly Lys Thr Val Gly Ser Ser Ser 2770 2775 2780 cgc ttc cag gcc aca cgt cag ggc cga aaa tac atc ctg gtg gtc cgg 8462 Arg Phe Gln Ala Thr Arg Gln Gly Arg Lys Tyr Ile Leu Val Val Arg 2785 2790 2795 gag gct gca cca agt gat gcc ggg gag gtg gtc ttc tct gtg cgg ggc 8510 Glu Ala Ala Pro Ser Asp Ala Gly Glu Val Val Phe Ser Val Arg Gly 2800 2805 2810 ctc acc tcc aag gcc tca ctc att gtc aga gag agg ccg gcc gcc atc 8558 Leu Thr Ser Lys Ala Ser Leu Ile Val Arg Glu Arg Pro Ala Ala Ile 2815 2820 2825 atc aag ccc ctg gaa gac cag tgg gtg gcg cca ggg gag gac gtg gag 8606 Ile Lys Pro Leu Glu Asp Gln Trp Val Ala Pro Gly Glu Asp Val Glu 2830 2835 2840 2845 ctg cgc tgt gag ctg tca cgg gcg gga acg ccc gtg cac tgg ctg aag 8654 Leu Arg Cys Glu Leu Ser Arg Ala Gly Thr Pro Val His Trp Leu Lys 2850 2855 2860 gac agg aag gcc atc cgc aag agc cag aag tat gat gtg gtc tgc gag 8702 Asp Arg Lys Ala Ile Arg Lys Ser Gln Lys Tyr Asp Val Val Cys Glu 2865 2870 2875 ggc acg atg gcc atg ctg gtc atc cgc ggg gcc tcg ctc aag gac gcg 8750 Gly Thr Met Ala Met Leu Val Ile Arg Gly Ala Ser Leu Lys Asp Ala 2880 2885 2890 ggc gag tac acg tgt gag gtg gag gct tcc aag agc aca gcc agc ctc 8798 Gly Glu Tyr Thr Cys Glu Val Glu Ala Ser Lys Ser Thr Ala Ser Leu 2895 2900 2905 cat gtg gaa gaa aaa gca aac tgc ttc aca gag gag ctg acc aat ctg 8846 His Val Glu Glu Lys Ala Asn Cys Phe Thr Glu Glu Leu Thr Asn Leu 2910 2915 2920 2925 cag gtg gag gag aaa ggc aca gct gtg ttc acg tgc aag acg gag cac 8894 Gln Val Glu Glu Lys Gly Thr Ala Val Phe Thr Cys Lys Thr Glu His 2930 2935 2940 ccc gcg gcc aca gtg acc tgg cgc aag ggc ctc ttg gag cta cgg gcc 8942 Pro Ala Ala Thr Val Thr Trp Arg Lys Gly Leu Leu Glu Leu Arg Ala 2945 2950 2955 tca ggg aag cac cag ccc agc cag gag ggc ctg acc ctg cgg ctc acc 8990 Ser Gly Lys His Gln Pro Ser Gln Glu Gly Leu Thr Leu Arg Leu Thr 2960 2965 2970 atc agt gcc ctg gag aag gca gac agc gac acc tat acc tgc gac att 9038 Ile Ser Ala Leu Glu Lys Ala Asp Ser Asp Thr Tyr Thr Cys Asp Ile 2975 2980 2985 ggc cag gcc cag tcc cgg gcc cag ctc cta gtg caa ggc cgg aga gtg 9086 Gly Gln Ala Gln Ser Arg Ala Gln Leu Leu Val Gln Gly Arg Arg Val 2990 2995 3000 3005 cac atc atc gag gac ctg gag gat gtg gat gtg cag gag ggc tcc tcg 9134 His Ile Ile Glu Asp Leu Glu Asp Val Asp Val Gln Glu Gly Ser Ser 3010 3015 3020 gcc acc ttc cgt tgc cgg atc tcc ccg gcc aac tac gag cct gtg cac 9182 Ala Thr Phe Arg Cys Arg Ile Ser Pro Ala Asn Tyr Glu Pro Val His 3025 3030 3035 tgg ttc ctg gac aag aca ccc ctg cat gcc aac gag ctc aat gag atc 9230 Trp Phe Leu Asp Lys Thr Pro Leu His Ala Asn Glu Leu Asn Glu Ile 3040 3045 3050 gat gcc cag ccc ggg ggc tac cac gtg ctg acc ctg cgg cag ctg gcg 9278 Asp Ala Gln Pro Gly Gly Tyr His Val Leu Thr Leu Arg Gln Leu Ala 3055 3060 3065 ctc aag gac tcg ggc acc atc tac ttt gag gcg ggt gac cag cgg gcc 9326 Leu Lys Asp Ser Gly Thr Ile Tyr Phe Glu Ala Gly Asp Gln Arg Ala 3070 3075 3080 3085 tcg gcc gcc ctg cgg gtc act gag aag cca agc gtc ttc tcc cgg gag 9374 Ser Ala Ala Leu Arg Val Thr Glu Lys Pro Ser Val Phe Ser Arg Glu 3090 3095 3100 ctc aca gat gcc acc atc aca gag ggt gag gac ttg acc ctg gtg tgc 9422 Leu Thr Asp Ala Thr Ile Thr Glu Gly Glu Asp Leu Thr Leu Val Cys 3105 3110 3115 gag acc agc acc tgc gac att cct atg tgc tgg acc aag gat ggg aag 9470 Glu Thr Ser Thr Cys Asp Ile Pro Met Cys Trp Thr Lys Asp Gly Lys 3120 3125 3130 acc ctg cgg ggg tct gcc cgg tgc cag ctg agc cat gag ggc cac cgg 9518 Thr Leu Arg Gly Ser Ala Arg Cys Gln Leu Ser His Glu Gly His Arg 3135 3140 3145 gcc cag ctg ctc atc act ggg gcc acc ctg cag gac agt gga cgc tac 9566 Ala Gln Leu Leu Ile Thr Gly Ala Thr Leu Gln Asp Ser Gly Arg Tyr 3150 3155 3160 3165 aag tgt gag gct ggg ggc gcc tgc agc agc tcc att gtc agg gtg cat 9614 Lys Cys Glu Ala Gly Gly Ala Cys Ser Ser Ser Ile Val Arg Val His 3170 3175 3180 gcg cgg cca gtg cgg ttc cag gag gcc ctg aag gac ctg gag gtg ctg 9662 Ala Arg Pro Val Arg Phe Gln Glu Ala Leu Lys Asp Leu Glu Val Leu 3185 3190 3195 gag ggt ggt gct gcc aca ctg cgc tgt gtg ctg tca tct gtg gct gcg 9710 Glu Gly Gly Ala Ala Thr Leu Arg Cys Val Leu Ser Ser Val Ala Ala 3200 3205 3210 ccc gtg aag tgg tgc tat gga aac aac gtc ctg agg cca ggt gac aaa 9758 Pro Val Lys Trp Cys Tyr Gly Asn Asn Val Leu Arg Pro Gly Asp Lys 3215 3220 3225 tac agc cta cgc cag gag ggt gcc atg ctg gag ctg gtg gtc cgg aac 9806 Tyr Ser Leu Arg Gln Glu Gly Ala Met Leu Glu Leu Val Val Arg Asn 3230 3235 3240 3245 ctc cgg ccg cag gac agc ggg cgg tac tca tgc tcc ttc ggg gac cag 9854 Leu Arg Pro Gln Asp Ser Gly Arg Tyr Ser Cys Ser Phe Gly Asp Gln 3250 3255 3260 act act tct gcc acc ctc aca gtg act gcc ctg cct gcc cag ttc atc 9902 Thr Thr Ser Ala Thr Leu Thr Val Thr Ala Leu Pro Ala Gln Phe Ile 3265 3270 3275 ggg aaa ctg aga aac aag gag gcc aca gaa ggg gcc acg gcc acg ctg 9950 Gly Lys Leu Arg Asn Lys Glu Ala Thr Glu Gly Ala Thr Ala Thr Leu 3280 3285 3290 cgg tgt gag ctg agc aag aca gcc cct gtg gag tgg aga aag ggg tcc 9998 Arg Cys Glu Leu Ser Lys Thr Ala Pro Val Glu Trp Arg Lys Gly Ser 3295 3300 3305 gag acc ctc aga gat ggg gac aga tac tgt ctg agg cag gac ggg gcc 10046 Glu Thr Leu Arg Asp Gly Asp Arg Tyr Cys Leu Arg Gln Asp Gly Ala 3310 3315 3320 3325 atg tgt gag ctg cag atc cgt ggc ctg gcc atg gtg gat gcc gcg gag 10094 Met Cys Glu Leu Gln Ile Arg Gly Leu Ala Met Val Asp Ala Ala Glu 3330 3335 3340 tac tcg tgt gtg tgt gga gag gag agg acc tca gcc tca ctc acc atc 10142 Tyr Ser Cys Val Cys Gly Glu Glu Arg Thr Ser Ala Ser Leu Thr Ile 3345 3350 3355 agg ccc atg cct gcc cac ttc ata gga aga ctg aga cac caa gag agc 10190 Arg Pro Met Pro Ala His Phe Ile Gly Arg Leu Arg His Gln Glu Ser 3360 3365 3370 ata gaa ggg gcc aca gcc acg ctg cgg tgt gag ctg agc aag gcg gcc 10238 Ile Glu Gly Ala Thr Ala Thr Leu Arg Cys Glu Leu Ser Lys Ala Ala 3375 3380 3385 ccc gtg gag tgg agg aag ggg cgt gag agc ctc aga gat ggg gac aga 10286 Pro Val Glu Trp Arg Lys Gly Arg Glu Ser Leu Arg Asp Gly Asp Arg 3390 3395 3400 3405 cat agc ctg agg cag gac ggg gct gtg tgc gag ctg cag atc tgt ggc 10334 His Ser Leu Arg Gln Asp Gly Ala Val Cys Glu Leu Gln Ile Cys Gly 3410 3415 3420 ctg gct gtg gca gat gct ggg gag tac tcc tgt gtg tgt ggg gag gag 10382 Leu Ala Val Ala Asp Ala Gly Glu Tyr Ser Cys Val Cys Gly Glu Glu 3425 3430 3435 agg acc tct gcc act ctc acc gtg aag gcc ctg cca gcc aag ttc aca 10430 Arg Thr Ser Ala Thr Leu Thr Val Lys Ala Leu Pro Ala Lys Phe Thr 3440 3445 3450 gag ggt ctg agg aat gaa gag gcc gtg gaa ggg gcc aca gcc atg ttg 10478 Glu Gly Leu Arg Asn Glu Glu Ala Val Glu Gly Ala Thr Ala Met Leu 3455 3460 3465 tgg tgt gaa ctg agc aag gtg gcc cct gtg gag tgg agg aag ggg ccc 10526 Trp Cys Glu Leu Ser Lys Val Ala Pro Val Glu Trp Arg Lys Gly Pro 3470 3475 3480 3485 gag aac ctc aga gat ggg gac aga tac atc ctg agg cag gag ggg acc 10574 Glu Asn Leu Arg Asp Gly Asp Arg Tyr Ile Leu Arg Gln Glu Gly Thr 3490 3495 3500 agg tgt gag ctg cag atc tgt ggc ctg gcc atg gcg gac gcc ggg gag 10622 Arg Cys Glu Leu Gln Ile Cys Gly Leu Ala Met Ala Asp Ala Gly Glu 3505 3510 3515 tac ttg tgt gtg tgc ggg cag gag agg acc tca gcc acg ctc acc atc 10670 Tyr Leu Cys Val Cys Gly Gln Glu Arg Thr Ser Ala Thr Leu Thr Ile 3520 3525 3530 agg gct ctg cct gcc agg ttc ata gaa gat gtg aaa aac cag gag gcc 10718 Arg Ala Leu Pro Ala Arg Phe Ile Glu Asp Val Lys Asn Gln Glu Ala 3535 3540 3545 aga gaa ggg gcc acg gct gtg ctg cag tgt gag ctg aac agt gca gcc 10766 Arg Glu Gly Ala Thr Ala Val Leu Gln Cys Glu Leu Asn Ser Ala Ala 3550 3555 3560 3565 cct gtg gag tgg aga aag ggg tct gag acc ctc aga gat ggg gac aga 10814 Pro Val Glu Trp Arg Lys Gly Ser Glu Thr Leu Arg Asp Gly Asp Arg 3570 3575 3580 tac agc ctg agg cag gac ggg act aaa tgt gag ctg cag att cgt ggc 10862 Tyr Ser Leu Arg Gln Asp Gly Thr Lys Cys Glu Leu Gln Ile Arg Gly 3585 3590 3595 ctg gcc atg gca gac act ggg gag tac tcg tgc gtg tgc ggg cag gag 10910 Leu Ala Met Ala Asp Thr Gly Glu Tyr Ser Cys Val Cys Gly Gln Glu 3600 3605 3610 agg acc tcg gct atg ctc acc gtc agg gct cta ccc atc aag ttc aca 10958 Arg Thr Ser Ala Met Leu Thr Val Arg Ala Leu Pro Ile Lys Phe Thr 3615 3620 3625 gag ggt ctg agg aac gaa gag gcc aca gaa ggg gca aca gcc gtg ctg 11006 Glu Gly Leu Arg Asn Glu Glu Ala Thr Glu Gly Ala Thr Ala Val Leu 3630 3635 3640 3645 cgg tgt gag ctg agc aag atg gcc ccc gtg gag tgg tgg aag ggg cat 11054 Arg Cys Glu Leu Ser Lys Met Ala Pro Val Glu Trp Trp Lys Gly His 3650 3655 3660 gag acc ctc aga gat gga gac aga cac agc ctg agg cag gac ggg gcc 11102 Glu Thr Leu Arg Asp Gly Asp Arg His Ser Leu Arg Gln Asp Gly Ala 3665 3670 3675 agg tgt gag ctg cag atc cgc ggc ctc gtg gca gag gac gct ggg gag 11150 Arg Cys Glu Leu Gln Ile Arg Gly Leu Val Ala Glu Asp Ala Gly Glu 3680 3685 3690 tac ctg tgc atg tgc ggg aag gag agg acc tca gcc atg ctc acc gtc 11198 Tyr Leu Cys Met Cys Gly Lys Glu Arg Thr Ser Ala Met Leu Thr Val 3695 3700 3705 agg gcc atg cct tcc aag ttc ata gag ggt ctg agg aat gaa gag gcc 11246 Arg Ala Met Pro Ser Lys Phe Ile Glu Gly Leu Arg Asn Glu Glu Ala 3710 3715 3720 3725 aca gaa ggg gac acg gcc acg ctg tgg tgt gag ctg agc aag gcg gca 11294 Thr Glu Gly Asp Thr Ala Thr Leu Trp Cys Glu Leu Ser Lys Ala Ala 3730 3735 3740 ccg gtg gag tgg agg aag ggg cat gag acc ctc aga gat ggg gac aga 11342 Pro Val Glu Trp Arg Lys Gly His Glu Thr Leu Arg Asp Gly Asp Arg 3745 3750 3755 cac agc ctg agg cag gac ggg tcc agg tgt gag ctg cag atc cgt ggc 11390 His Ser Leu Arg Gln Asp Gly Ser Arg Cys Glu Leu Gln Ile Arg Gly 3760 3765 3770 ctg gct gtg gtg gat gcc ggg gag tac tcg tgt gtg tgc ggg cag gag 11438 Leu Ala Val Val Asp Ala Gly Glu Tyr Ser Cys Val Cys Gly Gln Glu 3775 3780 3785 agg acc tca gcc aca ctc act gtc agg gcc ctg cct gcc aga ttc ata 11486 Arg Thr Ser Ala Thr Leu Thr Val Arg Ala Leu Pro Ala Arg Phe Ile 3790 3795 3800 3805 gaa gat gtg aaa aac cag gag gcc aga gaa ggg gcc acg gcc gtg ctg 11534 Glu Asp Val Lys Asn Gln Glu Ala Arg Glu Gly Ala Thr Ala Val Leu 3810 3815 3820 caa tgt gag ctg agc aag gcg gcc ccc gtg gag tgg agg aag ggg tct 11582 Gln Cys Glu Leu Ser Lys Ala Ala Pro Val Glu Trp Arg Lys Gly Ser 3825 3830 3835 gag acc ctc aga ggt ggg gac aga tac agc ctg agg cag gat ggg acc 11630 Glu Thr Leu Arg Gly Gly Asp Arg Tyr Ser Leu Arg Gln Asp Gly Thr 3840 3845 3850 aga tgt gag ctg cag att cat ggc ctg tct gtg gca gac act ggg gag 11678 Arg Cys Glu Leu Gln Ile His Gly Leu Ser Val Ala Asp Thr Gly Glu 3855 3860 3865 tac tcg tgt gtg tgc ggg cag gag agg acc tcg gcc aca ctc acc gtc 11726 Tyr Ser Cys Val Cys Gly Gln Glu Arg Thr Ser Ala Thr Leu Thr Val 3870 3875 3880 3885 agg gcc cca cag cca gtg ttc cgg gag ccg ctg cag agt ctg cag gcg 11774 Arg Ala Pro Gln Pro Val Phe Arg Glu Pro Leu Gln Ser Leu Gln Ala 3890 3895 3900 gag gag ggc tcc acg gcc acc ctg cag tgt gag ctg tct gag ccc act 11822 Glu Glu Gly Ser Thr Ala Thr Leu Gln Cys Glu Leu Ser Glu Pro Thr 3905 3910 3915 gct aca gtg gtc tgg agc aag ggt ggc ctg cag ctg cag gcc aat ggg 11870 Ala Thr Val Val Trp Ser Lys Gly Gly Leu Gln Leu Gln Ala Asn Gly 3920 3925 3930 cgc cgg gag cca cgg ctt cag ggc tgc acc gcg gag ctg gtg tta cag 11918 Arg Arg Glu Pro Arg Leu

Gln Gly Cys Thr Ala Glu Leu Val Leu Gln 3935 3940 3945 gac cta caa cgt gaa gac act ggc gaa tac act tgc acc tgt ggc tcc 11966 Asp Leu Gln Arg Glu Asp Thr Gly Glu Tyr Thr Cys Thr Cys Gly Ser 3950 3955 3960 3965 cag gcc acc agt gcc acc ctc act gtc aca gct gcg cct gtg cgg ttc 12014 Gln Ala Thr Ser Ala Thr Leu Thr Val Thr Ala Ala Pro Val Arg Phe 3970 3975 3980 ctc cga gag ctg cag cac cag gag gtg gat gag gga ggc acc gca cac 12062 Leu Arg Glu Leu Gln His Gln Glu Val Asp Glu Gly Gly Thr Ala His 3985 3990 3995 tta tgc tgc gag ctg agc cgg gcg ggt gcg agc gtg gag tgg cgc aag 12110 Leu Cys Cys Glu Leu Ser Arg Ala Gly Ala Ser Val Glu Trp Arg Lys 4000 4005 4010 ggc tcc cta cag ctc ttc cct tgt gcc aag tac cag atg gtg cag gat 12158 Gly Ser Leu Gln Leu Phe Pro Cys Ala Lys Tyr Gln Met Val Gln Asp 4015 4020 4025 ggt gca gct gca gag ctg ctg gta cgc gga gtg gag cag gag gat gcg 12206 Gly Ala Ala Ala Glu Leu Leu Val Arg Gly Val Glu Gln Glu Asp Ala 4030 4035 4040 4045 ggt gac tac acg tgt gac acg ggc cac acg cag agc atg gcc agc ctc 12254 Gly Asp Tyr Thr Cys Asp Thr Gly His Thr Gln Ser Met Ala Ser Leu 4050 4055 4060 tct gtc cgt gtc ccc agg ccc aag ttc aag acc cgg ctt cag agt ctg 12302 Ser Val Arg Val Pro Arg Pro Lys Phe Lys Thr Arg Leu Gln Ser Leu 4065 4070 4075 gag cag gag aca ggt gac ata gcc cgg ctg tgc tgt cag ctg agt gat 12350 Glu Gln Glu Thr Gly Asp Ile Ala Arg Leu Cys Cys Gln Leu Ser Asp 4080 4085 4090 gca gag tcg ggg gcc gtg gtg caa tgg ctc aag gag ggc gtg gag ctg 12398 Ala Glu Ser Gly Ala Val Val Gln Trp Leu Lys Glu Gly Val Glu Leu 4095 4100 4105 cat gcg ggc ccc aag tac gag atg cgg agc cag ggg gcc acg cgg gag 12446 His Ala Gly Pro Lys Tyr Glu Met Arg Ser Gln Gly Ala Thr Arg Glu 4110 4115 4120 4125 ctg ctg atc cac caa ctg gag gcc aag gac acg ggc gag tat gcc tgt 12494 Leu Leu Ile His Gln Leu Glu Ala Lys Asp Thr Gly Glu Tyr Ala Cys 4130 4135 4140 gtg aca ggc ggc cag aaa acc gct gcc tcc ctc agg gtc aca gag cct 12542 Val Thr Gly Gly Gln Lys Thr Ala Ala Ser Leu Arg Val Thr Glu Pro 4145 4150 4155 gag gtg acc att gta cgg ggg ctg gtt gat gcg gag gtg acg gcc gat 12590 Glu Val Thr Ile Val Arg Gly Leu Val Asp Ala Glu Val Thr Ala Asp 4160 4165 4170 gag gat gtt gag ttc agc tgt gag gtg tcc agg gct gga gcc aca ggc 12638 Glu Asp Val Glu Phe Ser Cys Glu Val Ser Arg Ala Gly Ala Thr Gly 4175 4180 4185 gtg cag tgg tgc cta cag ggc ctg cca ctg caa agc aat gag gtg aca 12686 Val Gln Trp Cys Leu Gln Gly Leu Pro Leu Gln Ser Asn Glu Val Thr 4190 4195 4200 4205 gag gtg gct gtg cgg gat ggc cgc atc cac acc ctg cgg ctg aag ggc 12734 Glu Val Ala Val Arg Asp Gly Arg Ile His Thr Leu Arg Leu Lys Gly 4210 4215 4220 gtg acg ccc gag gac gct ggc act gtc tcc ttc cat ttg gga aac cat 12782 Val Thr Pro Glu Asp Ala Gly Thr Val Ser Phe His Leu Gly Asn His 4225 4230 4235 gct tcc tct gcc cag ctc acc gtc aga gct cct gag gtg acc atc ctg 12830 Ala Ser Ser Ala Gln Leu Thr Val Arg Ala Pro Glu Val Thr Ile Leu 4240 4245 4250 gag ccc ctg cag gac gtg cag ctc agt gag ggc cag gat gcc agc ttc 12878 Glu Pro Leu Gln Asp Val Gln Leu Ser Glu Gly Gln Asp Ala Ser Phe 4255 4260 4265 cag tgc cgg cta tcc aga gct tca ggc cag gag gcc cgc tgg gct tta 12926 Gln Cys Arg Leu Ser Arg Ala Ser Gly Gln Glu Ala Arg Trp Ala Leu 4270 4275 4280 4285 gga ggg gtg ccc ctg cag gcc aac gag atg aat gac atc act gtg gag 12974 Gly Gly Val Pro Leu Gln Ala Asn Glu Met Asn Asp Ile Thr Val Glu 4290 4295 4300 cag ggc aca ctc cac ctg ctc acc ctg cac aag gtg acc ctt gag gat 13022 Gln Gly Thr Leu His Leu Leu Thr Leu His Lys Val Thr Leu Glu Asp 4305 4310 4315 gct gga act gtc agt ttc cac gtg ggc acg tgt agc tct gag gcc cag 13070 Ala Gly Thr Val Ser Phe His Val Gly Thr Cys Ser Ser Glu Ala Gln 4320 4325 4330 ctg aaa gtc aca gcc aag aac acg gtg gtg cgg ggg ctg gag aat gtg 13118 Leu Lys Val Thr Ala Lys Asn Thr Val Val Arg Gly Leu Glu Asn Val 4335 4340 4345 gag gcg ctg gag ggc ggc gag gcg ctg ttc gag tgc cag ctg tcc cag 13166 Glu Ala Leu Glu Gly Gly Glu Ala Leu Phe Glu Cys Gln Leu Ser Gln 4350 4355 4360 4365 ccc gag gtg gcc gcc cac acc tgg ctg ctg gac gac gaa ccc gtg cgc 13214 Pro Glu Val Ala Ala His Thr Trp Leu Leu Asp Asp Glu Pro Val Arg 4370 4375 4380 acc tcg gag aac gcc gag gtg gtc ttc ttc gag aac ggc ctg cgc cac 13262 Thr Ser Glu Asn Ala Glu Val Val Phe Phe Glu Asn Gly Leu Arg His 4385 4390 4395 ctg ctg ctg ctc aaa aac ttg cgg cca caa gac agc tgc cgg gtg acc 13310 Leu Leu Leu Leu Lys Asn Leu Arg Pro Gln Asp Ser Cys Arg Val Thr 4400 4405 4410 ttc ctg gct ggg gat atg gtg acg tcc gca ttc ctc acg gtc cga ggc 13358 Phe Leu Ala Gly Asp Met Val Thr Ser Ala Phe Leu Thr Val Arg Gly 4415 4420 4425 tgg cgc ctg gag atc ctg gag cct ctg aaa aac gcg gcg gtc cgg gcc 13406 Trp Arg Leu Glu Ile Leu Glu Pro Leu Lys Asn Ala Ala Val Arg Ala 4430 4435 4440 4445 ggc gca cag gca cgc ttc acc tgc acg ctc agc gag gcg gtg ccc gtg 13454 Gly Ala Gln Ala Arg Phe Thr Cys Thr Leu Ser Glu Ala Val Pro Val 4450 4455 4460 gga gag gcg tcc tgg tac atc aat ggc gcg gca gtg cag ccg gat gac 13502 Gly Glu Ala Ser Trp Tyr Ile Asn Gly Ala Ala Val Gln Pro Asp Asp 4465 4470 4475 agc gac tgg act gtc acc gcc gac ggc agt cac caa gcc cta ctg ctg 13550 Ser Asp Trp Thr Val Thr Ala Asp Gly Ser His Gln Ala Leu Leu Leu 4480 4485 4490 cgc agc gcc cag ccc cac cac gcc ggg gag gtc acc ttc gct tgc cgc 13598 Arg Ser Ala Gln Pro His His Ala Gly Glu Val Thr Phe Ala Cys Arg 4495 4500 4505 gac gcc gtg gcc tct gca cgg ctc acc gtg ctg ggc ctc cct gat ccc 13646 Asp Ala Val Ala Ser Ala Arg Leu Thr Val Leu Gly Leu Pro Asp Pro 4510 4515 4520 4525 cca gag gat gct gag gtg gtg gct cac agc agc cac act gtg aca ctg 13694 Pro Glu Asp Ala Glu Val Val Ala His Ser Ser His Thr Val Thr Leu 4530 4535 4540 tct tgg gca gct ccc atg agt gat gga ggc ggt ggt ctc tgt ggc tac 13742 Ser Trp Ala Ala Pro Met Ser Asp Gly Gly Gly Gly Leu Cys Gly Tyr 4545 4550 4555 cgc gtg gag gtg aag gag ggg gcc aca ggc cag tgg cgg ctg tgc cac 13790 Arg Val Glu Val Lys Glu Gly Ala Thr Gly Gln Trp Arg Leu Cys His 4560 4565 4570 gag ctg gtg cct gga ccc gag tgt gtg gtg gat ggc ctg gcc ccc ggg 13838 Glu Leu Val Pro Gly Pro Glu Cys Val Val Asp Gly Leu Ala Pro Gly 4575 4580 4585 gag acc tac cgc ttc cgt gtg gca gct gtg ggc cct gtg ggt gct ggg 13886 Glu Thr Tyr Arg Phe Arg Val Ala Ala Val Gly Pro Val Gly Ala Gly 4590 4595 4600 4605 gaa ccg gtt cac ctg ccc cag aca gtg cgg ctt gca gag cca ccg aag 13934 Glu Pro Val His Leu Pro Gln Thr Val Arg Leu Ala Glu Pro Pro Lys 4610 4615 4620 cct gtg cct ccc cag ccc tca gcc cct gag agc cgg cag gtg gca gct 13982 Pro Val Pro Pro Gln Pro Ser Ala Pro Glu Ser Arg Gln Val Ala Ala 4625 4630 4635 ggt gaa gat gtc tct ctg gag ctt gag gtg gtg gct gag gct ggt gag 14030 Gly Glu Asp Val Ser Leu Glu Leu Glu Val Val Ala Glu Ala Gly Glu 4640 4645 4650 gtc atc tgg cac aag gga atg gag cgc atc cag ccc ggt ggg cgg ttc 14078 Val Ile Trp His Lys Gly Met Glu Arg Ile Gln Pro Gly Gly Arg Phe 4655 4660 4665 gag gtg gtc tcc cag ggt cgg caa cag atg ctg gtg atc aag ggc ttc 14126 Glu Val Val Ser Gln Gly Arg Gln Gln Met Leu Val Ile Lys Gly Phe 4670 4675 4680 4685 acg gca gaa gac cag ggc gag tac cac tgt ggc ctg gct cag ggc tcc 14174 Thr Ala Glu Asp Gln Gly Glu Tyr His Cys Gly Leu Ala Gln Gly Ser 4690 4695 4700 atc tgc cct gcg gct gcc acc ttc cag gtg gca ctg agc cca gcc tct 14222 Ile Cys Pro Ala Ala Ala Thr Phe Gln Val Ala Leu Ser Pro Ala Ser 4705 4710 4715 gtg gat gag gcc cct cag ccc agc ttg ccc ccc gag gca gcc cag gag 14270 Val Asp Glu Ala Pro Gln Pro Ser Leu Pro Pro Glu Ala Ala Gln Glu 4720 4725 4730 ggt gac ctg cac cta ctg tgg gag gcc ctg gct cgg aaa cgt cgc atg 14318 Gly Asp Leu His Leu Leu Trp Glu Ala Leu Ala Arg Lys Arg Arg Met 4735 4740 4745 agc cgt gag ccc acg ctg gac tcc att agc gag ctg cca gag gag gac 14366 Ser Arg Glu Pro Thr Leu Asp Ser Ile Ser Glu Leu Pro Glu Glu Asp 4750 4755 4760 4765 ggc cgc tcg cag cgc ctg cca cag gag gca gag gag gtg gca cct gat 14414 Gly Arg Ser Gln Arg Leu Pro Gln Glu Ala Glu Glu Val Ala Pro Asp 4770 4775 4780 ctc tct gaa ggc tac tcc acg gcc gat gag ctg gcc cgc act gga gat 14462 Leu Ser Glu Gly Tyr Ser Thr Ala Asp Glu Leu Ala Arg Thr Gly Asp 4785 4790 4795 gct gac ctc tca cac acc agc tct gat gat gag tcc cgg gca ggc acc 14510 Ala Asp Leu Ser His Thr Ser Ser Asp Asp Glu Ser Arg Ala Gly Thr 4800 4805 4810 cct tcc ctg gtc acc tac ctc aag aag gct ggg agg cca ggc acc tca 14558 Pro Ser Leu Val Thr Tyr Leu Lys Lys Ala Gly Arg Pro Gly Thr Ser 4815 4820 4825 cca ctg gcc agc aag gtt ggg gcc cca gca gcc ccc tct gtg aag cca 14606 Pro Leu Ala Ser Lys Val Gly Ala Pro Ala Ala Pro Ser Val Lys Pro 4830 4835 4840 4845 cag cag cag cag gag cca ctg gct gct gtg cgc cca cca ctg gga gac 14654 Gln Gln Gln Gln Glu Pro Leu Ala Ala Val Arg Pro Pro Leu Gly Asp 4850 4855 4860 ctg agc acc aaa gac ctg ggt gat ccc tca atg gac aag gca gct gtg 14702 Leu Ser Thr Lys Asp Leu Gly Asp Pro Ser Met Asp Lys Ala Ala Val 4865 4870 4875 aag atc cag gct gcc ttt aag ggc tac aag gtc cgg aag gag atg aag 14750 Lys Ile Gln Ala Ala Phe Lys Gly Tyr Lys Val Arg Lys Glu Met Lys 4880 4885 4890 cag cag gaa ggg ccc atg ttc tcc cac aca ttt ggg gac acc gag gca 14798 Gln Gln Glu Gly Pro Met Phe Ser His Thr Phe Gly Asp Thr Glu Ala 4895 4900 4905 cag gtg ggg gat gcc ctg cgg ctg gag tgt gtc gtg gcc agc aag gca 14846 Gln Val Gly Asp Ala Leu Arg Leu Glu Cys Val Val Ala Ser Lys Ala 4910 4915 4920 4925 gat gtg cga gcc cgc tgg ctg aag gat ggt gtg gag ctg acc gat ggg 14894 Asp Val Arg Ala Arg Trp Leu Lys Asp Gly Val Glu Leu Thr Asp Gly 4930 4935 4940 cgg cac cat cac atc gac cag ctt ggg gat ggc acc tgc tct ctg ctg 14942 Arg His His His Ile Asp Gln Leu Gly Asp Gly Thr Cys Ser Leu Leu 4945 4950 4955 atc gct ggc ctg gac cgt gct gat gct ggc tgc tac acc tgt cag gtg 14990 Ile Ala Gly Leu Asp Arg Ala Asp Ala Gly Cys Tyr Thr Cys Gln Val 4960 4965 4970 agc aac aag ttt ggc cag gtg acc cac agt gcc tgt gtg gtg gtc agt 15038 Ser Asn Lys Phe Gly Gln Val Thr His Ser Ala Cys Val Val Val Ser 4975 4980 4985 ggg tca gag agt gaa gcc gag agc tcc tct ggg ggt gag ctg gac gat 15086 Gly Ser Glu Ser Glu Ala Glu Ser Ser Ser Gly Gly Glu Leu Asp Asp 4990 4995 5000 5005 gcc ttc cgc cgg gct gcc cgt cgg ctg cac cgg ctc ttc cgc acc aaa 15134 Ala Phe Arg Arg Ala Ala Arg Arg Leu His Arg Leu Phe Arg Thr Lys 5010 5015 5020 agt ccg gct gaa gtt tca gat gag gag ctc ttc ctg agt gca gac gag 15182 Ser Pro Ala Glu Val Ser Asp Glu Glu Leu Phe Leu Ser Ala Asp Glu 5025 5030 5035 ggc cct gca gag cca gag gag ccc gcg gac tgg cag aca tac cgc gaa 15230 Gly Pro Ala Glu Pro Glu Glu Pro Ala Asp Trp Gln Thr Tyr Arg Glu 5040 5045 5050 gat gag cat ttc atc tgc atc cgt ttt gag gcg ctc act gag gcc cgc 15278 Asp Glu His Phe Ile Cys Ile Arg Phe Glu Ala Leu Thr Glu Ala Arg 5055 5060 5065 cag gcg gta act cgc ttc cag gag atg ttt gcc aca ctg ggc att ggg 15326 Gln Ala Val Thr Arg Phe Gln Glu Met Phe Ala Thr Leu Gly Ile Gly 5070 5075 5080 5085 gtg gag atc aag ctg gtg gaa cag ggg cct cgg agg gta gag atg tgc 15374 Val Glu Ile Lys Leu Val Glu Gln Gly Pro Arg Arg Val Glu Met Cys 5090 5095 5100 atc agc aaa gag act cct gcc cct gtg gtg cct cca gag cca ttg ccc 15422 Ile Ser Lys Glu Thr Pro Ala Pro Val Val Pro Pro Glu Pro Leu Pro 5105 5110 5115 agc cta ctg act tct gac gct gcc cca gtg ttc ctg act gag ttg cag 15470 Ser Leu Leu Thr Ser Asp Ala Ala Pro Val Phe Leu Thr Glu Leu Gln 5120 5125 5130 aac caa gaa gtg cag gat ggg tat cct gtg agc ttt gac tgc gtg gtg 15518 Asn Gln Glu Val Gln Asp Gly Tyr Pro Val Ser Phe Asp Cys Val Val 5135 5140 5145 aca ggt cag ccc atg ccc agt gtg cgc tgg ttc aag gat ggg aag ttg 15566 Thr Gly Gln Pro Met Pro Ser Val Arg Trp Phe Lys Asp Gly Lys Leu 5150 5155 5160 5165 ttg gag gag gat gat cac tac atg att aat gaa gac caa cag ggt ggc 15614 Leu Glu Glu Asp Asp His Tyr Met Ile Asn Glu Asp Gln Gln Gly Gly 5170 5175 5180 cat cag ctc atc atc aca gcc gtg gtg cca gca gac atg ggc gtc tac 15662 His Gln Leu Ile Ile Thr Ala Val Val Pro Ala Asp Met Gly Val Tyr 5185 5190 5195 cgc tgc ctg gcc gag aac agc atg ggt gtc tcc tcc acc aag gct gag 15710 Arg Cys Leu Ala Glu Asn Ser Met Gly Val Ser Ser Thr Lys Ala Glu 5200 5205 5210 ctc cgt gtg gac ttg aca agc aca gac tat gac act gca gca gat gcc 15758 Leu Arg Val Asp Leu Thr Ser Thr Asp Tyr Asp Thr Ala Ala Asp Ala 5215 5220 5225 acg gag tcc tca tcc tac ttc agt gcc caa ggc tac ctg tcc agc cgg 15806 Thr Glu Ser Ser Ser Tyr Phe Ser Ala Gln Gly Tyr Leu Ser Ser Arg 5230 5235 5240 5245 gag cag gag gga aca gag tcc acc act gat gag ggc cag ctg ccc cag 15854 Glu Gln Glu Gly Thr Glu Ser Thr Thr Asp Glu Gly Gln Leu Pro Gln 5250 5255 5260 gtg gtg gag gag ctg aga gac ctc cag gtg gcc cct ggc aca cgc ctg 15902 Val Val Glu Glu Leu Arg Asp Leu Gln Val Ala Pro Gly Thr Arg Leu 5265 5270 5275 gcc aag ttc cag ctc aag gtg aaa ggc tac cct gct ccc aga tta tac 15950 Ala Lys Phe Gln Leu Lys Val Lys Gly Tyr Pro Ala Pro Arg Leu Tyr 5280 5285 5290 tgg ttc aaa gat ggc cag ccc ctg acc gca tct gcc cac atc cgc atg 15998 Trp Phe Lys Asp Gly Gln Pro Leu Thr Ala Ser Ala His Ile Arg Met 5295 5300 5305 act ggc aag aag atc ctg cac acc ctg gag atc atc tcc gtc acc cgg 16046 Thr Gly Lys Lys Ile Leu His Thr Leu Glu Ile Ile Ser Val Thr Arg 5310 5315 5320 5325 gag gac tct ggc cag tat gca gcc tat atc agc aat gcc atg ggt gct 16094 Glu Asp Ser Gly Gln Tyr Ala Ala Tyr Ile Ser Asn Ala Met Gly Ala 5330 5335 5340 gcc tac tcg tct gcc cgg ctg ctg gtt cga ggc cct gat gag cca gaa 16142 Ala Tyr Ser Ser Ala Arg Leu Leu Val Arg Gly Pro Asp Glu Pro Glu 5345 5350 5355 gag aag cct gca tca gat gtg cat gag cag ctg gtg ccg ccc cga atg 16190 Glu Lys Pro Ala Ser Asp Val His Glu Gln Leu Val Pro Pro Arg Met 5360 5365 5370 ctg gag agg ttc acc ccc aag aaa gtg aag aaa ggc tcc agc atc acc 16238 Leu Glu Arg Phe Thr Pro Lys Lys Val Lys Lys Gly Ser Ser Ile Thr 5375 5380 5385 ttc tct gtg aag gta gaa gga cgc ccg gtg ccc acc gtg cac tgg ctc 16286 Phe Ser Val Lys Val Glu Gly Arg Pro Val Pro Thr Val His Trp Leu 5390 5395 5400 5405 agg gag gag gct gag aga ggc gtg ctg tgg att ggc cct gac aca ccg 16334 Arg Glu Glu Ala Glu Arg Gly Val Leu Trp Ile Gly Pro Asp Thr Pro 5410 5415 5420 ggc tac acc gtg gcc agc tct gcg cag cag cac agc ctg gtc ctg ctg 16382 Gly Tyr Thr Val Ala Ser Ser Ala Gln Gln His Ser Leu Val Leu Leu 5425 5430 5435 gac gtg ggc cgg cag cac cag ggc acc tac aca tgc att gcc agc aac 16430 Asp Val Gly Arg Gln His Gln Gly Thr Tyr Thr

Cys Ile Ala Ser Asn 5440 5445 5450 gct gcc ggc cag gcc ctc tgc tcc gcc agc ctg cac gtc tcg ggc ctg 16478 Ala Ala Gly Gln Ala Leu Cys Ser Ala Ser Leu His Val Ser Gly Leu 5455 5460 5465 cct aag gtg gag gag cag gag aaa gtg aag gaa gcg ctg att tcc act 16526 Pro Lys Val Glu Glu Gln Glu Lys Val Lys Glu Ala Leu Ile Ser Thr 5470 5475 5480 5485 ttc ctg cag ggg acc aca caa gcc atc tca gca cag ggg ttg gaa act 16574 Phe Leu Gln Gly Thr Thr Gln Ala Ile Ser Ala Gln Gly Leu Glu Thr 5490 5495 5500 gcg agt ttt gct gac ctt ggt ggg cag agg aaa gaa gag cct ctg gct 16622 Ala Ser Phe Ala Asp Leu Gly Gly Gln Arg Lys Glu Glu Pro Leu Ala 5505 5510 5515 gcc aag gag gcc ctc ggc cac ctg tcc ctc gct gag gtg ggc aca gag 16670 Ala Lys Glu Ala Leu Gly His Leu Ser Leu Ala Glu Val Gly Thr Glu 5520 5525 5530 gag ttc ctg cag aaa ctg acc tcc cag atc act gag atg gta tcg gcc 16718 Glu Phe Leu Gln Lys Leu Thr Ser Gln Ile Thr Glu Met Val Ser Ala 5535 5540 5545 aag atc acg cag gcc aag ctg cag gtg ccc gga ggt gac agt gat gag 16766 Lys Ile Thr Gln Ala Lys Leu Gln Val Pro Gly Gly Asp Ser Asp Glu 5550 5555 5560 5565 gac tcc aag aca cca tct gca tcc ccc cgc cat ggc cga tca cgg cca 16814 Asp Ser Lys Thr Pro Ser Ala Ser Pro Arg His Gly Arg Ser Arg Pro 5570 5575 5580 tcc tcc agc atc cag gag tct tcc tca gag tca gag gac ggc gat gcc 16862 Ser Ser Ser Ile Gln Glu Ser Ser Ser Glu Ser Glu Asp Gly Asp Ala 5585 5590 5595 cga ggc gag atc ttt gac atc tac gtg gtc acc gct gac tac ctg ccc 16910 Arg Gly Glu Ile Phe Asp Ile Tyr Val Val Thr Ala Asp Tyr Leu Pro 5600 5605 5610 cta ggg gct gag cag gat gcc atc acg ctg cgg gaa ggc cag tat gtg 16958 Leu Gly Ala Glu Gln Asp Ala Ile Thr Leu Arg Glu Gly Gln Tyr Val 5615 5620 5625 gag gtc ctg gat gca gcc cac cca ctg cgc tgg ctt gtc cgc acc aag 17006 Glu Val Leu Asp Ala Ala His Pro Leu Arg Trp Leu Val Arg Thr Lys 5630 5635 5640 5645 ccc acc aag tcc agc ccc tca cgg cag ggc tgg gtg tca cca gcc tac 17054 Pro Thr Lys Ser Ser Pro Ser Arg Gln Gly Trp Val Ser Pro Ala Tyr 5650 5655 5660 ctg gac agg agg ctc aag ctg tca cct gag tgg ggg gcc gct gag gcc 17102 Leu Asp Arg Arg Leu Lys Leu Ser Pro Glu Trp Gly Ala Ala Glu Ala 5665 5670 5675 cct gag ttc cct ggg gag gct gtg tct gaa gac gaa tac aag gca agg 17150 Pro Glu Phe Pro Gly Glu Ala Val Ser Glu Asp Glu Tyr Lys Ala Arg 5680 5685 5690 ctg agc tct gtg atc cag gag ctg ctg agt tct gag cag gcc ttc gtg 17198 Leu Ser Ser Val Ile Gln Glu Leu Leu Ser Ser Glu Gln Ala Phe Val 5695 5700 5705 gag gag ctg cag ttc ctg cag agc cac cac ctg cag cac ctg gag cgc 17246 Glu Glu Leu Gln Phe Leu Gln Ser His His Leu Gln His Leu Glu Arg 5710 5715 5720 5725 tgc ccc cac gtg ccc ata gcc gtg gcc ggc cag aag gca gtc atc ttc 17294 Cys Pro His Val Pro Ile Ala Val Ala Gly Gln Lys Ala Val Ile Phe 5730 5735 5740 cgc aat gtg cgg gac atc ggc cgc ttc cac agc agc ttc ctg cag gag 17342 Arg Asn Val Arg Asp Ile Gly Arg Phe His Ser Ser Phe Leu Gln Glu 5745 5750 5755 ttg cag cag tgc gac acg gac gac gac gtg gcc atg tgc ttc atc aag 17390 Leu Gln Gln Cys Asp Thr Asp Asp Asp Val Ala Met Cys Phe Ile Lys 5760 5765 5770 aac cag gcg gcc ttt gag cag tac ctg gag ttc ctg gtg ggg cgt gtg 17438 Asn Gln Ala Ala Phe Glu Gln Tyr Leu Glu Phe Leu Val Gly Arg Val 5775 5780 5785 cag gct gag tcg gtg gtc gtc agc acg gcc atc cag gag ttc tac aag 17486 Gln Ala Glu Ser Val Val Val Ser Thr Ala Ile Gln Glu Phe Tyr Lys 5790 5795 5800 5805 aaa tac gcg gag gag gcc ctg ttg gca ggg gac ccc tct cag ccc ccg 17534 Lys Tyr Ala Glu Glu Ala Leu Leu Ala Gly Asp Pro Ser Gln Pro Pro 5810 5815 5820 cca cca cct ctg cag cac tac ctg gag cag cca gtg gag cgg gtg cag 17582 Pro Pro Pro Leu Gln His Tyr Leu Glu Gln Pro Val Glu Arg Val Gln 5825 5830 5835 cgc tac cag gcc ttg ctg aag gag ttg atc cgc aac aag gcg cgg aac 17630 Arg Tyr Gln Ala Leu Leu Lys Glu Leu Ile Arg Asn Lys Ala Arg Asn 5840 5845 5850 aga cag aac tgc gcg ctg ctg gag cag gcc tat gcc gtg gtg tct gcc 17678 Arg Gln Asn Cys Ala Leu Leu Glu Gln Ala Tyr Ala Val Val Ser Ala 5855 5860 5865 ctg cca cag cgc gct gag aac aag ctg cac gtg tcc ctc atg gag aac 17726 Leu Pro Gln Arg Ala Glu Asn Lys Leu His Val Ser Leu Met Glu Asn 5870 5875 5880 5885 tac cca ggc acc ctg gag gcc ctg ggc gag ccc atc cgc cag ggc cac 17774 Tyr Pro Gly Thr Leu Glu Ala Leu Gly Glu Pro Ile Arg Gln Gly His 5890 5895 5900 ttc atc gtg tgg gag ggt gca ccg ggg gcc cgc atg ccc tgg aag ggc 17822 Phe Ile Val Trp Glu Gly Ala Pro Gly Ala Arg Met Pro Trp Lys Gly 5905 5910 5915 cac aac cgt cac gtg ttc ctc ttc cgc aac cac ctg gta atc tgc aag 17870 His Asn Arg His Val Phe Leu Phe Arg Asn His Leu Val Ile Cys Lys 5920 5925 5930 ccc cgg cga gac tcc cgc acc gat acc gtc agc tac gtg ttc cgg aac 17918 Pro Arg Arg Asp Ser Arg Thr Asp Thr Val Ser Tyr Val Phe Arg Asn 5935 5940 5945 atg atg aag ctg agc agc atc gac ctg aac gac cag gtg gag ggg gat 17966 Met Met Lys Leu Ser Ser Ile Asp Leu Asn Asp Gln Val Glu Gly Asp 5950 5955 5960 5965 gac cgc gcc ttc gag gtg tgg cag gag cgg gag gac tcg gtg cgc aag 18014 Asp Arg Ala Phe Glu Val Trp Gln Glu Arg Glu Asp Ser Val Arg Lys 5970 5975 5980 tac ctg ctg cag gca cgg aca gcc att atc aag agc tcg tgg gtg aag 18062 Tyr Leu Leu Gln Ala Arg Thr Ala Ile Ile Lys Ser Ser Trp Val Lys 5985 5990 5995 gag atc tgt ggc atc cag cag cgt ctg gcc ctg cct gtg tgg cgg ccc 18110 Glu Ile Cys Gly Ile Gln Gln Arg Leu Ala Leu Pro Val Trp Arg Pro 6000 6005 6010 ccg gac ttt gaa gag gag ctg gcc gac tgc aca gcc gag ctg ggt gag 18158 Pro Asp Phe Glu Glu Glu Leu Ala Asp Cys Thr Ala Glu Leu Gly Glu 6015 6020 6025 aca gtc aag ctg gcc tgc cgc gtg acg ggc aca ccc aag cct gtc atc 18206 Thr Val Lys Leu Ala Cys Arg Val Thr Gly Thr Pro Lys Pro Val Ile 6030 6035 6040 6045 agc tgg tac aaa gat ggg aaa gca gtg cag gtg gac ccc cac cac atc 18254 Ser Trp Tyr Lys Asp Gly Lys Ala Val Gln Val Asp Pro His His Ile 6050 6055 6060 ctc att gaa gac cct gat ggc tcg tgt gca ctc atc ctg gac agc ctg 18302 Leu Ile Glu Asp Pro Asp Gly Ser Cys Ala Leu Ile Leu Asp Ser Leu 6065 6070 6075 acc ggt gtg gac tct ggc cag tac atg tgc ttc gcg gcc agc gcc gct 18350 Thr Gly Val Asp Ser Gly Gln Tyr Met Cys Phe Ala Ala Ser Ala Ala 6080 6085 6090 ggc aac tgc agt acc ctg ggc aag atc ctg gtg caa gtc cca cca cgg 18398 Gly Asn Cys Ser Thr Leu Gly Lys Ile Leu Val Gln Val Pro Pro Arg 6095 6100 6105 ttc gtg aac aag gtc cgg gcc tca ccc ttt gtg gag gga gag gac gcc 18446 Phe Val Asn Lys Val Arg Ala Ser Pro Phe Val Glu Gly Glu Asp Ala 6110 6115 6120 6125 cag ttc acc tgc acc atc gaa ggc gcc ccg tac ccg cag atc agg tgg 18494 Gln Phe Thr Cys Thr Ile Glu Gly Ala Pro Tyr Pro Gln Ile Arg Trp 6130 6135 6140 tac aag gac ggg gcc ctg ctg acc act ggc aac aag ttc cag aca ctg 18542 Tyr Lys Asp Gly Ala Leu Leu Thr Thr Gly Asn Lys Phe Gln Thr Leu 6145 6150 6155 agt gag cct cgc agc ggc ctg cta gtg ctg gtg atc cgg gcg gcc agc 18590 Ser Glu Pro Arg Ser Gly Leu Leu Val Leu Val Ile Arg Ala Ala Ser 6160 6165 6170 aag gag gac ctg ggg ctc tac gag tgt gag ctg gtg aac cgg ctg ggc 18638 Lys Glu Asp Leu Gly Leu Tyr Glu Cys Glu Leu Val Asn Arg Leu Gly 6175 6180 6185 tcc gcg cgg gct agt gcg gag ctg cgc att cag agc ccc atg ctg cag 18686 Ser Ala Arg Ala Ser Ala Glu Leu Arg Ile Gln Ser Pro Met Leu Gln 6190 6195 6200 6205 gcc cag gag cag tgt cac agg gag cag ctc gtg gct gca gtg gaa gac 18734 Ala Gln Glu Gln Cys His Arg Glu Gln Leu Val Ala Ala Val Glu Asp 6210 6215 6220 acc acc ctg gag cga gcg gac cag gag gtc aca tct gtc ctg aag aga 18782 Thr Thr Leu Glu Arg Ala Asp Gln Glu Val Thr Ser Val Leu Lys Arg 6225 6230 6235 ctg ctg ggc ccc aag gcg cca ggc ccc tcc aca ggg gac ctc act ggc 18830 Leu Leu Gly Pro Lys Ala Pro Gly Pro Ser Thr Gly Asp Leu Thr Gly 6240 6245 6250 cct ggc ccc tgc ccc agg ggg gca ccc gca ctc cag gaa acc ggc tcc 18878 Pro Gly Pro Cys Pro Arg Gly Ala Pro Ala Leu Gln Glu Thr Gly Ser 6255 6260 6265 cag ccc cca gtc acc gga act tcg gag gca cct gcc gtg ccc ccg agg 18926 Gln Pro Pro Val Thr Gly Thr Ser Glu Ala Pro Ala Val Pro Pro Arg 6270 6275 6280 6285 gtg cca cag ccc ctc ctc cac gaa ggc cca gag cag gag ccg gag gcc 18974 Val Pro Gln Pro Leu Leu His Glu Gly Pro Glu Gln Glu Pro Glu Ala 6290 6295 6300 att gcc aga gcc cag gaa tgg act gtg ccc att cgg atg gag ggt gca 19022 Ile Ala Arg Ala Gln Glu Trp Thr Val Pro Ile Arg Met Glu Gly Ala 6305 6310 6315 gcc tgg ccc ggg gca ggc aca ggg gag ctg ctc tgg gac gtc cac agc 19070 Ala Trp Pro Gly Ala Gly Thr Gly Glu Leu Leu Trp Asp Val His Ser 6320 6325 6330 cac gtg gtc aga gag acc aca cag agg acc tac aca tac cag gcc atc 19118 His Val Val Arg Glu Thr Thr Gln Arg Thr Tyr Thr Tyr Gln Ala Ile 6335 6340 6345 gac acg cac acc gca cgg ccc cca tcc atg cag gta acc atc gag gat 19166 Asp Thr His Thr Ala Arg Pro Pro Ser Met Gln Val Thr Ile Glu Asp 6350 6355 6360 6365 gtg cag gca cag aca ggc gga acg gcc caa ttc gag gct atc att gag 19214 Val Gln Ala Gln Thr Gly Gly Thr Ala Gln Phe Glu Ala Ile Ile Glu 6370 6375 6380 ggc gac cca cag ccc tcg gtg acc tgg tac aag gac agc gtc cag ctg 19262 Gly Asp Pro Gln Pro Ser Val Thr Trp Tyr Lys Asp Ser Val Gln Leu 6385 6390 6395 gtg gac agc acc cgg ctt agc cag cag caa gaa ggc acc aca tac tcc 19310 Val Asp Ser Thr Arg Leu Ser Gln Gln Gln Glu Gly Thr Thr Tyr Ser 6400 6405 6410 ctg gtg ctg agg cat gtg gcc tcg aag gat gcc ggc gtt tac acc tgc 19358 Leu Val Leu Arg His Val Ala Ser Lys Asp Ala Gly Val Tyr Thr Cys 6415 6420 6425 ctg gcc caa aac act ggt ggc cag gtg ctc tgc aag gca gag ctg ctg 19406 Leu Ala Gln Asn Thr Gly Gly Gln Val Leu Cys Lys Ala Glu Leu Leu 6430 6435 6440 6445 gtg ctt ggg ggg gac aat gag ccg gac tca gag aag caa agc cac cgg 19454 Val Leu Gly Gly Asp Asn Glu Pro Asp Ser Glu Lys Gln Ser His Arg 6450 6455 6460 agg aag ctg cac tcc ttc tat gag gtc aag gag gag att gga agg ggc 19502 Arg Lys Leu His Ser Phe Tyr Glu Val Lys Glu Glu Ile Gly Arg Gly 6465 6470 6475 gtg ttt ggc ttc gta aaa aga gtg cag cac aaa gga aac aag atc ttg 19550 Val Phe Gly Phe Val Lys Arg Val Gln His Lys Gly Asn Lys Ile Leu 6480 6485 6490 tgc gct gcc aag ttc atc ccc cta cgg agc aga act cgg gcc cag gca 19598 Cys Ala Ala Lys Phe Ile Pro Leu Arg Ser Arg Thr Arg Ala Gln Ala 6495 6500 6505 tac agg gag cga gac atc ctg gcc gcg ctg agc cac ccg ctg gtc acg 19646 Tyr Arg Glu Arg Asp Ile Leu Ala Ala Leu Ser His Pro Leu Val Thr 6510 6515 6520 6525 ggg ctg ctg gac cag ttt gag acc cgc aag acc ctc atc ctc atc ctg 19694 Gly Leu Leu Asp Gln Phe Glu Thr Arg Lys Thr Leu Ile Leu Ile Leu 6530 6535 6540 gag ctg tgc tca tcc gag gag ctg ctg gac cgc ctg tac agg aag ggc 19742 Glu Leu Cys Ser Ser Glu Glu Leu Leu Asp Arg Leu Tyr Arg Lys Gly 6545 6550 6555 gtg gtg acg gag gcc gag gtc aag gtc tac atc cag cag ctg gtg gag 19790 Val Val Thr Glu Ala Glu Val Lys Val Tyr Ile Gln Gln Leu Val Glu 6560 6565 6570 ggg ctg cac tac ctg cac agc cat ggc gtt ctc cac ctg gac ata aag 19838 Gly Leu His Tyr Leu His Ser His Gly Val Leu His Leu Asp Ile Lys 6575 6580 6585 ccc tct aac atc ctg atg gtg cat cct gcc cgg gaa gac att aaa atc 19886 Pro Ser Asn Ile Leu Met Val His Pro Ala Arg Glu Asp Ile Lys Ile 6590 6595 6600 6605 tgc gac ttt ggc ttt gcc cag aac atc acc cca gca gag ctg cag ttc 19934 Cys Asp Phe Gly Phe Ala Gln Asn Ile Thr Pro Ala Glu Leu Gln Phe 6610 6615 6620 agc cag tac ggc tcc cct gag ttc gtc tcc ccc gag atc atc cag cag 19982 Ser Gln Tyr Gly Ser Pro Glu Phe Val Ser Pro Glu Ile Ile Gln Gln 6625 6630 6635 aac cct gtg agc gaa gcc tcc gac att tgg gcc atg ggt gtc atc tcc 20030 Asn Pro Val Ser Glu Ala Ser Asp Ile Trp Ala Met Gly Val Ile Ser 6640 6645 6650 tac ctc agc ctg acc tgc tca tcc cca ttt gcc ggc gag agt gac cgt 20078 Tyr Leu Ser Leu Thr Cys Ser Ser Pro Phe Ala Gly Glu Ser Asp Arg 6655 6660 6665 gcc acc ctc ctg aac gtc ctg gag ggg cgc gtg tca tgg agc agc ccc 20126 Ala Thr Leu Leu Asn Val Leu Glu Gly Arg Val Ser Trp Ser Ser Pro 6670 6675 6680 6685 atg gct gcc cac ctc agc gaa gac gcc aaa gac ttc atc aag gct acg 20174 Met Ala Ala His Leu Ser Glu Asp Ala Lys Asp Phe Ile Lys Ala Thr 6690 6695 6700 ctg cag aga gcc cct cag gcc cgg cct agt gcg gcc cag tgc ctc tcc 20222 Leu Gln Arg Ala Pro Gln Ala Arg Pro Ser Ala Ala Gln Cys Leu Ser 6705 6710 6715 cac ccc tgg ttc ctg aaa tcc atg cct gcg gag gag gcc cac ttc atc 20270 His Pro Trp Phe Leu Lys Ser Met Pro Ala Glu Glu Ala His Phe Ile 6720 6725 6730 aac acc aag cag ctc aag ttc ctc ctg gcc cga agt cgc tgg cag cgt 20318 Asn Thr Lys Gln Leu Lys Phe Leu Leu Ala Arg Ser Arg Trp Gln Arg 6735 6740 6745 tcc ctg atg agc tac aag tcc atc ctg gtg atg cgc tcc atc cct gag 20366 Ser Leu Met Ser Tyr Lys Ser Ile Leu Val Met Arg Ser Ile Pro Glu 6750 6755 6760 6765 ctg ctg cgg ggc cca ccc gac agc ccc tcc ctc ggc gta gcc cgg cac 20414 Leu Leu Arg Gly Pro Pro Asp Ser Pro Ser Leu Gly Val Ala Arg His 6770 6775 6780 ctc tgc agg gac act ggt ggc tcc tcc agt tcc tcc tcc tcc tct gac 20462 Leu Cys Arg Asp Thr Gly Gly Ser Ser Ser Ser Ser Ser Ser Ser Asp 6785 6790 6795 aac gag ctc gcc cca ttt gcc cgg gct aag tca ctg cca ccc tcc ccg 20510 Asn Glu Leu Ala Pro Phe Ala Arg Ala Lys Ser Leu Pro Pro Ser Pro 6800 6805 6810 gtg aca cac tca cca ctg ctg cac ccc cgg ggc ttc ctg cgg ccc tcg 20558 Val Thr His Ser Pro Leu Leu His Pro Arg Gly Phe Leu Arg Pro Ser 6815 6820 6825 gcc agc ctg cct gag gaa gcc gag gcc agt gag cgc tcc acc gag gcc 20606 Ala Ser Leu Pro Glu Glu Ala Glu Ala Ser Glu Arg Ser Thr Glu Ala 6830 6835 6840 6845 cca gct ccg cct gca tct ccc gag ggt gcc ggg cca ccg gcc gcc cag 20654 Pro Ala Pro Pro Ala Ser Pro Glu Gly Ala Gly Pro Pro Ala Ala Gln 6850 6855 6860 ggc tgc gtg ccc cgg cac agc gtc atc cgc agc ctg ttc tac cac cag 20702 Gly Cys Val Pro Arg His Ser Val Ile Arg Ser Leu Phe Tyr His Gln 6865 6870 6875 gcg ggt gag agc cct gag cac ggg gcc ctg gcc ccg ggg agc agg cgg 20750 Ala Gly Glu Ser Pro Glu His Gly Ala Leu Ala Pro Gly Ser Arg Arg 6880 6885 6890 cac ccg gcc cgg cgg cgg cac ctg ctg aag ggc ggg tac att gcg ggg 20798 His Pro Ala Arg Arg Arg His Leu Leu Lys Gly Gly Tyr Ile Ala Gly 6895 6900 6905 gcg ctg cca ggc ctg cgc gag cca ctg atg gag cac cgc gtg ctg gag 20846 Ala Leu Pro Gly Leu Arg Glu Pro Leu Met Glu His Arg Val Leu Glu 6910 6915 6920 6925 gag gag gcc gcc agg gag gag cag gcc acc ctc ctg gcc aaa gcc ccc 20894 Glu Glu Ala Ala Arg Glu Glu Gln Ala Thr Leu Leu Ala Lys Ala Pro 6930 6935 6940 tca ttc gag act gcc ctc cgg ctg cct gcc tct ggc acc cac ttg gcc 20942 Ser Phe Glu Thr Ala Leu Arg Leu Pro Ala Ser Gly Thr His Leu Ala

6945 6950 6955 cct ggc cac agc cac tcc ctg gaa cat gac tct ccg agc acc ccc cgc 20990 Pro Gly His Ser His Ser Leu Glu His Asp Ser Pro Ser Thr Pro Arg 6960 6965 6970 ccc tcc tcg gag gcc tgc ggt gag gca cag cga ctg cct tca gcc ccc 21038 Pro Ser Ser Glu Ala Cys Gly Glu Ala Gln Arg Leu Pro Ser Ala Pro 6975 6980 6985 tcc ggg ggg gcc cct atc agg gac atg ggg cac cct cag ggc tcc aag 21086 Ser Gly Gly Ala Pro Ile Arg Asp Met Gly His Pro Gln Gly Ser Lys 6990 6995 7000 7005 cag ctt cca tcc act ggt ggc cac cca ggc act gct cag cca gag agg 21134 Gln Leu Pro Ser Thr Gly Gly His Pro Gly Thr Ala Gln Pro Glu Arg 7010 7015 7020 cca tcc ccg gac agc cct tgg ggg cag cca gcc cct ttc tgc cac ccc 21182 Pro Ser Pro Asp Ser Pro Trp Gly Gln Pro Ala Pro Phe Cys His Pro 7025 7030 7035 aag cag ggt tct gcc ccc cag gag ggc tgc agc ccc cac cca gca gtt 21230 Lys Gln Gly Ser Ala Pro Gln Glu Gly Cys Ser Pro His Pro Ala Val 7040 7045 7050 gcc cca tgc cct cct ggc tcc ttc cct cca gga tct tgc aaa gag gcc 21278 Ala Pro Cys Pro Pro Gly Ser Phe Pro Pro Gly Ser Cys Lys Glu Ala 7055 7060 7065 ccc tta gta ccc tca agc ccc ttc ttg gga cag ccc cag gca ccc cct 21326 Pro Leu Val Pro Ser Ser Pro Phe Leu Gly Gln Pro Gln Ala Pro Pro 7070 7075 7080 7085 gcc cct gcc aaa gca agc ccc cca ttg gac tct aag atg ggg cct gga 21374 Ala Pro Ala Lys Ala Ser Pro Pro Leu Asp Ser Lys Met Gly Pro Gly 7090 7095 7100 gac atc tct ctt cct ggg agg cca aaa ccc ggc ccc tgc agt tcc cca 21422 Asp Ile Ser Leu Pro Gly Arg Pro Lys Pro Gly Pro Cys Ser Ser Pro 7105 7110 7115 ggg tca gcc tcc cag gcg agc tct tcc caa gtg agc tcc ctc agg gtg 21470 Gly Ser Ala Ser Gln Ala Ser Ser Ser Gln Val Ser Ser Leu Arg Val 7120 7125 7130 ggc tcc tcc cag gtg ggc aca gag cct ggc ccc tcc ctg gat gcg gag 21518 Gly Ser Ser Gln Val Gly Thr Glu Pro Gly Pro Ser Leu Asp Ala Glu 7135 7140 7145 ggc tgg acc cag gag gct gag gat ctg tcc gac tcc aca ccc acc ttg 21566 Gly Trp Thr Gln Glu Ala Glu Asp Leu Ser Asp Ser Thr Pro Thr Leu 7150 7155 7160 7165 cag cgg cct cag gaa cag gcg acc atg cgc aag ttc tcc ctg ggt ggt 21614 Gln Arg Pro Gln Glu Gln Ala Thr Met Arg Lys Phe Ser Leu Gly Gly 7170 7175 7180 cgc ggg ggc tac gca ggc gtg gct ggc tat ggc acc ttt gcc ttt ggt 21662 Arg Gly Gly Tyr Ala Gly Val Ala Gly Tyr Gly Thr Phe Ala Phe Gly 7185 7190 7195 gga gat gca ggg ggc atg ctg ggg cag ggg ccc atg tgg gcc agg ata 21710 Gly Asp Ala Gly Gly Met Leu Gly Gln Gly Pro Met Trp Ala Arg Ile 7200 7205 7210 gcc tgg gct gtg tcc cag tcg gag gag gag gag cag gag gag gcc agg 21758 Ala Trp Ala Val Ser Gln Ser Glu Glu Glu Glu Gln Glu Glu Ala Arg 7215 7220 7225 gct gag tcc cag tcg gag gag cag cag gag gcc agg gct gag agc cca 21806 Ala Glu Ser Gln Ser Glu Glu Gln Gln Glu Ala Arg Ala Glu Ser Pro 7230 7235 7240 7245 ctg ccc cag gtc agt gca agg cct gtg cct gag gtc ggc agg gct ccc 21854 Leu Pro Gln Val Ser Ala Arg Pro Val Pro Glu Val Gly Arg Ala Pro 7250 7255 7260 acc agg agc tct cca gag ccc acc cca tgg gag gac atc ggg cag gtc 21902 Thr Arg Ser Ser Pro Glu Pro Thr Pro Trp Glu Asp Ile Gly Gln Val 7265 7270 7275 tcc ctg gtg cag atc cgg gac ctg tca ggt gat gcg gag gcg gcc gac 21950 Ser Leu Val Gln Ile Arg Asp Leu Ser Gly Asp Ala Glu Ala Ala Asp 7280 7285 7290 aca ata tcc ctg gac att tcc gag gtg gac ccc gcc tac ctc aac ctc 21998 Thr Ile Ser Leu Asp Ile Ser Glu Val Asp Pro Ala Tyr Leu Asn Leu 7295 7300 7305 tca gac ctg tac gat atc aag tac ctc cca ttc gag ttt atg atc ttc 22046 Ser Asp Leu Tyr Asp Ile Lys Tyr Leu Pro Phe Glu Phe Met Ile Phe 7310 7315 7320 7325 agg aaa gtc ccc aag tcc gct cag cca gag ccg ccc tcc ccc atg gct 22094 Arg Lys Val Pro Lys Ser Ala Gln Pro Glu Pro Pro Ser Pro Met Ala 7330 7335 7340 gag gag gag ctg gcc gag ttc ccg gag ccc acg tgg ccc tgg cca ggt 22142 Glu Glu Glu Leu Ala Glu Phe Pro Glu Pro Thr Trp Pro Trp Pro Gly 7345 7350 7355 gaa ctg ggc ccc cac gca ggc ctg gag atc aca gag gag tca gag gat 22190 Glu Leu Gly Pro His Ala Gly Leu Glu Ile Thr Glu Glu Ser Glu Asp 7360 7365 7370 gtg gac gcg ctg ctg gca gag gct gcc gtg ggc agg aag cgc aag tgg 22238 Val Asp Ala Leu Leu Ala Glu Ala Ala Val Gly Arg Lys Arg Lys Trp 7375 7380 7385 tcc tcg ccg tca cgc agc ctc ttc cac ttc cct ggg agg cac ctg ccg 22286 Ser Ser Pro Ser Arg Ser Leu Phe His Phe Pro Gly Arg His Leu Pro 7390 7395 7400 7405 ctg gat gag cct gca gag ctg ggg ctg cgt gag aga gtg aag gcc tcc 22334 Leu Asp Glu Pro Ala Glu Leu Gly Leu Arg Glu Arg Val Lys Ala Ser 7410 7415 7420 gtg gag cac atc tcc cgg atc ctg aag ggc agg ccg gaa ggt ctg gag 22382 Val Glu His Ile Ser Arg Ile Leu Lys Gly Arg Pro Glu Gly Leu Glu 7425 7430 7435 aag gag ggg ccc ccc agg aag aag cca ggc ctt gct tcc ttc cgg ctc 22430 Lys Glu Gly Pro Pro Arg Lys Lys Pro Gly Leu Ala Ser Phe Arg Leu 7440 7445 7450 tca ggt ctg aag agc tgg gac cga gcg ccg aca ttc cta agg gag ctc 22478 Ser Gly Leu Lys Ser Trp Asp Arg Ala Pro Thr Phe Leu Arg Glu Leu 7455 7460 7465 tca gat gag act gtg gtc ctg ggc cag tca gtg aca ctg gcc tgc cag 22526 Ser Asp Glu Thr Val Val Leu Gly Gln Ser Val Thr Leu Ala Cys Gln 7470 7475 7480 7485 gtg tca gcc cag cca gct gcc cag gcc acc tgg agc aaa gac gga gcc 22574 Val Ser Ala Gln Pro Ala Ala Gln Ala Thr Trp Ser Lys Asp Gly Ala 7490 7495 7500 ccc ctg gag agc agc agc cgt gtc ctc atc tct gcc acc ctc aag aac 22622 Pro Leu Glu Ser Ser Ser Arg Val Leu Ile Ser Ala Thr Leu Lys Asn 7505 7510 7515 ttc cag ctt ctg acc atc ctg gtg gtg gtg gct gag gac ctg ggt gtg 22670 Phe Gln Leu Leu Thr Ile Leu Val Val Val Ala Glu Asp Leu Gly Val 7520 7525 7530 tac acc tgc agc gtg agc aat gcg ctg ggg aca gtg acc acc acg ggc 22718 Tyr Thr Cys Ser Val Ser Asn Ala Leu Gly Thr Val Thr Thr Thr Gly 7535 7540 7545 gtc ctc cgg aag gca gag cgc ccc tca tct tcg cca tgc ccg gat atc 22766 Val Leu Arg Lys Ala Glu Arg Pro Ser Ser Ser Pro Cys Pro Asp Ile 7550 7555 7560 7565 ggg gag gtg tac gcg gat ggg gtg ctg ctg gtc tgg aag ccc gtg gaa 22814 Gly Glu Val Tyr Ala Asp Gly Val Leu Leu Val Trp Lys Pro Val Glu 7570 7575 7580 tcc tac ggc cct gtg acc tac att gtg cag tgc agc cta gaa ggc ggc 22862 Ser Tyr Gly Pro Val Thr Tyr Ile Val Gln Cys Ser Leu Glu Gly Gly 7585 7590 7595 agc tgg acc aca ctg gcc tcc gac atc ttt gac tgc tgc tac ctg acc 22910 Ser Trp Thr Thr Leu Ala Ser Asp Ile Phe Asp Cys Cys Tyr Leu Thr 7600 7605 7610 agc aag ctc tcc cgg ggt ggc acc tac acc ttc cgc acg gca tgt gtc 22958 Ser Lys Leu Ser Arg Gly Gly Thr Tyr Thr Phe Arg Thr Ala Cys Val 7615 7620 7625 agc aag gca gga atg ggt ccc tac agc agc ccc tcg gag caa gtc ctc 23006 Ser Lys Ala Gly Met Gly Pro Tyr Ser Ser Pro Ser Glu Gln Val Leu 7630 7635 7640 7645 ctg gga ggg ccc agc cac ctg gcc tct gag gag gag agc cag ggg cgg 23054 Leu Gly Gly Pro Ser His Leu Ala Ser Glu Glu Glu Ser Gln Gly Arg 7650 7655 7660 tca gcc caa ccc ctg ccc agc aca aag acc ttc gca ttc cag aca cag 23102 Ser Ala Gln Pro Leu Pro Ser Thr Lys Thr Phe Ala Phe Gln Thr Gln 7665 7670 7675 atc cag agg ggc cgc ttc agc gtg gtg cgg caa tgc tgg gag aag gcc 23150 Ile Gln Arg Gly Arg Phe Ser Val Val Arg Gln Cys Trp Glu Lys Ala 7680 7685 7690 agc ggg cgg gcg ctg gcc gcc aag atc atc ccc tac cac ccc aag gac 23198 Ser Gly Arg Ala Leu Ala Ala Lys Ile Ile Pro Tyr His Pro Lys Asp 7695 7700 7705 aag aca gca gtg ctg cgc gaa tac gag gcc ctc aag ggc ctg cgc cac 23246 Lys Thr Ala Val Leu Arg Glu Tyr Glu Ala Leu Lys Gly Leu Arg His 7710 7715 7720 7725 ccg cac ctg gcc cag ctg cac gca gcc tac ctc agc ccc cgg cac ctg 23294 Pro His Leu Ala Gln Leu His Ala Ala Tyr Leu Ser Pro Arg His Leu 7730 7735 7740 gtg ctc atc ttg gag ctg tgc tct ggg ccc gag ctg ctc ccc tgc ctg 23342 Val Leu Ile Leu Glu Leu Cys Ser Gly Pro Glu Leu Leu Pro Cys Leu 7745 7750 7755 gcc gag agg gcc tcc tac tca gaa tcc gag gtg aag gac tac ctg tgg 23390 Ala Glu Arg Ala Ser Tyr Ser Glu Ser Glu Val Lys Asp Tyr Leu Trp 7760 7765 7770 cag atg ttg agt gcc acc cag tac ctg cac aac cag cac atc ctg cac 23438 Gln Met Leu Ser Ala Thr Gln Tyr Leu His Asn Gln His Ile Leu His 7775 7780 7785 ctg gac ctg agg tcc gag aac atg atc atc acc gaa tac aac ctg ctc 23486 Leu Asp Leu Arg Ser Glu Asn Met Ile Ile Thr Glu Tyr Asn Leu Leu 7790 7795 7800 7805 aag gtc gtg gac ctg ggc aat gca cag agc ctc agc cag gag aag gtg 23534 Lys Val Val Asp Leu Gly Asn Ala Gln Ser Leu Ser Gln Glu Lys Val 7810 7815 7820 ctg ccc tca gac aag ttc aag gac tac cta gag acc atg gct cca gag 23582 Leu Pro Ser Asp Lys Phe Lys Asp Tyr Leu Glu Thr Met Ala Pro Glu 7825 7830 7835 ctc ctg gag ggc cag ggg gct gtt cca cag aca gac atc tgg gcc atc 23630 Leu Leu Glu Gly Gln Gly Ala Val Pro Gln Thr Asp Ile Trp Ala Ile 7840 7845 7850 ggt gtg aca gcc ttc atc atg ctg agc gcc gag tac ccg gtg agc agc 23678 Gly Val Thr Ala Phe Ile Met Leu Ser Ala Glu Tyr Pro Val Ser Ser 7855 7860 7865 gag ggt gca cgc gac ctg cag aga gga ctg cgc aag ggg ctg gtc cgg 23726 Glu Gly Ala Arg Asp Leu Gln Arg Gly Leu Arg Lys Gly Leu Val Arg 7870 7875 7880 7885 ctg agc cgc tgc tac gcg ggg ctg tcc ggg ggc gcc gtg gcc ttc ctg 23774 Leu Ser Arg Cys Tyr Ala Gly Leu Ser Gly Gly Ala Val Ala Phe Leu 7890 7895 7900 cgc agc act ctg tgc gcc cag ccc tgg ggc cgg ccc tgc gcg tcc agc 23822 Arg Ser Thr Leu Cys Ala Gln Pro Trp Gly Arg Pro Cys Ala Ser Ser 7905 7910 7915 tgc ctg cag tgc ccg tgg cta aca gag gag ggc ccg gcc tgt tcg cgg 23870 Cys Leu Gln Cys Pro Trp Leu Thr Glu Glu Gly Pro Ala Cys Ser Arg 7920 7925 7930 ccc gcg ccc gtg acc ttc cct acc gcg cgg ctg cgc gtc ttc gtg cgc 23918 Pro Ala Pro Val Thr Phe Pro Thr Ala Arg Leu Arg Val Phe Val Arg 7935 7940 7945 aat cgc gag aag aga cgc gcg ctg ctg tac aag agg cac aac ctg gcc 23966 Asn Arg Glu Lys Arg Arg Ala Leu Leu Tyr Lys Arg His Asn Leu Ala 7950 7955 7960 7965 cag gtg cgc tga gggtcgcccc ggccacaccc ttggtctccc cgctgggggt 24018 Gln Val Arg * cgctgcagac gcgccaataa aaacgcccag ccgggcgaga aaaaaaaaaa aaaaaaaaaa 24078 aaaaaaaaaa aaaaaaaaag gcggccgcta aaaaagtcta ga 24120 5 7968 PRT Homo sapiens 5 Met Asp Gln Pro Gln Phe Ser Gly Ala Pro Arg Phe Leu Thr Arg Pro 1 5 10 15 Lys Ala Phe Val Val Ser Val Gly Lys Asp Ala Thr Leu Ser Cys Gln 20 25 30 Ile Val Gly Asn Pro Thr Pro Gln Val Ser Trp Glu Lys Asp Gln Gln 35 40 45 Pro Val Thr Ala Gly Ala Arg Phe Arg Leu Ala Gln Asp Gly Asp Leu 50 55 60 Tyr Arg Leu Thr Ile Leu Asp Leu Ala Leu Gly Asp Ser Gly Gln Tyr 65 70 75 80 Val Cys Arg Ala Arg Asn Ala Ile Gly Glu Ala Phe Ala Ala Val Gly 85 90 95 Leu Gln Val Asp Ala Glu Ala Ala Cys Ala Glu Gln Ala Pro His Phe 100 105 110 Leu Leu Arg Pro Thr Ser Ile Arg Val Arg Glu Gly Ser Glu Ala Thr 115 120 125 Phe Arg Cys Arg Val Gly Gly Ser Pro Arg Pro Ala Val Ser Trp Ser 130 135 140 Lys Asp Gly Arg Arg Leu Gly Glu Pro Asp Gly Pro Arg Val Arg Val 145 150 155 160 Glu Glu Leu Gly Glu Ala Ser Ala Leu Arg Ile Arg Ala Ala Arg Pro 165 170 175 Arg Asp Gly Gly Thr Tyr Glu Val Arg Ala Glu Asn Pro Leu Gly Ala 180 185 190 Ala Ser Ala Ala Ala Ala Leu Val Val Asp Ser Asp Ala Ala Asp Thr 195 200 205 Ala Ser Arg Pro Gly Thr Ser Thr Ala Ala Leu Leu Ala His Leu Gln 210 215 220 Arg Arg Arg Glu Ala Met Arg Ala Glu Gly Ala Pro Ala Ser Pro Pro 225 230 235 240 Ser Thr Gly Thr Arg Thr Cys Thr Val Thr Glu Gly Lys His Ala Arg 245 250 255 Leu Ser Cys Tyr Val Thr Gly Glu Pro Lys Pro Glu Thr Val Trp Lys 260 265 270 Lys Asp Gly Gln Leu Val Thr Glu Gly Arg Arg His Val Val Tyr Glu 275 280 285 Asp Ala Gln Glu Asn Phe Val Leu Lys Ile Leu Phe Cys Lys Gln Ser 290 295 300 Asp Arg Gly Leu Tyr Thr Cys Thr Ala Ser Asn Leu Val Gly Gln Thr 305 310 315 320 Tyr Ser Ser Val Leu Val Val Val Arg Glu Pro Ala Val Pro Phe Lys 325 330 335 Lys Arg Leu Gln Asp Leu Glu Val Arg Glu Lys Glu Ser Ala Thr Phe 340 345 350 Leu Cys Glu Val Pro Gln Pro Ser Thr Glu Ala Ala Trp Phe Lys Glu 355 360 365 Glu Thr Arg Leu Trp Ala Ser Ala Lys Tyr Gly Ile Glu Glu Glu Gly 370 375 380 Thr Glu Arg Arg Leu Thr Val Arg Asn Val Ser Ala Asp Asp Asp Ala 385 390 395 400 Val Tyr Ile Cys Glu Thr Pro Glu Gly Ser Arg Thr Val Ala Glu Leu 405 410 415 Ala Val Gln Gly Asn Leu Leu Arg Lys Leu Pro Arg Lys Thr Ala Val 420 425 430 Arg Val Gly Asp Thr Ala Met Phe Cys Val Glu Leu Ala Val Pro Val 435 440 445 Gly Pro Val His Trp Leu Arg Asn Gln Glu Glu Val Val Ala Gly Gly 450 455 460 Arg Val Ala Ile Ser Ala Glu Gly Thr Arg His Thr Leu Thr Ile Ser 465 470 475 480 Gln Cys Cys Leu Glu Asp Val Gly Gln Val Ala Phe Met Ala Gly Asp 485 490 495 Cys Gln Thr Ser Thr Arg Phe Cys Val Ser Ala Pro Arg Lys Pro Pro 500 505 510 Leu Gln Pro Pro Val Asp Pro Val Val Lys Ala Arg Met Glu Ser Ser 515 520 525 Val Ile Leu Ser Trp Ser Pro Pro Pro His Gly Glu Arg Pro Val Thr 530 535 540 Ile Asp Gly Tyr Leu Val Glu Lys Lys Lys Leu Gly Thr Tyr Thr Trp 545 550 555 560 Ile Arg Cys His Glu Ala Glu Trp Val Ala Thr Pro Glu Leu Thr Val 565 570 575 Ala Asp Val Ala Glu Glu Gly Asn Phe Gln Phe Arg Val Ser Ala Leu 580 585 590 Asn Ser Phe Gly Gln Ser Pro Tyr Leu Glu Phe Pro Gly Thr Val His 595 600 605 Leu Ala Pro Lys Leu Ala Val Arg Thr Pro Leu Lys Ala Val Gln Ala 610 615 620 Val Glu Gly Gly Glu Val Thr Phe Ser Val Asp Leu Thr Val Ala Ser 625 630 635 640 Ala Gly Glu Trp Phe Leu Asp Gly Gln Ala Leu Lys Ala Ser Ser Val 645 650 655 Tyr Glu Ile His Cys Asp Arg Thr Arg His Thr Leu Thr Ile Arg Glu 660 665 670 Val Pro Ala Ser Leu His Gly Ala Gln Leu Lys Phe Val Ala Asn Gly 675 680 685 Ile Glu Ser Ser Ile Arg Met Glu Val Arg Ala Ala Pro Gly Leu Thr 690 695 700 Ala Asn Lys Pro Pro Ala Ala Ala Ala Arg Glu Val Leu Ala Arg Leu 705 710 715 720 His Glu Glu Ala Gln Leu Leu Ala Glu Leu Ser Asp Gln Ala Ala Ala 725 730 735 Val Thr Trp Leu Lys Asp Gly Arg Thr Leu Ser Pro Gly Pro Lys Tyr 740 745 750 Glu Val Gln Ala Ser Ala Gly Arg Arg Val Leu Leu Val Arg Asp Val 755 760 765

Ala Arg Asp Asp Ala Gly Leu Tyr Glu Cys Val Ser Arg Gly Gly Arg 770 775 780 Ile Ala Tyr Gln Leu Ser Val Gln Gly Leu Ala Arg Phe Leu His Lys 785 790 795 800 Asp Met Ala Gly Ser Cys Val Asp Ala Val Ala Gly Gly Pro Ala Gln 805 810 815 Phe Glu Cys Glu Thr Ser Glu Ala His Val His Val His Trp Tyr Lys 820 825 830 Asp Gly Met Glu Leu Gly His Ser Gly Glu Arg Phe Leu Gln Glu Asp 835 840 845 Val Gly Thr Arg His Arg Leu Val Ala Ala Thr Val Thr Arg Gln Asp 850 855 860 Glu Gly Thr Tyr Ser Cys Arg Val Gly Glu Asp Ser Val Asp Phe Arg 865 870 875 880 Leu Arg Val Ser Glu Pro Lys Val Val Phe Ala Lys Glu Gln Leu Ala 885 890 895 Arg Arg Lys Leu Gln Ala Glu Ala Gly Ala Ser Ala Thr Leu Ser Cys 900 905 910 Glu Val Ala Gln Ala Gln Thr Glu Val Thr Trp Tyr Lys Asp Gly Lys 915 920 925 Lys Leu Ser Ser Ser Ser Lys Val Cys Met Glu Ala Thr Gly Cys Thr 930 935 940 Arg Arg Leu Val Val Gln Gln Ala Gly Gln Ala Asp Ala Gly Glu Tyr 945 950 955 960 Ser Cys Glu Ala Gly Gly Gln Arg Leu Ser Phe His Leu Asp Val Lys 965 970 975 Glu Pro Lys Val Val Phe Ala Lys Asp Gln Val Ala His Ser Glu Val 980 985 990 Gln Ala Glu Ala Gly Ala Asn Ala Thr Leu Ser Cys Glu Val Ala Gln 995 1000 1005 Ala Gln Ala Glu Val Met Trp Tyr Lys Asp Gly Lys Lys Leu Ser Ser 1010 1015 1020 Ser Leu Lys Val His Val Glu Ala Lys Gly Cys Arg Arg Arg Leu Val 1025 1030 1035 1040 Val Gln Gln Ala Gly Lys Thr Asp Ala Gly Asp Tyr Ser Cys Glu Ala 1045 1050 1055 Arg Gly Gln Arg Val Ser Phe Arg Leu His Ile Thr Glu Pro Lys Met 1060 1065 1070 Met Phe Ala Lys Glu Gln Ser Val His Asn Glu Val Gln Ala Glu Ala 1075 1080 1085 Gly Ala Ser Ala Met Leu Ser Cys Glu Val Ala Gln Ala Gln Thr Glu 1090 1095 1100 Val Thr Trp Tyr Lys Asp Gly Lys Lys Leu Ser Ser Ser Ser Lys Val 1105 1110 1115 1120 Gly Met Glu Val Lys Gly Cys Thr Arg Arg Leu Val Leu Pro Gln Ala 1125 1130 1135 Gly Lys Ala Asp Ala Gly Glu Tyr Ser Cys Glu Ala Gly Gly Gln Arg 1140 1145 1150 Val Ser Phe His Leu His Ile Thr Glu Pro Lys Gly Val Phe Ala Lys 1155 1160 1165 Glu Gln Ser Val His Asn Glu Val Gln Ala Glu Ala Gly Thr Thr Ala 1170 1175 1180 Met Leu Ser Cys Glu Val Ala Gln Pro Gln Thr Glu Val Thr Trp Tyr 1185 1190 1195 1200 Lys Asp Gly Lys Lys Leu Ser Ser Ser Ser Lys Val Arg Met Glu Val 1205 1210 1215 Lys Gly Cys Thr Arg Arg Leu Val Val Gln Gln Val Gly Lys Ala Asp 1220 1225 1230 Ala Gly Glu Tyr Ser Cys Glu Ala Gly Gly Gln Arg Val Ser Phe Gln 1235 1240 1245 Leu His Ile Thr Glu Pro Lys Ala Val Phe Ala Lys Glu Gln Leu Val 1250 1255 1260 His Asn Glu Val Arg Thr Glu Ala Gly Ala Ser Ala Thr Leu Ser Cys 1265 1270 1275 1280 Glu Val Ala Gln Ala Gln Thr Glu Val Thr Trp Tyr Lys Asp Gly Lys 1285 1290 1295 Lys Leu Ser Ser Ser Ser Lys Val Arg Ile Glu Ala Ala Gly Cys Met 1300 1305 1310 Arg Gln Leu Val Val Gln Gln Ala Gly Gln Ala Asp Ala Gly Glu Tyr 1315 1320 1325 Thr Cys Glu Ala Gly Gly Gln Arg Leu Ser Phe His Leu Asp Val Ser 1330 1335 1340 Glu Pro Lys Ala Val Phe Ala Lys Glu Gln Leu Ala His Arg Lys Val 1345 1350 1355 1360 Gln Ala Glu Ala Gly Ala Ile Ala Thr Leu Ser Cys Glu Val Ala Gln 1365 1370 1375 Ala Gln Thr Glu Val Thr Trp Tyr Lys Asp Gly Lys Lys Leu Ser Ser 1380 1385 1390 Ser Ser Lys Val Arg Met Glu Ala Val Gly Cys Thr Arg Arg Leu Val 1395 1400 1405 Val Gln Gln Ala Cys Gln Ala Asp Thr Gly Glu Tyr Ser Cys Glu Ala 1410 1415 1420 Gly Gly Gln Arg Leu Ser Phe Ser Leu Asp Val Ala Glu Pro Lys Val 1425 1430 1435 1440 Val Phe Ala Lys Glu Gln Pro Val His Arg Glu Val Gln Ala Gln Ala 1445 1450 1455 Gly Ala Ser Thr Thr Leu Ser Cys Glu Val Ala Gln Ala Gln Thr Glu 1460 1465 1470 Val Met Trp Tyr Lys Asp Gly Lys Lys Leu Ser Phe Ser Ser Lys Val 1475 1480 1485 Arg Met Glu Ala Val Gly Cys Thr Arg Arg Leu Val Val Gln Gln Ala 1490 1495 1500 Gly Gln Ala Asp Ala Gly Glu Tyr Ser Cys Glu Ala Gly Ser Gln Arg 1505 1510 1515 1520 Leu Ser Phe His Leu His Val Ala Glu Pro Lys Ala Val Phe Ala Lys 1525 1530 1535 Glu Gln Pro Ala Ser Arg Glu Val Gln Ala Glu Ala Gly Thr Ser Ala 1540 1545 1550 Thr Leu Ser Cys Glu Val Ala Gln Ala Gln Thr Glu Val Thr Trp Tyr 1555 1560 1565 Lys Asp Gly Lys Lys Leu Ser Ser Ser Ser Lys Val Arg Met Glu Ala 1570 1575 1580 Val Gly Cys Thr Arg Arg Leu Val Val Gln Glu Ala Gly Gln Ala Asp 1585 1590 1595 1600 Ala Gly Glu Tyr Ser Cys Lys Ala Gly Asp Gln Arg Leu Ser Phe His 1605 1610 1615 Leu His Val Ala Glu Pro Lys Val Val Phe Ala Lys Glu Gln Pro Ala 1620 1625 1630 His Arg Glu Val Gln Ala Glu Ala Gly Ala Ser Ala Thr Leu Ser Cys 1635 1640 1645 Glu Val Ala Gln Ala Gln Thr Glu Val Thr Trp Tyr Lys Asp Gly Lys 1650 1655 1660 Lys Leu Ser Ser Ser Ser Lys Val Arg Val Glu Ala Val Gly Cys Thr 1665 1670 1675 1680 Arg Arg Leu Val Val Gln Gln Ala Gly Gln Ala Asp Ala Gly Glu Tyr 1685 1690 1695 Ser Cys Glu Ala Gly Gly Gln Arg Leu Ser Phe Arg Leu His Val Ala 1700 1705 1710 Glu Leu Glu Pro Gln Ile Ser Glu Arg Pro Cys Arg Arg Glu Pro Leu 1715 1720 1725 Val Val Lys Glu His Glu Asp Ile Ile Leu Thr Ala Thr Leu Ala Thr 1730 1735 1740 Pro Ser Ala Ala Thr Val Thr Trp Leu Lys Asp Gly Val Glu Ile Arg 1745 1750 1755 1760 Arg Ser Lys Arg His Glu Thr Ala Ser Gln Gly Asp Thr His Thr Leu 1765 1770 1775 Thr Val His Gly Ala Gln Val Leu Asp Ser Ala Ile Tyr Ser Cys Arg 1780 1785 1790 Val Gly Ala Glu Gly Gln Asp Phe Pro Val Gln Val Glu Glu Val Ala 1795 1800 1805 Ala Lys Phe Cys Arg Leu Leu Glu Pro Val Cys Gly Glu Leu Gly Gly 1810 1815 1820 Thr Val Thr Leu Ala Cys Glu Leu Ser Pro Ala Cys Ala Glu Val Val 1825 1830 1835 1840 Trp Arg Cys Gly Asn Thr Gln Pro Arg Val Gly Lys Arg Phe Gln Met 1845 1850 1855 Val Ala Glu Gly Pro Val Arg Ser Leu Thr Val Leu Gly Leu Arg Ala 1860 1865 1870 Glu Asp Ala Gly Glu Tyr Val Cys Glu Ser Arg Asp Asp His Thr Ser 1875 1880 1885 Ala Gln Leu Thr Val Ser Val Pro Arg Val Val Lys Phe Met Ser Gly 1890 1895 1900 Leu Ser Thr Val Val Ala Glu Glu Gly Gly Glu Ala Thr Phe Gln Cys 1905 1910 1915 1920 Val Val Ser Pro Ser Asp Val Ala Val Val Trp Phe Arg Asp Gly Ala 1925 1930 1935 Leu Leu Gln Pro Ser Glu Lys Phe Ala Ile Ser Gln Ser Gly Ala Ser 1940 1945 1950 His Ser Leu Thr Ile Ser Asp Leu Val Leu Glu Asp Ala Gly Gln Ile 1955 1960 1965 Thr Val Glu Ala Glu Gly Ala Ser Ser Ser Ala Ala Leu Arg Val Arg 1970 1975 1980 Glu Ala Pro Val Leu Phe Lys Lys Lys Leu Glu Pro Gln Thr Val Glu 1985 1990 1995 2000 Glu Arg Ser Ser Val Thr Leu Glu Val Glu Leu Thr Arg Pro Trp Pro 2005 2010 2015 Glu Leu Arg Trp Thr Arg Asn Ala Thr Ala Leu Ala Pro Gly Lys Asn 2020 2025 2030 Val Glu Ile His Ala Glu Gly Ala Arg His Arg Leu Val Leu His Asn 2035 2040 2045 Val Gly Phe Ala Asp Arg Gly Phe Phe Gly Cys Glu Thr Pro Asp Asp 2050 2055 2060 Lys Thr Gln Ala Lys Leu Thr Val Glu Met Arg Gln Val Arg Leu Val 2065 2070 2075 2080 Arg Gly Leu Gln Ala Val Glu Ala Arg Glu Gln Gly Thr Ala Thr Met 2085 2090 2095 Glu Val Gln Leu Ser His Ala Asp Val Asp Gly Ser Trp Thr Arg Asp 2100 2105 2110 Gly Leu Arg Phe Gln Gln Gly Pro Thr Cys His Leu Ala Val Arg Gly 2115 2120 2125 Pro Met His Thr Leu Thr Leu Ser Gly Leu Arg Pro Glu Asp Ser Gly 2130 2135 2140 Leu Met Val Phe Lys Ala Glu Gly Val His Thr Ser Ala Arg Leu Val 2145 2150 2155 2160 Val Thr Glu Leu Pro Val Ser Phe Ser Arg Pro Leu Gln Asp Val Val 2165 2170 2175 Thr Thr Glu Lys Glu Lys Val Thr Leu Glu Cys Glu Leu Ser Arg Pro 2180 2185 2190 Asn Val Asp Val Arg Trp Leu Lys Asp Gly Val Glu Leu Arg Ala Gly 2195 2200 2205 Lys Thr Met Ala Ile Ala Ala Gln Gly Ala Cys Arg Ser Leu Thr Ile 2210 2215 2220 Tyr Arg Cys Glu Phe Ala Asp Gln Gly Val Tyr Val Cys Asp Ala His 2225 2230 2235 2240 Asp Ala Gln Ser Ser Ala Ser Val Lys Val Gln Gly Arg Thr Tyr Thr 2245 2250 2255 Leu Ile Tyr Arg Arg Val Leu Ala Glu Asp Ala Gly Glu Ile Gln Phe 2260 2265 2270 Val Ala Glu Asn Ala Glu Ser Arg Ala Gln Leu Arg Val Lys Glu Leu 2275 2280 2285 Pro Val Thr Leu Val Arg Pro Leu Arg Asp Lys Ile Ala Met Glu Lys 2290 2295 2300 His Arg Gly Val Leu Glu Cys Gln Val Ser Arg Ala Ser Ala Gln Val 2305 2310 2315 2320 Arg Trp Phe Lys Gly Ser Gln Glu Leu Gln Pro Gly Pro Lys Tyr Glu 2325 2330 2335 Leu Val Ser Asp Gly Leu Tyr Arg Lys Leu Ile Ile Ser Asp Val His 2340 2345 2350 Ala Glu Asp Glu Asp Thr Tyr Thr Cys Asp Ala Gly Asp Val Lys Thr 2355 2360 2365 Ser Ala Gln Phe Phe Val Glu Glu Gln Ser Ile Thr Ile Val Arg Gly 2370 2375 2380 Leu Gln Asp Val Thr Val Met Glu Pro Ala Pro Ala Trp Phe Glu Cys 2385 2390 2395 2400 Glu Thr Ser Ile Pro Ser Val Arg Pro Pro Lys Trp Leu Leu Gly Lys 2405 2410 2415 Thr Val Leu Gln Ala Gly Gly Asn Val Gly Leu Glu Gln Glu Gly Thr 2420 2425 2430 Val His Arg Leu Met Leu Arg Arg Thr Cys Ser Thr Met Thr Gly Pro 2435 2440 2445 Val His Phe Thr Val Gly Lys Ser Arg Ser Ser Ala Arg Leu Val Val 2450 2455 2460 Ser Asp Ile Pro Val Val Leu Thr Arg Pro Leu Glu Pro Lys Thr Gly 2465 2470 2475 2480 Arg Glu Leu Gln Ser Val Val Leu Ser Cys Asp Phe Arg Pro Ala Pro 2485 2490 2495 Lys Ala Val Gln Trp Tyr Lys Asp Asp Thr Pro Leu Ser Pro Ser Glu 2500 2505 2510 Lys Phe Lys Met Ser Leu Glu Gly Gln Met Ala Glu Leu Arg Ile Leu 2515 2520 2525 Arg Leu Met Pro Ala Asp Ala Gly Val Tyr Arg Cys Gln Ala Gly Ser 2530 2535 2540 Ala His Ser Ser Thr Glu Val Thr Val Glu Ala Arg Glu Val Thr Val 2545 2550 2555 2560 Thr Gly Pro Leu Gln Asp Ala Glu Ala Thr Glu Glu Gly Trp Ala Ser 2565 2570 2575 Phe Ser Cys Glu Leu Ser His Glu Asp Glu Glu Val Glu Trp Ser Leu 2580 2585 2590 Asn Gly Met Pro Leu Tyr Asn Asp Ser Phe His Glu Ile Ser His Lys 2595 2600 2605 Gly Arg Arg His Thr Leu Val Leu Lys Ser Ile Gln Arg Ala Asp Ala 2610 2615 2620 Gly Ile Val Arg Ala Ser Ser Leu Lys Val Ser Thr Ser Ala Arg Leu 2625 2630 2635 2640 Glu Val Arg Val Lys Pro Val Val Phe Leu Lys Ala Leu Asp Asp Leu 2645 2650 2655 Ser Ala Glu Glu Arg Gly Thr Leu Ala Leu Gln Cys Glu Val Ser Asp 2660 2665 2670 Pro Glu Ala His Val Val Trp Arg Lys Asp Gly Val Gln Leu Gly Pro 2675 2680 2685 Ser Asp Lys Tyr Asp Phe Leu His Thr Ala Gly Thr Arg Gly Leu Val 2690 2695 2700 Val His Asp Val Ser Pro Glu Asp Ala Gly Leu Tyr Thr Cys His Val 2705 2710 2715 2720 Gly Ser Glu Glu Thr Arg Ala Arg Val Arg Val His Asp Leu His Val 2725 2730 2735 Gly Ile Thr Lys Arg Leu Lys Thr Met Glu Val Leu Glu Gly Glu Ser 2740 2745 2750 Cys Ser Phe Glu Cys Val Leu Ser His Glu Ser Ala Ser Asp Pro Ala 2755 2760 2765 Met Trp Thr Val Gly Gly Lys Thr Val Gly Ser Ser Ser Arg Phe Gln 2770 2775 2780 Ala Thr Arg Gln Gly Arg Lys Tyr Ile Leu Val Val Arg Glu Ala Ala 2785 2790 2795 2800 Pro Ser Asp Ala Gly Glu Val Val Phe Ser Val Arg Gly Leu Thr Ser 2805 2810 2815 Lys Ala Ser Leu Ile Val Arg Glu Arg Pro Ala Ala Ile Ile Lys Pro 2820 2825 2830 Leu Glu Asp Gln Trp Val Ala Pro Gly Glu Asp Val Glu Leu Arg Cys 2835 2840 2845 Glu Leu Ser Arg Ala Gly Thr Pro Val His Trp Leu Lys Asp Arg Lys 2850 2855 2860 Ala Ile Arg Lys Ser Gln Lys Tyr Asp Val Val Cys Glu Gly Thr Met 2865 2870 2875 2880 Ala Met Leu Val Ile Arg Gly Ala Ser Leu Lys Asp Ala Gly Glu Tyr 2885 2890 2895 Thr Cys Glu Val Glu Ala Ser Lys Ser Thr Ala Ser Leu His Val Glu 2900 2905 2910 Glu Lys Ala Asn Cys Phe Thr Glu Glu Leu Thr Asn Leu Gln Val Glu 2915 2920 2925 Glu Lys Gly Thr Ala Val Phe Thr Cys Lys Thr Glu His Pro Ala Ala 2930 2935 2940 Thr Val Thr Trp Arg Lys Gly Leu Leu Glu Leu Arg Ala Ser Gly Lys 2945 2950 2955 2960 His Gln Pro Ser Gln Glu Gly Leu Thr Leu Arg Leu Thr Ile Ser Ala 2965 2970 2975 Leu Glu Lys Ala Asp Ser Asp Thr Tyr Thr Cys Asp Ile Gly Gln Ala 2980 2985 2990 Gln Ser Arg Ala Gln Leu Leu Val Gln Gly Arg Arg Val His Ile Ile 2995 3000 3005 Glu Asp Leu Glu Asp Val Asp Val Gln Glu Gly Ser Ser Ala Thr Phe 3010 3015 3020 Arg Cys Arg Ile Ser Pro Ala Asn Tyr Glu Pro Val His Trp Phe Leu 3025 3030 3035 3040 Asp Lys Thr Pro Leu His Ala Asn Glu Leu Asn Glu Ile Asp Ala Gln 3045 3050 3055 Pro Gly Gly Tyr His Val Leu Thr Leu Arg Gln Leu Ala Leu Lys Asp 3060 3065 3070 Ser Gly Thr Ile Tyr Phe Glu Ala Gly Asp Gln Arg Ala Ser Ala Ala 3075 3080 3085 Leu Arg Val Thr Glu Lys Pro Ser Val Phe Ser Arg Glu Leu Thr Asp 3090 3095 3100 Ala Thr Ile Thr Glu Gly Glu Asp Leu Thr Leu Val Cys Glu Thr Ser 3105 3110 3115 3120 Thr Cys Asp Ile Pro Met Cys Trp Thr Lys Asp Gly Lys Thr Leu Arg 3125 3130 3135 Gly Ser Ala Arg Cys Gln Leu Ser His Glu Gly His Arg Ala Gln Leu 3140 3145 3150 Leu Ile Thr Gly Ala Thr Leu Gln Asp Ser Gly Arg Tyr Lys Cys Glu 3155 3160 3165 Ala Gly Gly Ala Cys Ser Ser Ser Ile Val Arg Val His Ala Arg Pro 3170 3175

3180 Val Arg Phe Gln Glu Ala Leu Lys Asp Leu Glu Val Leu Glu Gly Gly 3185 3190 3195 3200 Ala Ala Thr Leu Arg Cys Val Leu Ser Ser Val Ala Ala Pro Val Lys 3205 3210 3215 Trp Cys Tyr Gly Asn Asn Val Leu Arg Pro Gly Asp Lys Tyr Ser Leu 3220 3225 3230 Arg Gln Glu Gly Ala Met Leu Glu Leu Val Val Arg Asn Leu Arg Pro 3235 3240 3245 Gln Asp Ser Gly Arg Tyr Ser Cys Ser Phe Gly Asp Gln Thr Thr Ser 3250 3255 3260 Ala Thr Leu Thr Val Thr Ala Leu Pro Ala Gln Phe Ile Gly Lys Leu 3265 3270 3275 3280 Arg Asn Lys Glu Ala Thr Glu Gly Ala Thr Ala Thr Leu Arg Cys Glu 3285 3290 3295 Leu Ser Lys Thr Ala Pro Val Glu Trp Arg Lys Gly Ser Glu Thr Leu 3300 3305 3310 Arg Asp Gly Asp Arg Tyr Cys Leu Arg Gln Asp Gly Ala Met Cys Glu 3315 3320 3325 Leu Gln Ile Arg Gly Leu Ala Met Val Asp Ala Ala Glu Tyr Ser Cys 3330 3335 3340 Val Cys Gly Glu Glu Arg Thr Ser Ala Ser Leu Thr Ile Arg Pro Met 3345 3350 3355 3360 Pro Ala His Phe Ile Gly Arg Leu Arg His Gln Glu Ser Ile Glu Gly 3365 3370 3375 Ala Thr Ala Thr Leu Arg Cys Glu Leu Ser Lys Ala Ala Pro Val Glu 3380 3385 3390 Trp Arg Lys Gly Arg Glu Ser Leu Arg Asp Gly Asp Arg His Ser Leu 3395 3400 3405 Arg Gln Asp Gly Ala Val Cys Glu Leu Gln Ile Cys Gly Leu Ala Val 3410 3415 3420 Ala Asp Ala Gly Glu Tyr Ser Cys Val Cys Gly Glu Glu Arg Thr Ser 3425 3430 3435 3440 Ala Thr Leu Thr Val Lys Ala Leu Pro Ala Lys Phe Thr Glu Gly Leu 3445 3450 3455 Arg Asn Glu Glu Ala Val Glu Gly Ala Thr Ala Met Leu Trp Cys Glu 3460 3465 3470 Leu Ser Lys Val Ala Pro Val Glu Trp Arg Lys Gly Pro Glu Asn Leu 3475 3480 3485 Arg Asp Gly Asp Arg Tyr Ile Leu Arg Gln Glu Gly Thr Arg Cys Glu 3490 3495 3500 Leu Gln Ile Cys Gly Leu Ala Met Ala Asp Ala Gly Glu Tyr Leu Cys 3505 3510 3515 3520 Val Cys Gly Gln Glu Arg Thr Ser Ala Thr Leu Thr Ile Arg Ala Leu 3525 3530 3535 Pro Ala Arg Phe Ile Glu Asp Val Lys Asn Gln Glu Ala Arg Glu Gly 3540 3545 3550 Ala Thr Ala Val Leu Gln Cys Glu Leu Asn Ser Ala Ala Pro Val Glu 3555 3560 3565 Trp Arg Lys Gly Ser Glu Thr Leu Arg Asp Gly Asp Arg Tyr Ser Leu 3570 3575 3580 Arg Gln Asp Gly Thr Lys Cys Glu Leu Gln Ile Arg Gly Leu Ala Met 3585 3590 3595 3600 Ala Asp Thr Gly Glu Tyr Ser Cys Val Cys Gly Gln Glu Arg Thr Ser 3605 3610 3615 Ala Met Leu Thr Val Arg Ala Leu Pro Ile Lys Phe Thr Glu Gly Leu 3620 3625 3630 Arg Asn Glu Glu Ala Thr Glu Gly Ala Thr Ala Val Leu Arg Cys Glu 3635 3640 3645 Leu Ser Lys Met Ala Pro Val Glu Trp Trp Lys Gly His Glu Thr Leu 3650 3655 3660 Arg Asp Gly Asp Arg His Ser Leu Arg Gln Asp Gly Ala Arg Cys Glu 3665 3670 3675 3680 Leu Gln Ile Arg Gly Leu Val Ala Glu Asp Ala Gly Glu Tyr Leu Cys 3685 3690 3695 Met Cys Gly Lys Glu Arg Thr Ser Ala Met Leu Thr Val Arg Ala Met 3700 3705 3710 Pro Ser Lys Phe Ile Glu Gly Leu Arg Asn Glu Glu Ala Thr Glu Gly 3715 3720 3725 Asp Thr Ala Thr Leu Trp Cys Glu Leu Ser Lys Ala Ala Pro Val Glu 3730 3735 3740 Trp Arg Lys Gly His Glu Thr Leu Arg Asp Gly Asp Arg His Ser Leu 3745 3750 3755 3760 Arg Gln Asp Gly Ser Arg Cys Glu Leu Gln Ile Arg Gly Leu Ala Val 3765 3770 3775 Val Asp Ala Gly Glu Tyr Ser Cys Val Cys Gly Gln Glu Arg Thr Ser 3780 3785 3790 Ala Thr Leu Thr Val Arg Ala Leu Pro Ala Arg Phe Ile Glu Asp Val 3795 3800 3805 Lys Asn Gln Glu Ala Arg Glu Gly Ala Thr Ala Val Leu Gln Cys Glu 3810 3815 3820 Leu Ser Lys Ala Ala Pro Val Glu Trp Arg Lys Gly Ser Glu Thr Leu 3825 3830 3835 3840 Arg Gly Gly Asp Arg Tyr Ser Leu Arg Gln Asp Gly Thr Arg Cys Glu 3845 3850 3855 Leu Gln Ile His Gly Leu Ser Val Ala Asp Thr Gly Glu Tyr Ser Cys 3860 3865 3870 Val Cys Gly Gln Glu Arg Thr Ser Ala Thr Leu Thr Val Arg Ala Pro 3875 3880 3885 Gln Pro Val Phe Arg Glu Pro Leu Gln Ser Leu Gln Ala Glu Glu Gly 3890 3895 3900 Ser Thr Ala Thr Leu Gln Cys Glu Leu Ser Glu Pro Thr Ala Thr Val 3905 3910 3915 3920 Val Trp Ser Lys Gly Gly Leu Gln Leu Gln Ala Asn Gly Arg Arg Glu 3925 3930 3935 Pro Arg Leu Gln Gly Cys Thr Ala Glu Leu Val Leu Gln Asp Leu Gln 3940 3945 3950 Arg Glu Asp Thr Gly Glu Tyr Thr Cys Thr Cys Gly Ser Gln Ala Thr 3955 3960 3965 Ser Ala Thr Leu Thr Val Thr Ala Ala Pro Val Arg Phe Leu Arg Glu 3970 3975 3980 Leu Gln His Gln Glu Val Asp Glu Gly Gly Thr Ala His Leu Cys Cys 3985 3990 3995 4000 Glu Leu Ser Arg Ala Gly Ala Ser Val Glu Trp Arg Lys Gly Ser Leu 4005 4010 4015 Gln Leu Phe Pro Cys Ala Lys Tyr Gln Met Val Gln Asp Gly Ala Ala 4020 4025 4030 Ala Glu Leu Leu Val Arg Gly Val Glu Gln Glu Asp Ala Gly Asp Tyr 4035 4040 4045 Thr Cys Asp Thr Gly His Thr Gln Ser Met Ala Ser Leu Ser Val Arg 4050 4055 4060 Val Pro Arg Pro Lys Phe Lys Thr Arg Leu Gln Ser Leu Glu Gln Glu 4065 4070 4075 4080 Thr Gly Asp Ile Ala Arg Leu Cys Cys Gln Leu Ser Asp Ala Glu Ser 4085 4090 4095 Gly Ala Val Val Gln Trp Leu Lys Glu Gly Val Glu Leu His Ala Gly 4100 4105 4110 Pro Lys Tyr Glu Met Arg Ser Gln Gly Ala Thr Arg Glu Leu Leu Ile 4115 4120 4125 His Gln Leu Glu Ala Lys Asp Thr Gly Glu Tyr Ala Cys Val Thr Gly 4130 4135 4140 Gly Gln Lys Thr Ala Ala Ser Leu Arg Val Thr Glu Pro Glu Val Thr 4145 4150 4155 4160 Ile Val Arg Gly Leu Val Asp Ala Glu Val Thr Ala Asp Glu Asp Val 4165 4170 4175 Glu Phe Ser Cys Glu Val Ser Arg Ala Gly Ala Thr Gly Val Gln Trp 4180 4185 4190 Cys Leu Gln Gly Leu Pro Leu Gln Ser Asn Glu Val Thr Glu Val Ala 4195 4200 4205 Val Arg Asp Gly Arg Ile His Thr Leu Arg Leu Lys Gly Val Thr Pro 4210 4215 4220 Glu Asp Ala Gly Thr Val Ser Phe His Leu Gly Asn His Ala Ser Ser 4225 4230 4235 4240 Ala Gln Leu Thr Val Arg Ala Pro Glu Val Thr Ile Leu Glu Pro Leu 4245 4250 4255 Gln Asp Val Gln Leu Ser Glu Gly Gln Asp Ala Ser Phe Gln Cys Arg 4260 4265 4270 Leu Ser Arg Ala Ser Gly Gln Glu Ala Arg Trp Ala Leu Gly Gly Val 4275 4280 4285 Pro Leu Gln Ala Asn Glu Met Asn Asp Ile Thr Val Glu Gln Gly Thr 4290 4295 4300 Leu His Leu Leu Thr Leu His Lys Val Thr Leu Glu Asp Ala Gly Thr 4305 4310 4315 4320 Val Ser Phe His Val Gly Thr Cys Ser Ser Glu Ala Gln Leu Lys Val 4325 4330 4335 Thr Ala Lys Asn Thr Val Val Arg Gly Leu Glu Asn Val Glu Ala Leu 4340 4345 4350 Glu Gly Gly Glu Ala Leu Phe Glu Cys Gln Leu Ser Gln Pro Glu Val 4355 4360 4365 Ala Ala His Thr Trp Leu Leu Asp Asp Glu Pro Val Arg Thr Ser Glu 4370 4375 4380 Asn Ala Glu Val Val Phe Phe Glu Asn Gly Leu Arg His Leu Leu Leu 4385 4390 4395 4400 Leu Lys Asn Leu Arg Pro Gln Asp Ser Cys Arg Val Thr Phe Leu Ala 4405 4410 4415 Gly Asp Met Val Thr Ser Ala Phe Leu Thr Val Arg Gly Trp Arg Leu 4420 4425 4430 Glu Ile Leu Glu Pro Leu Lys Asn Ala Ala Val Arg Ala Gly Ala Gln 4435 4440 4445 Ala Arg Phe Thr Cys Thr Leu Ser Glu Ala Val Pro Val Gly Glu Ala 4450 4455 4460 Ser Trp Tyr Ile Asn Gly Ala Ala Val Gln Pro Asp Asp Ser Asp Trp 4465 4470 4475 4480 Thr Val Thr Ala Asp Gly Ser His Gln Ala Leu Leu Leu Arg Ser Ala 4485 4490 4495 Gln Pro His His Ala Gly Glu Val Thr Phe Ala Cys Arg Asp Ala Val 4500 4505 4510 Ala Ser Ala Arg Leu Thr Val Leu Gly Leu Pro Asp Pro Pro Glu Asp 4515 4520 4525 Ala Glu Val Val Ala His Ser Ser His Thr Val Thr Leu Ser Trp Ala 4530 4535 4540 Ala Pro Met Ser Asp Gly Gly Gly Gly Leu Cys Gly Tyr Arg Val Glu 4545 4550 4555 4560 Val Lys Glu Gly Ala Thr Gly Gln Trp Arg Leu Cys His Glu Leu Val 4565 4570 4575 Pro Gly Pro Glu Cys Val Val Asp Gly Leu Ala Pro Gly Glu Thr Tyr 4580 4585 4590 Arg Phe Arg Val Ala Ala Val Gly Pro Val Gly Ala Gly Glu Pro Val 4595 4600 4605 His Leu Pro Gln Thr Val Arg Leu Ala Glu Pro Pro Lys Pro Val Pro 4610 4615 4620 Pro Gln Pro Ser Ala Pro Glu Ser Arg Gln Val Ala Ala Gly Glu Asp 4625 4630 4635 4640 Val Ser Leu Glu Leu Glu Val Val Ala Glu Ala Gly Glu Val Ile Trp 4645 4650 4655 His Lys Gly Met Glu Arg Ile Gln Pro Gly Gly Arg Phe Glu Val Val 4660 4665 4670 Ser Gln Gly Arg Gln Gln Met Leu Val Ile Lys Gly Phe Thr Ala Glu 4675 4680 4685 Asp Gln Gly Glu Tyr His Cys Gly Leu Ala Gln Gly Ser Ile Cys Pro 4690 4695 4700 Ala Ala Ala Thr Phe Gln Val Ala Leu Ser Pro Ala Ser Val Asp Glu 4705 4710 4715 4720 Ala Pro Gln Pro Ser Leu Pro Pro Glu Ala Ala Gln Glu Gly Asp Leu 4725 4730 4735 His Leu Leu Trp Glu Ala Leu Ala Arg Lys Arg Arg Met Ser Arg Glu 4740 4745 4750 Pro Thr Leu Asp Ser Ile Ser Glu Leu Pro Glu Glu Asp Gly Arg Ser 4755 4760 4765 Gln Arg Leu Pro Gln Glu Ala Glu Glu Val Ala Pro Asp Leu Ser Glu 4770 4775 4780 Gly Tyr Ser Thr Ala Asp Glu Leu Ala Arg Thr Gly Asp Ala Asp Leu 4785 4790 4795 4800 Ser His Thr Ser Ser Asp Asp Glu Ser Arg Ala Gly Thr Pro Ser Leu 4805 4810 4815 Val Thr Tyr Leu Lys Lys Ala Gly Arg Pro Gly Thr Ser Pro Leu Ala 4820 4825 4830 Ser Lys Val Gly Ala Pro Ala Ala Pro Ser Val Lys Pro Gln Gln Gln 4835 4840 4845 Gln Glu Pro Leu Ala Ala Val Arg Pro Pro Leu Gly Asp Leu Ser Thr 4850 4855 4860 Lys Asp Leu Gly Asp Pro Ser Met Asp Lys Ala Ala Val Lys Ile Gln 4865 4870 4875 4880 Ala Ala Phe Lys Gly Tyr Lys Val Arg Lys Glu Met Lys Gln Gln Glu 4885 4890 4895 Gly Pro Met Phe Ser His Thr Phe Gly Asp Thr Glu Ala Gln Val Gly 4900 4905 4910 Asp Ala Leu Arg Leu Glu Cys Val Val Ala Ser Lys Ala Asp Val Arg 4915 4920 4925 Ala Arg Trp Leu Lys Asp Gly Val Glu Leu Thr Asp Gly Arg His His 4930 4935 4940 His Ile Asp Gln Leu Gly Asp Gly Thr Cys Ser Leu Leu Ile Ala Gly 4945 4950 4955 4960 Leu Asp Arg Ala Asp Ala Gly Cys Tyr Thr Cys Gln Val Ser Asn Lys 4965 4970 4975 Phe Gly Gln Val Thr His Ser Ala Cys Val Val Val Ser Gly Ser Glu 4980 4985 4990 Ser Glu Ala Glu Ser Ser Ser Gly Gly Glu Leu Asp Asp Ala Phe Arg 4995 5000 5005 Arg Ala Ala Arg Arg Leu His Arg Leu Phe Arg Thr Lys Ser Pro Ala 5010 5015 5020 Glu Val Ser Asp Glu Glu Leu Phe Leu Ser Ala Asp Glu Gly Pro Ala 5025 5030 5035 5040 Glu Pro Glu Glu Pro Ala Asp Trp Gln Thr Tyr Arg Glu Asp Glu His 5045 5050 5055 Phe Ile Cys Ile Arg Phe Glu Ala Leu Thr Glu Ala Arg Gln Ala Val 5060 5065 5070 Thr Arg Phe Gln Glu Met Phe Ala Thr Leu Gly Ile Gly Val Glu Ile 5075 5080 5085 Lys Leu Val Glu Gln Gly Pro Arg Arg Val Glu Met Cys Ile Ser Lys 5090 5095 5100 Glu Thr Pro Ala Pro Val Val Pro Pro Glu Pro Leu Pro Ser Leu Leu 5105 5110 5115 5120 Thr Ser Asp Ala Ala Pro Val Phe Leu Thr Glu Leu Gln Asn Gln Glu 5125 5130 5135 Val Gln Asp Gly Tyr Pro Val Ser Phe Asp Cys Val Val Thr Gly Gln 5140 5145 5150 Pro Met Pro Ser Val Arg Trp Phe Lys Asp Gly Lys Leu Leu Glu Glu 5155 5160 5165 Asp Asp His Tyr Met Ile Asn Glu Asp Gln Gln Gly Gly His Gln Leu 5170 5175 5180 Ile Ile Thr Ala Val Val Pro Ala Asp Met Gly Val Tyr Arg Cys Leu 5185 5190 5195 5200 Ala Glu Asn Ser Met Gly Val Ser Ser Thr Lys Ala Glu Leu Arg Val 5205 5210 5215 Asp Leu Thr Ser Thr Asp Tyr Asp Thr Ala Ala Asp Ala Thr Glu Ser 5220 5225 5230 Ser Ser Tyr Phe Ser Ala Gln Gly Tyr Leu Ser Ser Arg Glu Gln Glu 5235 5240 5245 Gly Thr Glu Ser Thr Thr Asp Glu Gly Gln Leu Pro Gln Val Val Glu 5250 5255 5260 Glu Leu Arg Asp Leu Gln Val Ala Pro Gly Thr Arg Leu Ala Lys Phe 5265 5270 5275 5280 Gln Leu Lys Val Lys Gly Tyr Pro Ala Pro Arg Leu Tyr Trp Phe Lys 5285 5290 5295 Asp Gly Gln Pro Leu Thr Ala Ser Ala His Ile Arg Met Thr Gly Lys 5300 5305 5310 Lys Ile Leu His Thr Leu Glu Ile Ile Ser Val Thr Arg Glu Asp Ser 5315 5320 5325 Gly Gln Tyr Ala Ala Tyr Ile Ser Asn Ala Met Gly Ala Ala Tyr Ser 5330 5335 5340 Ser Ala Arg Leu Leu Val Arg Gly Pro Asp Glu Pro Glu Glu Lys Pro 5345 5350 5355 5360 Ala Ser Asp Val His Glu Gln Leu Val Pro Pro Arg Met Leu Glu Arg 5365 5370 5375 Phe Thr Pro Lys Lys Val Lys Lys Gly Ser Ser Ile Thr Phe Ser Val 5380 5385 5390 Lys Val Glu Gly Arg Pro Val Pro Thr Val His Trp Leu Arg Glu Glu 5395 5400 5405 Ala Glu Arg Gly Val Leu Trp Ile Gly Pro Asp Thr Pro Gly Tyr Thr 5410 5415 5420 Val Ala Ser Ser Ala Gln Gln His Ser Leu Val Leu Leu Asp Val Gly 5425 5430 5435 5440 Arg Gln His Gln Gly Thr Tyr Thr Cys Ile Ala Ser Asn Ala Ala Gly 5445 5450 5455 Gln Ala Leu Cys Ser Ala Ser Leu His Val Ser Gly Leu Pro Lys Val 5460 5465 5470 Glu Glu Gln Glu Lys Val Lys Glu Ala Leu Ile Ser Thr Phe Leu Gln 5475 5480 5485 Gly Thr Thr Gln Ala Ile Ser Ala Gln Gly Leu Glu Thr Ala Ser Phe 5490 5495 5500 Ala Asp Leu Gly Gly Gln Arg Lys Glu Glu Pro Leu Ala Ala Lys Glu 5505 5510 5515 5520 Ala Leu Gly His Leu Ser Leu Ala Glu Val Gly Thr Glu Glu Phe Leu 5525 5530 5535 Gln Lys Leu Thr Ser Gln Ile Thr Glu Met Val Ser Ala Lys Ile Thr 5540 5545 5550 Gln Ala Lys Leu Gln Val Pro Gly Gly Asp Ser Asp Glu Asp Ser Lys 5555 5560 5565 Thr Pro Ser Ala Ser Pro Arg His Gly Arg Ser Arg Pro Ser Ser Ser 5570 5575 5580 Ile Gln Glu Ser Ser Ser Glu Ser Glu Asp Gly Asp Ala Arg Gly

Glu 5585 5590 5595 5600 Ile Phe Asp Ile Tyr Val Val Thr Ala Asp Tyr Leu Pro Leu Gly Ala 5605 5610 5615 Glu Gln Asp Ala Ile Thr Leu Arg Glu Gly Gln Tyr Val Glu Val Leu 5620 5625 5630 Asp Ala Ala His Pro Leu Arg Trp Leu Val Arg Thr Lys Pro Thr Lys 5635 5640 5645 Ser Ser Pro Ser Arg Gln Gly Trp Val Ser Pro Ala Tyr Leu Asp Arg 5650 5655 5660 Arg Leu Lys Leu Ser Pro Glu Trp Gly Ala Ala Glu Ala Pro Glu Phe 5665 5670 5675 5680 Pro Gly Glu Ala Val Ser Glu Asp Glu Tyr Lys Ala Arg Leu Ser Ser 5685 5690 5695 Val Ile Gln Glu Leu Leu Ser Ser Glu Gln Ala Phe Val Glu Glu Leu 5700 5705 5710 Gln Phe Leu Gln Ser His His Leu Gln His Leu Glu Arg Cys Pro His 5715 5720 5725 Val Pro Ile Ala Val Ala Gly Gln Lys Ala Val Ile Phe Arg Asn Val 5730 5735 5740 Arg Asp Ile Gly Arg Phe His Ser Ser Phe Leu Gln Glu Leu Gln Gln 5745 5750 5755 5760 Cys Asp Thr Asp Asp Asp Val Ala Met Cys Phe Ile Lys Asn Gln Ala 5765 5770 5775 Ala Phe Glu Gln Tyr Leu Glu Phe Leu Val Gly Arg Val Gln Ala Glu 5780 5785 5790 Ser Val Val Val Ser Thr Ala Ile Gln Glu Phe Tyr Lys Lys Tyr Ala 5795 5800 5805 Glu Glu Ala Leu Leu Ala Gly Asp Pro Ser Gln Pro Pro Pro Pro Pro 5810 5815 5820 Leu Gln His Tyr Leu Glu Gln Pro Val Glu Arg Val Gln Arg Tyr Gln 5825 5830 5835 5840 Ala Leu Leu Lys Glu Leu Ile Arg Asn Lys Ala Arg Asn Arg Gln Asn 5845 5850 5855 Cys Ala Leu Leu Glu Gln Ala Tyr Ala Val Val Ser Ala Leu Pro Gln 5860 5865 5870 Arg Ala Glu Asn Lys Leu His Val Ser Leu Met Glu Asn Tyr Pro Gly 5875 5880 5885 Thr Leu Glu Ala Leu Gly Glu Pro Ile Arg Gln Gly His Phe Ile Val 5890 5895 5900 Trp Glu Gly Ala Pro Gly Ala Arg Met Pro Trp Lys Gly His Asn Arg 5905 5910 5915 5920 His Val Phe Leu Phe Arg Asn His Leu Val Ile Cys Lys Pro Arg Arg 5925 5930 5935 Asp Ser Arg Thr Asp Thr Val Ser Tyr Val Phe Arg Asn Met Met Lys 5940 5945 5950 Leu Ser Ser Ile Asp Leu Asn Asp Gln Val Glu Gly Asp Asp Arg Ala 5955 5960 5965 Phe Glu Val Trp Gln Glu Arg Glu Asp Ser Val Arg Lys Tyr Leu Leu 5970 5975 5980 Gln Ala Arg Thr Ala Ile Ile Lys Ser Ser Trp Val Lys Glu Ile Cys 5985 5990 5995 6000 Gly Ile Gln Gln Arg Leu Ala Leu Pro Val Trp Arg Pro Pro Asp Phe 6005 6010 6015 Glu Glu Glu Leu Ala Asp Cys Thr Ala Glu Leu Gly Glu Thr Val Lys 6020 6025 6030 Leu Ala Cys Arg Val Thr Gly Thr Pro Lys Pro Val Ile Ser Trp Tyr 6035 6040 6045 Lys Asp Gly Lys Ala Val Gln Val Asp Pro His His Ile Leu Ile Glu 6050 6055 6060 Asp Pro Asp Gly Ser Cys Ala Leu Ile Leu Asp Ser Leu Thr Gly Val 6065 6070 6075 6080 Asp Ser Gly Gln Tyr Met Cys Phe Ala Ala Ser Ala Ala Gly Asn Cys 6085 6090 6095 Ser Thr Leu Gly Lys Ile Leu Val Gln Val Pro Pro Arg Phe Val Asn 6100 6105 6110 Lys Val Arg Ala Ser Pro Phe Val Glu Gly Glu Asp Ala Gln Phe Thr 6115 6120 6125 Cys Thr Ile Glu Gly Ala Pro Tyr Pro Gln Ile Arg Trp Tyr Lys Asp 6130 6135 6140 Gly Ala Leu Leu Thr Thr Gly Asn Lys Phe Gln Thr Leu Ser Glu Pro 6145 6150 6155 6160 Arg Ser Gly Leu Leu Val Leu Val Ile Arg Ala Ala Ser Lys Glu Asp 6165 6170 6175 Leu Gly Leu Tyr Glu Cys Glu Leu Val Asn Arg Leu Gly Ser Ala Arg 6180 6185 6190 Ala Ser Ala Glu Leu Arg Ile Gln Ser Pro Met Leu Gln Ala Gln Glu 6195 6200 6205 Gln Cys His Arg Glu Gln Leu Val Ala Ala Val Glu Asp Thr Thr Leu 6210 6215 6220 Glu Arg Ala Asp Gln Glu Val Thr Ser Val Leu Lys Arg Leu Leu Gly 6225 6230 6235 6240 Pro Lys Ala Pro Gly Pro Ser Thr Gly Asp Leu Thr Gly Pro Gly Pro 6245 6250 6255 Cys Pro Arg Gly Ala Pro Ala Leu Gln Glu Thr Gly Ser Gln Pro Pro 6260 6265 6270 Val Thr Gly Thr Ser Glu Ala Pro Ala Val Pro Pro Arg Val Pro Gln 6275 6280 6285 Pro Leu Leu His Glu Gly Pro Glu Gln Glu Pro Glu Ala Ile Ala Arg 6290 6295 6300 Ala Gln Glu Trp Thr Val Pro Ile Arg Met Glu Gly Ala Ala Trp Pro 6305 6310 6315 6320 Gly Ala Gly Thr Gly Glu Leu Leu Trp Asp Val His Ser His Val Val 6325 6330 6335 Arg Glu Thr Thr Gln Arg Thr Tyr Thr Tyr Gln Ala Ile Asp Thr His 6340 6345 6350 Thr Ala Arg Pro Pro Ser Met Gln Val Thr Ile Glu Asp Val Gln Ala 6355 6360 6365 Gln Thr Gly Gly Thr Ala Gln Phe Glu Ala Ile Ile Glu Gly Asp Pro 6370 6375 6380 Gln Pro Ser Val Thr Trp Tyr Lys Asp Ser Val Gln Leu Val Asp Ser 6385 6390 6395 6400 Thr Arg Leu Ser Gln Gln Gln Glu Gly Thr Thr Tyr Ser Leu Val Leu 6405 6410 6415 Arg His Val Ala Ser Lys Asp Ala Gly Val Tyr Thr Cys Leu Ala Gln 6420 6425 6430 Asn Thr Gly Gly Gln Val Leu Cys Lys Ala Glu Leu Leu Val Leu Gly 6435 6440 6445 Gly Asp Asn Glu Pro Asp Ser Glu Lys Gln Ser His Arg Arg Lys Leu 6450 6455 6460 His Ser Phe Tyr Glu Val Lys Glu Glu Ile Gly Arg Gly Val Phe Gly 6465 6470 6475 6480 Phe Val Lys Arg Val Gln His Lys Gly Asn Lys Ile Leu Cys Ala Ala 6485 6490 6495 Lys Phe Ile Pro Leu Arg Ser Arg Thr Arg Ala Gln Ala Tyr Arg Glu 6500 6505 6510 Arg Asp Ile Leu Ala Ala Leu Ser His Pro Leu Val Thr Gly Leu Leu 6515 6520 6525 Asp Gln Phe Glu Thr Arg Lys Thr Leu Ile Leu Ile Leu Glu Leu Cys 6530 6535 6540 Ser Ser Glu Glu Leu Leu Asp Arg Leu Tyr Arg Lys Gly Val Val Thr 6545 6550 6555 6560 Glu Ala Glu Val Lys Val Tyr Ile Gln Gln Leu Val Glu Gly Leu His 6565 6570 6575 Tyr Leu His Ser His Gly Val Leu His Leu Asp Ile Lys Pro Ser Asn 6580 6585 6590 Ile Leu Met Val His Pro Ala Arg Glu Asp Ile Lys Ile Cys Asp Phe 6595 6600 6605 Gly Phe Ala Gln Asn Ile Thr Pro Ala Glu Leu Gln Phe Ser Gln Tyr 6610 6615 6620 Gly Ser Pro Glu Phe Val Ser Pro Glu Ile Ile Gln Gln Asn Pro Val 6625 6630 6635 6640 Ser Glu Ala Ser Asp Ile Trp Ala Met Gly Val Ile Ser Tyr Leu Ser 6645 6650 6655 Leu Thr Cys Ser Ser Pro Phe Ala Gly Glu Ser Asp Arg Ala Thr Leu 6660 6665 6670 Leu Asn Val Leu Glu Gly Arg Val Ser Trp Ser Ser Pro Met Ala Ala 6675 6680 6685 His Leu Ser Glu Asp Ala Lys Asp Phe Ile Lys Ala Thr Leu Gln Arg 6690 6695 6700 Ala Pro Gln Ala Arg Pro Ser Ala Ala Gln Cys Leu Ser His Pro Trp 6705 6710 6715 6720 Phe Leu Lys Ser Met Pro Ala Glu Glu Ala His Phe Ile Asn Thr Lys 6725 6730 6735 Gln Leu Lys Phe Leu Leu Ala Arg Ser Arg Trp Gln Arg Ser Leu Met 6740 6745 6750 Ser Tyr Lys Ser Ile Leu Val Met Arg Ser Ile Pro Glu Leu Leu Arg 6755 6760 6765 Gly Pro Pro Asp Ser Pro Ser Leu Gly Val Ala Arg His Leu Cys Arg 6770 6775 6780 Asp Thr Gly Gly Ser Ser Ser Ser Ser Ser Ser Ser Asp Asn Glu Leu 6785 6790 6795 6800 Ala Pro Phe Ala Arg Ala Lys Ser Leu Pro Pro Ser Pro Val Thr His 6805 6810 6815 Ser Pro Leu Leu His Pro Arg Gly Phe Leu Arg Pro Ser Ala Ser Leu 6820 6825 6830 Pro Glu Glu Ala Glu Ala Ser Glu Arg Ser Thr Glu Ala Pro Ala Pro 6835 6840 6845 Pro Ala Ser Pro Glu Gly Ala Gly Pro Pro Ala Ala Gln Gly Cys Val 6850 6855 6860 Pro Arg His Ser Val Ile Arg Ser Leu Phe Tyr His Gln Ala Gly Glu 6865 6870 6875 6880 Ser Pro Glu His Gly Ala Leu Ala Pro Gly Ser Arg Arg His Pro Ala 6885 6890 6895 Arg Arg Arg His Leu Leu Lys Gly Gly Tyr Ile Ala Gly Ala Leu Pro 6900 6905 6910 Gly Leu Arg Glu Pro Leu Met Glu His Arg Val Leu Glu Glu Glu Ala 6915 6920 6925 Ala Arg Glu Glu Gln Ala Thr Leu Leu Ala Lys Ala Pro Ser Phe Glu 6930 6935 6940 Thr Ala Leu Arg Leu Pro Ala Ser Gly Thr His Leu Ala Pro Gly His 6945 6950 6955 6960 Ser His Ser Leu Glu His Asp Ser Pro Ser Thr Pro Arg Pro Ser Ser 6965 6970 6975 Glu Ala Cys Gly Glu Ala Gln Arg Leu Pro Ser Ala Pro Ser Gly Gly 6980 6985 6990 Ala Pro Ile Arg Asp Met Gly His Pro Gln Gly Ser Lys Gln Leu Pro 6995 7000 7005 Ser Thr Gly Gly His Pro Gly Thr Ala Gln Pro Glu Arg Pro Ser Pro 7010 7015 7020 Asp Ser Pro Trp Gly Gln Pro Ala Pro Phe Cys His Pro Lys Gln Gly 7025 7030 7035 7040 Ser Ala Pro Gln Glu Gly Cys Ser Pro His Pro Ala Val Ala Pro Cys 7045 7050 7055 Pro Pro Gly Ser Phe Pro Pro Gly Ser Cys Lys Glu Ala Pro Leu Val 7060 7065 7070 Pro Ser Ser Pro Phe Leu Gly Gln Pro Gln Ala Pro Pro Ala Pro Ala 7075 7080 7085 Lys Ala Ser Pro Pro Leu Asp Ser Lys Met Gly Pro Gly Asp Ile Ser 7090 7095 7100 Leu Pro Gly Arg Pro Lys Pro Gly Pro Cys Ser Ser Pro Gly Ser Ala 7105 7110 7115 7120 Ser Gln Ala Ser Ser Ser Gln Val Ser Ser Leu Arg Val Gly Ser Ser 7125 7130 7135 Gln Val Gly Thr Glu Pro Gly Pro Ser Leu Asp Ala Glu Gly Trp Thr 7140 7145 7150 Gln Glu Ala Glu Asp Leu Ser Asp Ser Thr Pro Thr Leu Gln Arg Pro 7155 7160 7165 Gln Glu Gln Ala Thr Met Arg Lys Phe Ser Leu Gly Gly Arg Gly Gly 7170 7175 7180 Tyr Ala Gly Val Ala Gly Tyr Gly Thr Phe Ala Phe Gly Gly Asp Ala 7185 7190 7195 7200 Gly Gly Met Leu Gly Gln Gly Pro Met Trp Ala Arg Ile Ala Trp Ala 7205 7210 7215 Val Ser Gln Ser Glu Glu Glu Glu Gln Glu Glu Ala Arg Ala Glu Ser 7220 7225 7230 Gln Ser Glu Glu Gln Gln Glu Ala Arg Ala Glu Ser Pro Leu Pro Gln 7235 7240 7245 Val Ser Ala Arg Pro Val Pro Glu Val Gly Arg Ala Pro Thr Arg Ser 7250 7255 7260 Ser Pro Glu Pro Thr Pro Trp Glu Asp Ile Gly Gln Val Ser Leu Val 7265 7270 7275 7280 Gln Ile Arg Asp Leu Ser Gly Asp Ala Glu Ala Ala Asp Thr Ile Ser 7285 7290 7295 Leu Asp Ile Ser Glu Val Asp Pro Ala Tyr Leu Asn Leu Ser Asp Leu 7300 7305 7310 Tyr Asp Ile Lys Tyr Leu Pro Phe Glu Phe Met Ile Phe Arg Lys Val 7315 7320 7325 Pro Lys Ser Ala Gln Pro Glu Pro Pro Ser Pro Met Ala Glu Glu Glu 7330 7335 7340 Leu Ala Glu Phe Pro Glu Pro Thr Trp Pro Trp Pro Gly Glu Leu Gly 7345 7350 7355 7360 Pro His Ala Gly Leu Glu Ile Thr Glu Glu Ser Glu Asp Val Asp Ala 7365 7370 7375 Leu Leu Ala Glu Ala Ala Val Gly Arg Lys Arg Lys Trp Ser Ser Pro 7380 7385 7390 Ser Arg Ser Leu Phe His Phe Pro Gly Arg His Leu Pro Leu Asp Glu 7395 7400 7405 Pro Ala Glu Leu Gly Leu Arg Glu Arg Val Lys Ala Ser Val Glu His 7410 7415 7420 Ile Ser Arg Ile Leu Lys Gly Arg Pro Glu Gly Leu Glu Lys Glu Gly 7425 7430 7435 7440 Pro Pro Arg Lys Lys Pro Gly Leu Ala Ser Phe Arg Leu Ser Gly Leu 7445 7450 7455 Lys Ser Trp Asp Arg Ala Pro Thr Phe Leu Arg Glu Leu Ser Asp Glu 7460 7465 7470 Thr Val Val Leu Gly Gln Ser Val Thr Leu Ala Cys Gln Val Ser Ala 7475 7480 7485 Gln Pro Ala Ala Gln Ala Thr Trp Ser Lys Asp Gly Ala Pro Leu Glu 7490 7495 7500 Ser Ser Ser Arg Val Leu Ile Ser Ala Thr Leu Lys Asn Phe Gln Leu 7505 7510 7515 7520 Leu Thr Ile Leu Val Val Val Ala Glu Asp Leu Gly Val Tyr Thr Cys 7525 7530 7535 Ser Val Ser Asn Ala Leu Gly Thr Val Thr Thr Thr Gly Val Leu Arg 7540 7545 7550 Lys Ala Glu Arg Pro Ser Ser Ser Pro Cys Pro Asp Ile Gly Glu Val 7555 7560 7565 Tyr Ala Asp Gly Val Leu Leu Val Trp Lys Pro Val Glu Ser Tyr Gly 7570 7575 7580 Pro Val Thr Tyr Ile Val Gln Cys Ser Leu Glu Gly Gly Ser Trp Thr 7585 7590 7595 7600 Thr Leu Ala Ser Asp Ile Phe Asp Cys Cys Tyr Leu Thr Ser Lys Leu 7605 7610 7615 Ser Arg Gly Gly Thr Tyr Thr Phe Arg Thr Ala Cys Val Ser Lys Ala 7620 7625 7630 Gly Met Gly Pro Tyr Ser Ser Pro Ser Glu Gln Val Leu Leu Gly Gly 7635 7640 7645 Pro Ser His Leu Ala Ser Glu Glu Glu Ser Gln Gly Arg Ser Ala Gln 7650 7655 7660 Pro Leu Pro Ser Thr Lys Thr Phe Ala Phe Gln Thr Gln Ile Gln Arg 7665 7670 7675 7680 Gly Arg Phe Ser Val Val Arg Gln Cys Trp Glu Lys Ala Ser Gly Arg 7685 7690 7695 Ala Leu Ala Ala Lys Ile Ile Pro Tyr His Pro Lys Asp Lys Thr Ala 7700 7705 7710 Val Leu Arg Glu Tyr Glu Ala Leu Lys Gly Leu Arg His Pro His Leu 7715 7720 7725 Ala Gln Leu His Ala Ala Tyr Leu Ser Pro Arg His Leu Val Leu Ile 7730 7735 7740 Leu Glu Leu Cys Ser Gly Pro Glu Leu Leu Pro Cys Leu Ala Glu Arg 7745 7750 7755 7760 Ala Ser Tyr Ser Glu Ser Glu Val Lys Asp Tyr Leu Trp Gln Met Leu 7765 7770 7775 Ser Ala Thr Gln Tyr Leu His Asn Gln His Ile Leu His Leu Asp Leu 7780 7785 7790 Arg Ser Glu Asn Met Ile Ile Thr Glu Tyr Asn Leu Leu Lys Val Val 7795 7800 7805 Asp Leu Gly Asn Ala Gln Ser Leu Ser Gln Glu Lys Val Leu Pro Ser 7810 7815 7820 Asp Lys Phe Lys Asp Tyr Leu Glu Thr Met Ala Pro Glu Leu Leu Glu 7825 7830 7835 7840 Gly Gln Gly Ala Val Pro Gln Thr Asp Ile Trp Ala Ile Gly Val Thr 7845 7850 7855 Ala Phe Ile Met Leu Ser Ala Glu Tyr Pro Val Ser Ser Glu Gly Ala 7860 7865 7870 Arg Asp Leu Gln Arg Gly Leu Arg Lys Gly Leu Val Arg Leu Ser Arg 7875 7880 7885 Cys Tyr Ala Gly Leu Ser Gly Gly Ala Val Ala Phe Leu Arg Ser Thr 7890 7895 7900 Leu Cys Ala Gln Pro Trp Gly Arg Pro Cys Ala Ser Ser Cys Leu Gln 7905 7910 7915 7920 Cys Pro Trp Leu Thr Glu Glu Gly Pro Ala Cys Ser Arg Pro Ala Pro 7925 7930 7935 Val Thr Phe Pro Thr Ala Arg Leu Arg Val Phe Val Arg Asn Arg Glu 7940 7945 7950 Lys Arg Arg Ala Leu Leu Tyr Lys Arg His Asn Leu Ala Gln Val Arg 7955 7960 7965 6 23907 DNA Homo sapiens 6 atggatcagc cacagttcag cggggcgccc cgctttctca cccggcccaa ggccttcgtg 60 gtgtcggtgg gcaaggacgc caccctcagc tgccagatcg tgggtaatcc cacgccacag 120 gtgagctggg agaaggacca gcagccggtg acggccggcg cgcgcttccg tctggcccag 180

gacggcgacc tctaccgcct cactatcctg gacctggcgc tgggcgacag tgggcaatac 240 gtgtgccgcg cgcgcaatgc cataggcgag gccttcgctg ccgtgggcct gcaggtggac 300 gcggaggccg cgtgcgccga gcaggcgccg cacttcctgc tgcggcccac gtccatccgc 360 gtgcgcgagg gctcagaggc caccttccgc tgccgcgtgg gtggctcccc gaggccggca 420 gtgagctggt ccaaggacgg gcggcgcctg ggtgagcccg acggcccccg cgtgcgcgtg 480 gaggagctcg gcgaggcaag tgcgctgcgc attcgggcgg cgcggccgcg cgacggcggc 540 acttacgagg tccgcgccga gaacccgctg ggcgctgcca gcgccgccgc ggcgctagtg 600 gtggactcgg acgccgcgga cacggccagc cggcccggga cctccacggc cgcgctcctg 660 gcgcacctgc agcggcggcg cgaggctatg cgcgccgagg gcgcccccgc ctcaccgccc 720 agcaccggca cgcgcacctg cacggtgact gaaggcaagc acgcgcgcct cagctgctac 780 gtgaccggcg agcccaagcc cgagacggtg tggaagaagg acggccagct ggtgaccgag 840 ggccggcgcc acgtggtgta cgaggacgcg caggagaact tcgtgctcaa gatcctcttc 900 tgcaagcagt cggaccgcgg cctctacacc tgcacggcgt ccaacctcgt gggccagacc 960 tacagctctg tgctggtcgt agtgcgcgag cccgcggttc ccttcaaaaa gcggctgcaa 1020 gatctggagg tgcgggagaa ggagtcggct acgttcctat gtgaggtgcc ccagccgtcc 1080 actgaggccg cgtggttcaa ggaggagacg cggttgtggg cgagcgccaa gtacggcatc 1140 gaggaggagg gcaccgagcg ccgcctgacc gtgcgcaatg tctcggccga cgacgacgcg 1200 gtgtacatct gcgagacgcc agagggcagc cgcacggtgg cggagctcgc agtccaagga 1260 aacctcctcc gaaagctccc tcggaagacg gcggtgcgcg tgggcgacac ggctatgttt 1320 tgcgtggagc tggcggtccc ggtgggcccc gtccactggc tgcggaacca ggaggaagtg 1380 gtggcggggg gccgcgtggc catctccgcg gagggcacgc gccacacact gaccatctcc 1440 cagtgctgcc tggaggatgt gggccaggtg gcctttatgg ctggcgactg ccagacgtcc 1500 acccggttct gcgtgtcggc ccccaggaag cctcccctgc aaccccctgt ggatcctgtg 1560 gtaaaggcca ggatggagag ttccgtgatt ctcagctggt ccccaccacc ccatggggaa 1620 cgccctgtca ctatcgacgg ctacctggta gagaagaaga agcttggcac ctacacctgg 1680 atcaggtgcc acgaggctga atgggtggct acacctgagc tgaccgtggc tgatgtggcg 1740 gaggagggga acttccagtt ccgagtgtcc gctctcaaca gctttggtca gagtccctac 1800 ctcgagttcc cggggactgt ccacctggcc cccaagctgg ccgtgaggac accgctgaag 1860 gcggtgcagg cggtagaggg tggcgaggtc actttctccg tggacctcac ggtggcctca 1920 gcgggtgagt ggttcctgga tgggcaggcc ctgaaggcca gcagtgtgta tgagatccac 1980 tgtgatcgca cccggcacac gctcaccatc cgggaggtgc ccgccagcct gcacggggcg 2040 cagctgaagt tcgtggccaa cggcattgag agcagcatcc ggatggaggt ccgggcggcc 2100 ccagggctga ctgccaacaa gccgccagcc gcagctgccc gggaggtgct ggctcggctg 2160 cacgaggagg cgcagctgct ggctgagctg tcagatcagg ctgcggctgt gacgtggctg 2220 aaggatggtc gcacactgtc cccaggcccc aagtatgagg tgcaggcatc ggccgggcgg 2280 cgggtgctcc ttgtgcgaga tgtggcccgg gacgatgcag gcctctacga gtgcgtcagc 2340 cgcgggggcc gcatcgccta ccagctctcc gtgcaaggcc tcgcgcgctt tctgcacaag 2400 gacatggcgg gcagctgtgt ggatgccgtg gctgggggcc cggcgcagtt tgagtgtgag 2460 acctccgaag cccacgtcca cgtgcactgg tacaaggatg gcatggagct gggccactcc 2520 ggtgagcgct tcttgcagga ggatgtgggg acgcggcacc ggctggtggc agccacagtc 2580 accaggcagg atgaaggcac ctactcctgc cgcgtgggcg aggactctgt ggacttccgg 2640 ctccgcgtct ctgagcccaa ggtggtgttt gctaaggagc agctggcacg caggaagctg 2700 caggcagagg caggagccag tgccacactg agctgcgagg tggcccaggc ccagacggag 2760 gtgacgtggt acaaggatgg gaagaagctg agctccagct cgaaagtgtg catggaggcc 2820 acaggctgca cgcgcaggct ggttgtgcag caggcaggcc aggcggatgc cggggagtat 2880 agctgcgagg ctgggggcca gcggctctcc ttccatctgg atgtcaaaga gcccaaggtg 2940 gtgtttgcca aggaccaggt ggcacacagt gaggtgcagg ctgaggcagg ggccaatgcc 3000 acgctgagct gcgaggtggc ccaggcccag gcggaggtga tgtggtacaa agatgggaag 3060 aagctgagct ccagcttgaa agtgcatgta gaggccaaag gctgcagacg gaggctggtg 3120 gtgcagcagg caggcaagac ggatgccggg gactacagct gcgaggccag gggccagagg 3180 gtctccttcc gcctgcacat cacagagccc aagatgatgt ttgcaaagga gcagtcagtg 3240 cataatgagg tgcaggctga ggcgggggcc agtgccatgc tgagctgtga ggtggcccag 3300 gcccagacgg aggtgacgtg gtacaaggat gggaagaagc tgagctccag ctcaaaagtg 3360 ggcatggagg tcaaagggtg cacacggagg ctggtgctgc cacaggcggg caaagcagat 3420 gctggggagt acagctgtga ggctgggggc cagagagtct ccttccacct gcacatcaca 3480 gagcccaagg gggtgtttgc gaaggagcag tcagtgcata atgaggtgca ggctgaggcg 3540 gggaccactg ccatgctgag ctgtgaggtg gcccagcccc agacggaggt gacgtggtac 3600 aaggacggga agaagctgag ctccagctca aaagtacgca tggaggtcaa gggctgcaca 3660 cgaaggctgg tagtgcagca ggtgggcaaa gcagatgctg gggagtacag ctgcgaggct 3720 gggggccaga gagtctcctt tcaactgcac atcacagagc ccaaggcagt gtttgccaag 3780 gagcagttgg tgcataatga ggtgcggact gaggcagggg ccagtgccac actgagctgt 3840 gaggtggccc aggcccagac agaggtgacg tggtacaagg atgggaagaa gctgagctcc 3900 agttcgaaag tgcgcataga ggctgcgggc tgcatgcggc agctggtggt gcagcaggca 3960 ggccaggcag atgctgggga gtacacctgt gaggctgggg gccagcggct ctccttccac 4020 ctggatgttt cagagcccaa ggcggtgttt gcaaaggagc agctggcaca caggaaggtg 4080 caggccgagg cgggggccat tgccacgctg agctgcgagg tggcccaggc ccagacagag 4140 gtgacgtggt acaaggacgg gaagaagctg agctccagct cgaaagttcg aatggaggct 4200 gtgggctgca cacggaggct ggtggtgcag caggcatgcc aggcggacac cggggagtat 4260 agctgcgagg ccgggggcca gcggctctcc ttcagcctgg acgtggcaga gcccaaggtg 4320 gtgtttgcca aggagcagcc agtgcacagg gaggtgcagg cccaggcggg ggccagcacc 4380 acactcagct gcgaggtggc tcaggcccag acggaggtga tgtggtacaa ggacgggaag 4440 aagctgagct tcagctcgaa agtgcgcatg gaggctgtgg gctgcacacg gaggctggtg 4500 gtgcagcagg cgggccaggc ggacgccggg gagtacagct gcgaggcggg gagccagcgg 4560 ctctccttcc acctgcacgt ggcagagccc aaggcggtgt ttgccaagga gcagccagcg 4620 agcagggagg tgcaggctga ggcggggacc agtgccacgc tgagctgcga ggtggcccag 4680 gcccagacag aggtgacgtg gtacaaggac gggaagaaac tgagctccag ctcgaaagtg 4740 cgaatggagg ccgtgggctg cacacggagg ctggtggtgc aggaggcagg ccaggcggac 4800 gccggggagt acagctgcaa ggccggggat cagcggctgt ccttccacct gcacgtggca 4860 gagcccaagg tggtgtttgc caaggagcag ccagcacaca gggaggtgca ggctgaggcg 4920 ggggccagtg ccacgctgag ctgcgaggtg gcccaggccc agacagaggt gacgtggtac 4980 aaggatggga agaagctgag ttccagctcg aaagtgcgcg tggaggccgt gggctgcaca 5040 cggaggctgg tggtgcagca ggcgggccag gcggatgctg gggagtacag ctgtgaggcg 5100 gggggccaac ggctgtcctt ccgcctgcac gtggcagagc tggagcccca aatttcagag 5160 agaccctgcc gcagggagcc tctggtggtc aaggagcatg aagacatcat cctgaccgcc 5220 acactggcca caccctctgc ggccacggtg acctggctca aggatggtgt ggagattcgc 5280 cgcagcaagc ggcatgagac agccagccag ggggacaccc acaccctgac cgtgcatggc 5340 gcccaggttc tggacagcgc catctacagc tgccgtgtgg gcgcagaggg gcaggacttc 5400 ccagtgcagg tggaagaggt ggccgccaag ttctgccggc tgctggagcc tgtgtgcggc 5460 gagctgggtg gcacggtgac actggcctgc gagctaagcc cagcgtgtgc agaggtggtg 5520 tggcgctgcg gcaacacgca gcctcgggtg ggcaagcgct tccagatggt ggccgagggg 5580 cccgtgcgct cactcactgt gttggggctg cgcgcagagg acgcagggga gtacgtgtgt 5640 gagagccgtg atgaccacac cagtgcgcag ctcaccgtca gtgtgccccg agtggtgaag 5700 tttatgtctg ggctgagcac cgtggtcgca gaggagggcg gcgaggccac cttccagtgc 5760 gtggtgtccc ccagtgatgt ggcagtcgtg tggttccggg acggtgccct gcttcagccc 5820 agcgagaagt ttgccatatc acagagtggc gccagccaca gcctgaccat ctcagacctg 5880 gtgctggagg acgcgggcca gatcaccgtg gaggctgagg gcgcctcatc ctctgctgcc 5940 ctgagggtcc gagaggcgcc tgtgctgttc aaaaagaagc tggagccgca gacggtggag 6000 gagcggagct cggtgaccct ggaggtggag ctgacgcggc cgtggccgga gctgaggtgg 6060 acacggaacg cgacggccct ggcgccggga aagaacgtgg agatccacgc cgagggcgcc 6120 cgccaccgcc tggttctgca caacgtaggt tttgccgacc gtggcttctt tggctgcgag 6180 acgccggatg acaagacaca ggccaaactc accgtggaga tgcgccaggt acggctcgta 6240 cggggcctgc aggcagtgga ggcacgggag cagggcacgg ctaccatgga ggtgcagctg 6300 tcgcatgcgg acgtggatgg cagctggact cgtgacggtc tgcggttcca gcaggggccc 6360 acgtgccacc tggctgtgcg gggccccatg cacaccctca cactctcggg gctgcggcca 6420 gaggatagtg gccttatggt cttcaaggcc gaaggagtgc acacgtcggc gcggctcgtg 6480 gtcaccgagc ttcccgtgag cttcagccgc ccgctgcagg acgtggtgac cactgagaag 6540 gagaaggtta ccctggagtg cgagctgtcg cgtcctaatg tggatgtgcg ctggctgaag 6600 gacggtgtgg agctgcgggc aggcaagacg atggccatcg cagcccaggg cgcctgcagg 6660 agcctcacca tttaccggtg cgagttcgcg gatcagggag tgtatgtgtg tgatgcccat 6720 gatgcccaga gctctgcctc cgtgaaggta caaggaagga catacactct catctaccgg 6780 agagtcctgg cggaagatgc aggagagatc caatttgtag ccgaaaatgc agaatcgcga 6840 gcccagctcc gagtgaagga gctgccagtg accctcgtgc gcccgctgcg ggacaagatt 6900 gccatggaga agcaccgcgg tgtgctggag tgtcaggtgt cccgggccag cgcccaggtg 6960 cggtggttca agggcagtca ggagctgcag cccgggccca agtacgagct ggtcagtgat 7020 ggcctctacc gcaagctgat catcagtgat gtccacgcag aggacgagga cacctacacc 7080 tgtgacgccg gtgatgtcaa gaccagtgca cagttcttcg tggaagagca atccatcacc 7140 attgtgcggg gtctgcagga cgtgacagtg atggagcccg ctcctgcctg gtttgagtgt 7200 gagacctcca tcccctcagt gcggccacct aagtggctcc tggggaagac ggtgttgcag 7260 gctgggggga acgtgggcct ggagcaggag ggcacggtgc accggctgat gctgcggcgg 7320 acctgctcca ccatgaccgg gcccgtgcac ttcaccgttg gcaagtcgcg ctcctctgcc 7380 cgcctggtgg tctcagacat ccccgtagtc ctcacacggc cgttggagcc caagacaggg 7440 cgtgagctgc agtcagtggt cctgtcctgc gacttccggc cagcccccaa ggctgtgcag 7500 tggtacaagg atgacacgcc cctgtctccc tctgagaagt ttaagatgag cctggagggt 7560 cagatggctg agctgcgcat cctccggctc atgcctgctg atgctggtgt ctaccggtgc 7620 caggcgggca gtgcccacag cagcactgag gtcactgtgg aagcgcggga ggtgacagtg 7680 acagggccgc tacaggatgc agaggccacg gaggagggct gggccagctt ctcctgtgag 7740 ctgtcccacg aggatgagga ggtcgagtgg tcgctcaacg ggatgcccct gtacaacgac 7800 agcttccatg agatctcaca caagggccgg cgccacacgc tggtactgaa gagcatccag 7860 cgggctgatg cgggcatagt acgcgcctcc tccctgaagg tgtcgacctc tgcccgcctg 7920 gaggtccgag tgaagccggt ggtgttcctg aaggcgctgg atgacctgtc cgcagaggag 7980 cgcggcaccc tggccctgca gtgtgaagtc tctgaccccg aggcccatgt ggtgtggcgc 8040 aaagatggcg tgcagctggg ccccagtgac aagtatgact tcctgcacac ggcgggcacg 8100 cgggggctcg tggtgcatga cgtgagccct gaagacgccg gcctgtacac ctgccacgtg 8160 ggctccgagg agacccgggc ccgggtccgc gtgcacgatc tgcacgtggg catcaccaag 8220 aggctgaaga caatggaggt gctggaaggg gaaagctgca gctttgagtg cgtcctgtcc 8280 cacgagagtg ccagcgaccc ggccatgtgg acagtcggtg ggaagacagt gggcagctcc 8340 agccgcttcc aggccacacg tcagggccga aaatacatcc tggtggtccg ggaggctgca 8400 ccaagtgatg ccggggaggt ggtcttctct gtgcggggcc tcacctccaa ggcctcactc 8460 attgtcagag agaggccggc cgccatcatc aagcccctgg aagaccagtg ggtggcgcca 8520 ggggaggacg tggagctgcg ctgtgagctg tcacgggcgg gaacgcccgt gcactggctg 8580 aaggacagga aggccatccg caagagccag aagtatgatg tggtctgcga gggcacgatg 8640 gccatgctgg tcatccgcgg ggcctcgctc aaggacgcgg gcgagtacac gtgtgaggtg 8700 gaggcttcca agagcacagc cagcctccat gtggaagaaa aagcaaactg cttcacagag 8760 gagctgacca atctgcaggt ggaggagaaa ggcacagctg tgttcacgtg caagacggag 8820 caccccgcgg ccacagtgac ctggcgcaag ggcctcttgg agctacgggc ctcagggaag 8880 caccagccca gccaggaggg cctgaccctg cggctcacca tcagtgccct ggagaaggca 8940 gacagcgaca cctatacctg cgacattggc caggcccagt cccgggccca gctcctagtg 9000 caaggccgga gagtgcacat catcgaggac ctggaggatg tggatgtgca ggagggctcc 9060 tcggccacct tccgttgccg gatctccccg gccaactacg agcctgtgca ctggttcctg 9120 gacaagacac ccctgcatgc caacgagctc aatgagatcg atgcccagcc cgggggctac 9180 cacgtgctga ccctgcggca gctggcgctc aaggactcgg gcaccatcta ctttgaggcg 9240 ggtgaccagc gggcctcggc cgccctgcgg gtcactgaga agccaagcgt cttctcccgg 9300 gagctcacag atgccaccat cacagagggt gaggacttga ccctggtgtg cgagaccagc 9360 acctgcgaca ttcctatgtg ctggaccaag gatgggaaga ccctgcgggg gtctgcccgg 9420 tgccagctga gccatgaggg ccaccgggcc cagctgctca tcactggggc caccctgcag 9480 gacagtggac gctacaagtg tgaggctggg ggcgcctgca gcagctccat tgtcagggtg 9540 catgcgcggc cagtgcggtt ccaggaggcc ctgaaggacc tggaggtgct ggagggtggt 9600 gctgccacac tgcgctgtgt gctgtcatct gtggctgcgc ccgtgaagtg gtgctatgga 9660 aacaacgtcc tgaggccagg tgacaaatac agcctacgcc aggagggtgc catgctggag 9720 ctggtggtcc ggaacctccg gccgcaggac agcgggcggt actcatgctc cttcggggac 9780 cagactactt ctgccaccct cacagtgact gccctgcctg cccagttcat cgggaaactg 9840 agaaacaagg aggccacaga aggggccacg gccacgctgc ggtgtgagct gagcaagaca 9900 gcccctgtgg agtggagaaa ggggtccgag accctcagag atggggacag atactgtctg 9960 aggcaggacg gggccatgtg tgagctgcag atccgtggcc tggccatggt ggatgccgcg 10020 gagtactcgt gtgtgtgtgg agaggagagg acctcagcct cactcaccat caggcccatg 10080 cctgcccact tcataggaag actgagacac caagagagca tagaaggggc cacagccacg 10140 ctgcggtgtg agctgagcaa ggcggccccc gtggagtgga ggaaggggcg tgagagcctc 10200 agagatgggg acagacatag cctgaggcag gacggggctg tgtgcgagct gcagatctgt 10260 ggcctggctg tggcagatgc tggggagtac tcctgtgtgt gtggggagga gaggacctct 10320 gccactctca ccgtgaaggc cctgccagcc aagttcacag agggtctgag gaatgaagag 10380 gccgtggaag gggccacagc catgttgtgg tgtgaactga gcaaggtggc ccctgtggag 10440 tggaggaagg ggcccgagaa cctcagagat ggggacagat acatcctgag gcaggagggg 10500 accaggtgtg agctgcagat ctgtggcctg gccatggcgg acgccgggga gtacttgtgt 10560 gtgtgcgggc aggagaggac ctcagccacg ctcaccatca gggctctgcc tgccaggttc 10620 atagaagatg tgaaaaacca ggaggccaga gaaggggcca cggctgtgct gcagtgtgag 10680 ctgaacagtg cagcccctgt ggagtggaga aaggggtctg agaccctcag agatggggac 10740 agatacagcc tgaggcagga cgggactaaa tgtgagctgc agattcgtgg cctggccatg 10800 gcagacactg gggagtactc gtgcgtgtgc gggcaggaga ggacctcggc tatgctcacc 10860 gtcagggctc tacccatcaa gttcacagag ggtctgagga acgaagaggc cacagaaggg 10920 gcaacagccg tgctgcggtg tgagctgagc aagatggccc ccgtggagtg gtggaagggg 10980 catgagaccc tcagagatgg agacagacac agcctgaggc aggacggggc caggtgtgag 11040 ctgcagatcc gcggcctcgt ggcagaggac gctggggagt acctgtgcat gtgcgggaag 11100 gagaggacct cagccatgct caccgtcagg gccatgcctt ccaagttcat agagggtctg 11160 aggaatgaag aggccacaga aggggacacg gccacgctgt ggtgtgagct gagcaaggcg 11220 gcaccggtgg agtggaggaa ggggcatgag accctcagag atggggacag acacagcctg 11280 aggcaggacg ggtccaggtg tgagctgcag atccgtggcc tggctgtggt ggatgccggg 11340 gagtactcgt gtgtgtgcgg gcaggagagg acctcagcca cactcactgt cagggccctg 11400 cctgccagat tcatagaaga tgtgaaaaac caggaggcca gagaaggggc cacggccgtg 11460 ctgcaatgtg agctgagcaa ggcggccccc gtggagtgga ggaaggggtc tgagaccctc 11520 agaggtgggg acagatacag cctgaggcag gatgggacca gatgtgagct gcagattcat 11580 ggcctgtctg tggcagacac tggggagtac tcgtgtgtgt gcgggcagga gaggacctcg 11640 gccacactca ccgtcagggc cccacagcca gtgttccggg agccgctgca gagtctgcag 11700 gcggaggagg gctccacggc caccctgcag tgtgagctgt ctgagcccac tgctacagtg 11760 gtctggagca agggtggcct gcagctgcag gccaatgggc gccgggagcc acggcttcag 11820 ggctgcaccg cggagctggt gttacaggac ctacaacgtg aagacactgg cgaatacact 11880 tgcacctgtg gctcccaggc caccagtgcc accctcactg tcacagctgc gcctgtgcgg 11940 ttcctccgag agctgcagca ccaggaggtg gatgagggag gcaccgcaca cttatgctgc 12000 gagctgagcc gggcgggtgc gagcgtggag tggcgcaagg gctccctaca gctcttccct 12060 tgtgccaagt accagatggt gcaggatggt gcagctgcag agctgctggt acgcggagtg 12120 gagcaggagg atgcgggtga ctacacgtgt gacacgggcc acacgcagag catggccagc 12180 ctctctgtcc gtgtccccag gcccaagttc aagacccggc ttcagagtct ggagcaggag 12240 acaggtgaca tagcccggct gtgctgtcag ctgagtgatg cagagtcggg ggccgtggtg 12300 caatggctca aggagggcgt ggagctgcat gcgggcccca agtacgagat gcggagccag 12360 ggggccacgc gggagctgct gatccaccaa ctggaggcca aggacacggg cgagtatgcc 12420 tgtgtgacag gcggccagaa aaccgctgcc tccctcaggg tcacagagcc tgaggtgacc 12480 attgtacggg ggctggttga tgcggaggtg acggccgatg aggatgttga gttcagctgt 12540 gaggtgtcca gggctggagc cacaggcgtg cagtggtgcc tacagggcct gccactgcaa 12600 agcaatgagg tgacagaggt ggctgtgcgg gatggccgca tccacaccct gcggctgaag 12660 ggcgtgacgc ccgaggacgc tggcactgtc tccttccatt tgggaaacca tgcttcctct 12720 gcccagctca ccgtcagagc tcctgaggtg accatcctgg agcccctgca ggacgtgcag 12780 ctcagtgagg gccaggatgc cagcttccag tgccggctat ccagagcttc aggccaggag 12840 gcccgctggg ctttaggagg ggtgcccctg caggccaacg agatgaatga catcactgtg 12900 gagcagggca cactccacct gctcaccctg cacaaggtga cccttgagga tgctggaact 12960 gtcagtttcc acgtgggcac gtgtagctct gaggcccagc tgaaagtcac agccaagaac 13020 acggtggtgc gggggctgga gaatgtggag gcgctggagg gcggcgaggc gctgttcgag 13080 tgccagctgt cccagcccga ggtggccgcc cacacctggc tgctggacga cgaacccgtg 13140 cgcacctcgg agaacgccga ggtggtcttc ttcgagaacg gcctgcgcca cctgctgctg 13200 ctcaaaaact tgcggccaca agacagctgc cgggtgacct tcctggctgg ggatatggtg 13260 acgtccgcat tcctcacggt ccgaggctgg cgcctggaga tcctggagcc tctgaaaaac 13320 gcggcggtcc gggccggcgc acaggcacgc ttcacctgca cgctcagcga ggcggtgccc 13380 gtgggagagg cgtcctggta catcaatggc gcggcagtgc agccggatga cagcgactgg 13440 actgtcaccg ccgacggcag tcaccaagcc ctactgctgc gcagcgccca gccccaccac 13500 gccggggagg tcaccttcgc ttgccgcgac gccgtggcct ctgcacggct caccgtgctg 13560 ggcctccctg atcccccaga ggatgctgag gtggtggctc acagcagcca cactgtgaca 13620 ctgtcttggg cagctcccat gagtgatgga ggcggtggtc tctgtggcta ccgcgtggag 13680 gtgaaggagg gggccacagg ccagtggcgg ctgtgccacg agctggtgcc tggacccgag 13740 tgtgtggtgg atggcctggc ccccggggag acctaccgct tccgtgtggc agctgtgggc 13800 cctgtgggtg ctggggaacc ggttcacctg ccccagacag tgcggcttgc agagccaccg 13860 aagcctgtgc ctccccagcc ctcagcccct gagagccggc aggtggcagc tggtgaagat 13920 gtctctctgg agcttgaggt ggtggctgag gctggtgagg tcatctggca caagggaatg 13980 gagcgcatcc agcccggtgg gcggttcgag gtggtctccc agggtcggca acagatgctg 14040 gtgatcaagg gcttcacggc agaagaccag ggcgagtacc actgtggcct ggctcagggc 14100 tccatctgcc ctgcggctgc caccttccag gtggcactga gcccagcctc tgtggatgag 14160 gcccctcagc ccagcttgcc ccccgaggca gcccaggagg gtgacctgca cctactgtgg 14220 gaggccctgg ctcggaaacg tcgcatgagc cgtgagccca cgctggactc cattagcgag 14280 ctgccagagg aggacggccg ctcgcagcgc ctgccacagg aggcagagga ggtggcacct 14340 gatctctctg aaggctactc cacggccgat gagctggccc gcactggaga tgctgacctc 14400 tcacacacca gctctgatga tgagtcccgg gcaggcaccc cttccctggt cacctacctc 14460 aagaaggctg ggaggccagg cacctcacca ctggccagca aggttggggc cccagcagcc 14520 ccctctgtga agccacagca gcagcaggag ccactggctg ctgtgcgccc accactggga 14580 gacctgagca ccaaagacct gggtgatccc tcaatggaca aggcagctgt gaagatccag 14640 gctgccttta agggctacaa ggtccggaag gagatgaagc agcaggaagg gcccatgttc 14700 tcccacacat ttggggacac cgaggcacag gtgggggatg ccctgcggct ggagtgtgtc 14760 gtggccagca aggcagatgt gcgagcccgc tggctgaagg atggtgtgga gctgaccgat 14820 gggcggcacc atcacatcga ccagcttggg gatggcacct gctctctgct gatcgctggc 14880 ctggaccgtg ctgatgctgg ctgctacacc tgtcaggtga gcaacaagtt tggccaggtg 14940 acccacagtg cctgtgtggt ggtcagtggg tcagagagtg aagccgagag ctcctctggg 15000 ggtgagctgg acgatgcctt ccgccgggct gcccgtcggc tgcaccggct cttccgcacc 15060 aaaagtccgg ctgaagtttc agatgaggag ctcttcctga gtgcagacga gggccctgca 15120 gagccagagg agcccgcgga ctggcagaca taccgcgaag atgagcattt catctgcatc 15180 cgttttgagg cgctcactga ggcccgccag gcggtaactc gcttccagga gatgtttgcc 15240

acactgggca ttggggtgga gatcaagctg gtggaacagg ggcctcggag ggtagagatg 15300 tgcatcagca aagagactcc tgcccctgtg gtgcctccag agccattgcc cagcctactg 15360 acttctgacg ctgccccagt gttcctgact gagttgcaga accaagaagt gcaggatggg 15420 tatcctgtga gctttgactg cgtggtgaca ggtcagccca tgcccagtgt gcgctggttc 15480 aaggatggga agttgttgga ggaggatgat cactacatga ttaatgaaga ccaacagggt 15540 ggccatcagc tcatcatcac agccgtggtg ccagcagaca tgggcgtcta ccgctgcctg 15600 gccgagaaca gcatgggtgt ctcctccacc aaggctgagc tccgtgtgga cttgacaagc 15660 acagactatg acactgcagc agatgccacg gagtcctcat cctacttcag tgcccaaggc 15720 tacctgtcca gccgggagca ggagggaaca gagtccacca ctgatgaggg ccagctgccc 15780 caggtggtgg aggagctgag agacctccag gtggcccctg gcacacgcct ggccaagttc 15840 cagctcaagg tgaaaggcta ccctgctccc agattatact ggttcaaaga tggccagccc 15900 ctgaccgcat ctgcccacat ccgcatgact ggcaagaaga tcctgcacac cctggagatc 15960 atctccgtca cccgggagga ctctggccag tatgcagcct atatcagcaa tgccatgggt 16020 gctgcctact cgtctgcccg gctgctggtt cgaggccctg atgagccaga agagaagcct 16080 gcatcagatg tgcatgagca gctggtgccg ccccgaatgc tggagaggtt cacccccaag 16140 aaagtgaaga aaggctccag catcaccttc tctgtgaagg tagaaggacg cccggtgccc 16200 accgtgcact ggctcaggga ggaggctgag agaggcgtgc tgtggattgg ccctgacaca 16260 ccgggctaca ccgtggccag ctctgcgcag cagcacagcc tggtcctgct ggacgtgggc 16320 cggcagcacc agggcaccta cacatgcatt gccagcaacg ctgccggcca ggccctctgc 16380 tccgccagcc tgcacgtctc gggcctgcct aaggtggagg agcaggagaa agtgaaggaa 16440 gcgctgattt ccactttcct gcaggggacc acacaagcca tctcagcaca ggggttggaa 16500 actgcgagtt ttgctgacct tggtgggcag aggaaagaag agcctctggc tgccaaggag 16560 gccctcggcc acctgtccct cgctgaggtg ggcacagagg agttcctgca gaaactgacc 16620 tcccagatca ctgagatggt atcggccaag atcacgcagg ccaagctgca ggtgcccgga 16680 ggtgacagtg atgaggactc caagacacca tctgcatccc cccgccatgg ccgatcacgg 16740 ccatcctcca gcatccagga gtcttcctca gagtcagagg acggcgatgc ccgaggcgag 16800 atctttgaca tctacgtggt caccgctgac tacctgcccc taggggctga gcaggatgcc 16860 atcacgctgc gggaaggcca gtatgtggag gtcctggatg cagcccaccc actgcgctgg 16920 cttgtccgca ccaagcccac caagtccagc ccctcacggc agggctgggt gtcaccagcc 16980 tacctggaca ggaggctcaa gctgtcacct gagtgggggg ccgctgaggc ccctgagttc 17040 cctggggagg ctgtgtctga agacgaatac aaggcaaggc tgagctctgt gatccaggag 17100 ctgctgagtt ctgagcaggc cttcgtggag gagctgcagt tcctgcagag ccaccacctg 17160 cagcacctgg agcgctgccc ccacgtgccc atagccgtgg ccggccagaa ggcagtcatc 17220 ttccgcaatg tgcgggacat cggccgcttc cacagcagct tcctgcagga gttgcagcag 17280 tgcgacacgg acgacgacgt ggccatgtgc ttcatcaaga accaggcggc ctttgagcag 17340 tacctggagt tcctggtggg gcgtgtgcag gctgagtcgg tggtcgtcag cacggccatc 17400 caggagttct acaagaaata cgcggaggag gccctgttgg caggggaccc ctctcagccc 17460 ccgccaccac ctctgcagca ctacctggag cagccagtgg agcgggtgca gcgctaccag 17520 gccttgctga aggagttgat ccgcaacaag gcgcggaaca gacagaactg cgcgctgctg 17580 gagcaggcct atgccgtggt gtctgccctg ccacagcgcg ctgagaacaa gctgcacgtg 17640 tccctcatgg agaactaccc aggcaccctg gaggccctgg gcgagcccat ccgccagggc 17700 cacttcatcg tgtgggaggg tgcaccgggg gcccgcatgc cctggaaggg ccacaaccgt 17760 cacgtgttcc tcttccgcaa ccacctggta atctgcaagc cccggcgaga ctcccgcacc 17820 gataccgtca gctacgtgtt ccggaacatg atgaagctga gcagcatcga cctgaacgac 17880 caggtggagg gggatgaccg cgccttcgag gtgtggcagg agcgggagga ctcggtgcgc 17940 aagtacctgc tgcaggcacg gacagccatt atcaagagct cgtgggtgaa ggagatctgt 18000 ggcatccagc agcgtctggc cctgcctgtg tggcggcccc cggactttga agaggagctg 18060 gccgactgca cagccgagct gggtgagaca gtcaagctgg cctgccgcgt gacgggcaca 18120 cccaagcctg tcatcagctg gtacaaagat gggaaagcag tgcaggtgga cccccaccac 18180 atcctcattg aagaccctga tggctcgtgt gcactcatcc tggacagcct gaccggtgtg 18240 gactctggcc agtacatgtg cttcgcggcc agcgccgctg gcaactgcag taccctgggc 18300 aagatcctgg tgcaagtccc accacggttc gtgaacaagg tccgggcctc accctttgtg 18360 gagggagagg acgcccagtt cacctgcacc atcgaaggcg ccccgtaccc gcagatcagg 18420 tggtacaagg acggggccct gctgaccact ggcaacaagt tccagacact gagtgagcct 18480 cgcagcggcc tgctagtgct ggtgatccgg gcggccagca aggaggacct ggggctctac 18540 gagtgtgagc tggtgaaccg gctgggctcc gcgcgggcta gtgcggagct gcgcattcag 18600 agccccatgc tgcaggccca ggagcagtgt cacagggagc agctcgtggc tgcagtggaa 18660 gacaccaccc tggagcgagc ggaccaggag gtcacatctg tcctgaagag actgctgggc 18720 cccaaggcgc caggcccctc cacaggggac ctcactggcc ctggcccctg ccccaggggg 18780 gcacccgcac tccaggaaac cggctcccag cccccagtca ccggaacttc ggaggcacct 18840 gccgtgcccc cgagggtgcc acagcccctc ctccacgaag gcccagagca ggagccggag 18900 gccattgcca gagcccagga atggactgtg cccattcgga tggagggtgc agcctggccc 18960 ggggcaggca caggggagct gctctgggac gtccacagcc acgtggtcag agagaccaca 19020 cagaggacct acacatacca ggccatcgac acgcacaccg cacggccccc atccatgcag 19080 gtaaccatcg aggatgtgca ggcacagaca ggcggaacgg cccaattcga ggctatcatt 19140 gagggcgacc cacagccctc ggtgacctgg tacaaggaca gcgtccagct ggtggacagc 19200 acccggctta gccagcagca agaaggcacc acatactccc tggtgctgag gcatgtggcc 19260 tcgaaggatg ccggcgttta cacctgcctg gcccaaaaca ctggtggcca ggtgctctgc 19320 aaggcagagc tgctggtgct tgggggggac aatgagccgg actcagagaa gcaaagccac 19380 cggaggaagc tgcactcctt ctatgaggtc aaggaggaga ttggaagggg cgtgtttggc 19440 ttcgtaaaaa gagtgcagca caaaggaaac aagatcttgt gcgctgccaa gttcatcccc 19500 ctacggagca gaactcgggc ccaggcatac agggagcgag acatcctggc cgcgctgagc 19560 cacccgctgg tcacggggct gctggaccag tttgagaccc gcaagaccct catcctcatc 19620 ctggagctgt gctcatccga ggagctgctg gaccgcctgt acaggaaggg cgtggtgacg 19680 gaggccgagg tcaaggtcta catccagcag ctggtggagg ggctgcacta cctgcacagc 19740 catggcgttc tccacctgga cataaagccc tctaacatcc tgatggtgca tcctgcccgg 19800 gaagacatta aaatctgcga ctttggcttt gcccagaaca tcaccccagc agagctgcag 19860 ttcagccagt acggctcccc tgagttcgtc tcccccgaga tcatccagca gaaccctgtg 19920 agcgaagcct ccgacatttg ggccatgggt gtcatctcct acctcagcct gacctgctca 19980 tccccatttg ccggcgagag tgaccgtgcc accctcctga acgtcctgga ggggcgcgtg 20040 tcatggagca gccccatggc tgcccacctc agcgaagacg ccaaagactt catcaaggct 20100 acgctgcaga gagcccctca ggcccggcct agtgcggccc agtgcctctc ccacccctgg 20160 ttcctgaaat ccatgcctgc ggaggaggcc cacttcatca acaccaagca gctcaagttc 20220 ctcctggccc gaagtcgctg gcagcgttcc ctgatgagct acaagtccat cctggtgatg 20280 cgctccatcc ctgagctgct gcggggccca cccgacagcc cctccctcgg cgtagcccgg 20340 cacctctgca gggacactgg tggctcctcc agttcctcct cctcctctga caacgagctc 20400 gccccatttg cccgggctaa gtcactgcca ccctccccgg tgacacactc accactgctg 20460 cacccccggg gcttcctgcg gccctcggcc agcctgcctg aggaagccga ggccagtgag 20520 cgctccaccg aggccccagc tccgcctgca tctcccgagg gtgccgggcc accggccgcc 20580 cagggctgcg tgccccggca cagcgtcatc cgcagcctgt tctaccacca ggcgggtgag 20640 agccctgagc acggggccct ggccccgggg agcaggcggc acccggcccg gcggcggcac 20700 ctgctgaagg gcgggtacat tgcgggggcg ctgccaggcc tgcgcgagcc actgatggag 20760 caccgcgtgc tggaggagga ggccgccagg gaggagcagg ccaccctcct ggccaaagcc 20820 ccctcattcg agactgccct ccggctgcct gcctctggca cccacttggc ccctggccac 20880 agccactccc tggaacatga ctctccgagc accccccgcc cctcctcgga ggcctgcggt 20940 gaggcacagc gactgccttc agccccctcc gggggggccc ctatcaggga catggggcac 21000 cctcagggct ccaagcagct tccatccact ggtggccacc caggcactgc tcagccagag 21060 aggccatccc cggacagccc ttgggggcag ccagcccctt tctgccaccc caagcagggt 21120 tctgcccccc aggagggctg cagcccccac ccagcagttg ccccatgccc tcctggctcc 21180 ttccctccag gatcttgcaa agaggccccc ttagtaccct caagcccctt cttgggacag 21240 ccccaggcac cccctgcccc tgccaaagca agccccccat tggactctaa gatggggcct 21300 ggagacatct ctcttcctgg gaggccaaaa cccggcccct gcagttcccc agggtcagcc 21360 tcccaggcga gctcttccca agtgagctcc ctcagggtgg gctcctccca ggtgggcaca 21420 gagcctggcc cctccctgga tgcggagggc tggacccagg aggctgagga tctgtccgac 21480 tccacaccca ccttgcagcg gcctcaggaa caggcgacca tgcgcaagtt ctccctgggt 21540 ggtcgcgggg gctacgcagg cgtggctggc tatggcacct ttgcctttgg tggagatgca 21600 gggggcatgc tggggcaggg gcccatgtgg gccaggatag cctgggctgt gtcccagtcg 21660 gaggaggagg agcaggagga ggccagggct gagtcccagt cggaggagca gcaggaggcc 21720 agggctgaga gcccactgcc ccaggtcagt gcaaggcctg tgcctgaggt cggcagggct 21780 cccaccagga gctctccaga gcccacccca tgggaggaca tcgggcaggt ctccctggtg 21840 cagatccggg acctgtcagg tgatgcggag gcggccgaca caatatccct ggacatttcc 21900 gaggtggacc ccgcctacct caacctctca gacctgtacg atatcaagta cctcccattc 21960 gagtttatga tcttcaggaa agtccccaag tccgctcagc cagagccgcc ctcccccatg 22020 gctgaggagg agctggccga gttcccggag cccacgtggc cctggccagg tgaactgggc 22080 ccccacgcag gcctggagat cacagaggag tcagaggatg tggacgcgct gctggcagag 22140 gctgccgtgg gcaggaagcg caagtggtcc tcgccgtcac gcagcctctt ccacttccct 22200 gggaggcacc tgccgctgga tgagcctgca gagctggggc tgcgtgagag agtgaaggcc 22260 tccgtggagc acatctcccg gatcctgaag ggcaggccgg aaggtctgga gaaggagggg 22320 ccccccagga agaagccagg ccttgcttcc ttccggctct caggtctgaa gagctgggac 22380 cgagcgccga cattcctaag ggagctctca gatgagactg tggtcctggg ccagtcagtg 22440 acactggcct gccaggtgtc agcccagcca gctgcccagg ccacctggag caaagacgga 22500 gcccccctgg agagcagcag ccgtgtcctc atctctgcca ccctcaagaa cttccagctt 22560 ctgaccatcc tggtggtggt ggctgaggac ctgggtgtgt acacctgcag cgtgagcaat 22620 gcgctgggga cagtgaccac cacgggcgtc ctccggaagg cagagcgccc ctcatcttcg 22680 ccatgcccgg atatcgggga ggtgtacgcg gatggggtgc tgctggtctg gaagcccgtg 22740 gaatcctacg gccctgtgac ctacattgtg cagtgcagcc tagaaggcgg cagctggacc 22800 acactggcct ccgacatctt tgactgctgc tacctgacca gcaagctctc ccggggtggc 22860 acctacacct tccgcacggc atgtgtcagc aaggcaggaa tgggtcccta cagcagcccc 22920 tcggagcaag tcctcctggg agggcccagc cacctggcct ctgaggagga gagccagggg 22980 cggtcagccc aacccctgcc cagcacaaag accttcgcat tccagacaca gatccagagg 23040 ggccgcttca gcgtggtgcg gcaatgctgg gagaaggcca gcgggcgggc gctggccgcc 23100 aagatcatcc cctaccaccc caaggacaag acagcagtgc tgcgcgaata cgaggccctc 23160 aagggcctgc gccacccgca cctggcccag ctgcacgcag cctacctcag cccccggcac 23220 ctggtgctca tcttggagct gtgctctggg cccgagctgc tcccctgcct ggccgagagg 23280 gcctcctact cagaatccga ggtgaaggac tacctgtggc agatgttgag tgccacccag 23340 tacctgcaca accagcacat cctgcacctg gacctgaggt ccgagaacat gatcatcacc 23400 gaatacaacc tgctcaaggt cgtggacctg ggcaatgcac agagcctcag ccaggagaag 23460 gtgctgccct cagacaagtt caaggactac ctagagacca tggctccaga gctcctggag 23520 ggccaggggg ctgttccaca gacagacatc tgggccatcg gtgtgacagc cttcatcatg 23580 ctgagcgccg agtacccggt gagcagcgag ggtgcacgcg acctgcagag aggactgcgc 23640 aaggggctgg tccggctgag ccgctgctac gcggggctgt ccgggggcgc cgtggccttc 23700 ctgcgcagca ctctgtgcgc ccagccctgg ggccggccct gcgcgtccag ctgcctgcag 23760 tgcccgtggc taacagagga gggcccggcc tgttcgcggc ccgcgcccgt gaccttccct 23820 accgcgcggc tgcgcgtctt cgtgcgcaat cgcgagaaga gacgcgcgct gctgtacaag 23880 aggcacaacc tggcccaggt gcgctga 23907 7 17 PRT Artificial Sequence VARIANT 1 The L at position 1 can be I or V. 7 Leu Gly Xaa Gly Xaa Phe Ser Xaa Leu Xaa Xaa Gly Xaa Leu Ala Leu 1 5 10 15 Lys 8 12 PRT Artificial Sequence VARIANT 1 The L at position 1 can be I, V, M, F, Y, or C. 8 Leu Xaa His Xaa Asp Leu Lys Xaa Asn Xaa Xaa Xaa 1 5 10 9 13 PRT Artificial Sequence VARIANT 1 The L at position 1 can be I, V, M, F, Y, or C. 9 Leu Xaa His Xaa Asp Leu Arg Xaa Xaa Asn Xaa Xaa Xaa 1 5 10

Claims

What is claimed is:

1. An isolated nucleic acid molecule selected from the group consisting of: a. a nucleic acid molecule comprising a nucleotide sequence which is at least 85% identical to the nucleotide sequence of SEQ ID NOs:1, 3, 4, or 6; b. a nucleic acid molecule comprising a fragment of at least 300 nucleotides of the nucleotide sequence of SEQ ID NOs:1, 3, 4, or 6; c. a nucleic acid molecule which encodes a polypeptide comprising the amino acid sequence of SEQ ID NO:2 or 5; d. a nucleic acid molecule which encodes a fragment of a polypeptide comprising the amino acid sequence of SEQ ID NO:2 or 5, wherein the fragment comprises at least 15 contiguous amino acids of SEQ ID NO: 2 or 5; and e. a nucleic acid molecule which encodes a naturally occurring allelic variant of a polypeptide comprising the amino acid sequence of SEQ ID NO:2 or 5, wherein the nucleic acid molecule hybridizes to a nucleic acid molecule comprising SEQ ID NO:1, 3, 4, or 6, or a complement thereof, under stringent conditions.

2. The isolated nucleic acid molecule of claim 1, which is selected from the group consisting of: a. a nucleic acid comprising the nucleotide sequence of SEQ ID NO:1, 3, 4, or 6; and b. a nucleic acid molecule which encodes a polypeptide comprising the amino acid sequence of SEQ ID NO:2 or 5.

3. The nucleic acid molecule of claim 1 further comprising vector nucleic acid sequences.

4. The nucleic acid molecule of claim 1 further comprising nucleic acid sequences encoding a heterologous polypeptide.

5. A host cell which contains the nucleic acid molecule of claim 1.

6. The host cell of claim 5 which is a mammalian host cell.

7. A non-human mammalian host cell containing the nucleic acid molecule of claim 1.

8. An isolated polypeptide selected from the group consisting of: a. a polypeptide which is encoded by a nucleic acid molecule comprising a nucleotide sequence which is at least 85% identical to a nucleic acid comprising the nucleotide sequence of SEQ ID NO:1, 3, 4, or 6, or a complement thereof; b. a naturally occurring allelic variant of a polypeptide comprising the amino acid sequence of SEQ ID NO:2 or 5, wherein the polypeptide is encoded by a nucleic acid molecule which hybridizes to a nucleic acid molecule comprising SEQ ID NO:1, 3, 4, or 6; and c. a fragment of a polypeptide comprising the amino acid sequence of SEQ ID NO:2 or 5, wherein the fragment comprises at least 15 contiguous amino acids of SEQ ID NO:2 or 5.

9. The isolated polypeptide of claim 8 comprising the amino acid sequence of SEQ ID NO:2 or 5.

10. The polypeptide of claim 8 further comprising heterologous amino acid sequences.

11. An antibody which selectively binds to a polypeptide of claim 8.

12. A method for producing a polypeptide selected from the group consisting of: a. a polypeptide comprising the amino acid sequence of SEQ ID NO:2 or 5; b. a polypeptide comprising a fragment of the amino acid sequence of SEQ ID NO:2 or 5, wherein the fragment comprises at least 15 contiguous amino acids of SEQ ID NO:2 or 5; and c. a naturally occurring allelic variant of a polypeptide comprising the amino acid sequence of SEQ ID NO:2 or 5, wherein the polypeptide is encoded by a nucleic acid molecule which hybridizes to a nucleic acid molecule comprising SEQ ID NO:1, 3, 4, or 5, or a complement thereof under stringent conditions; comprising culturing the host cell of claim 5 under conditions in which the nucleic acid molecule is expressed.

13. A method for detecting the presence of a polypeptide of claim 8 in a sample, comprising: contacting the sample with a compound which selectively binds to a polypeptide of claim 8; and determining whether the compound binds to the polypeptide in the sample.

14. The method of claim 13, wherein the compound which binds to the polypeptide is an antibody.

15. A kit comprising a compound which selectively binds to a polypeptide of claim 8 and instructions for use.

16. A method for detecting the presence of a nucleic acid molecule of claim 1 in a sample, comprising the steps of: contacting the sample with a nucleic acid probe or primer which selectively hybridizes to the nucleic acid molecule; and determining whether the nucleic acid probe or primer binds to a nucleic acid molecule in the sample.

17. The method of claim 16, wherein the sample comprises mRNA molecules and is contacted with a nucleic acid probe.

18. A kit comprising a compound which selectively hybridizes to a nucleic acid molecule of claim 1 and instructions for use.

19. A method for identifying a compound which binds to a polypeptide of claim 8 comprising the steps of: contacting a polypeptide, or a cell expressing a polypeptide of claim 8 with a test compound; and determining whether the polypeptide binds to the test compound.

20. The method of claim 19, wherein the binding of the test compound to the polypeptide is detected by a method selected from the group consisting of: a. detection of binding by direct detecting of test compound/polypeptide binding; b. detection of binding using a competition binding assay; and c. detection of binding using an assay for 59079- or 12599-mediated signal transduction.

21. A method for modulating the activity of a polypeptide of claim 8 comprising contacting a polypeptide or a cell expressing a polypeptide of claim 8 with a compound which binds to the polypeptide in a sufficient concentration to modulate the activity of the polypeptide.

22. A method for identifying a compound which modulates the activity of a polypeptide of claim 8, comprising: contacting a polypeptide of claim 8 with a test compound; and determining the effect of the test compound on the activity of the polypeptide to thereby identify a compound which modulates the activity of the polypeptide.