MXPA98001120A - Sequences of dna and secreted proteins and that are codified through - Google Patents

Abstract

They describe and provide novel polynucleotides and proteins encoded by said polynucleotides, together with therapeutic, diagnostic and research utilities for and of such polynucleotides and proteins.

Description

DNA SEQUENCES AND SECRETED PROTEINS THAT ARE CODED BY THESE Technical Field The present invention provides novel polynucleotides and proteins encoded by said polynucleotides, together with therapeutic, diagnostic and research utilities of said polynucleotides and proteins.

Background of the Invention Technology aimed at the discovery of protein factors (including, for example, cytokines, such as lymphokines, interferons, CSFs and interleukins) matured rapidly during the past decade. The now routine hybridization cloning and expression cloning techniques clone novel "directly" polynucleotides in the sense that they rest on information directly related to the discovered factor (ie, partial DNA / amino acid sequence of the factor in the case of the cloning of hybridization; factor activity in the case of expression cloning). The most recent "indirect" cloning techniques, such as signal sequence cloning, which isolates DNA sequences based on the presence of a now well known secretory leader sequence motif, as well as several hybridization cloning techniques based on PCR or low stringency, have advanced the state of the art by making accessible a large number of DNA / amino acid sequences for factors known to have biological activity by virtue of their secreted nature in the case of cloning leader sequences, or in virtue of the cell or tissue source in the case of PCR-based techniques. It is to these factors and the polynucleotides that encode them that the present invention is directed.

OBJECTIVES OF THE INVENTION In one embodiment, the present invention provides a composition comprising an isolated polynucleotide that is selected from the group consisting of: (a) a polynucleotide comprising the nucleotide sequence of SEQ ID NO: 1 from nucleotide 38 to the nucleotide 1447; (b) a polynucleotide comprising a fragment of the nucleotide sequence of SEQ ID NO: 1 encoding a protein having biological activity; (c) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO: 2; (d) a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID NO: 2 having biological activity; (e) a polynucleotide that is an allelic variant of SEQ ID NO: 1; and (f) a polynucleotide capable of hybridizing under stringent conditions to any one of the polynucleotides specified in (a) - (e). In another embodiment, the present invention provides a composition comprising an isolated polynucleotide that is selected from the group consisting of: (a) a polynucleotide comprising the nucleotide sequence of SEQ ID NO: 3 from nucleotide 52 to nucleotide 2034; (b) a polynucleotide comprising a fragment of the nucleotide sequence of SEQ ID NO: 3 encoding a protein having biological activity; (c) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO: 4; (d) a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID NO: 4 having biological activity; (e) a polynucleotide that is an allelic variant of SEQ ID NO: 4; and (f) a polynucleotide capable of hybridizing under stringent conditions to any one of the polynucleotides specified in (a) - (e). In another embodiment, the present invention provides a composition comprising an isolated polynucleotide that is selected from the group consisting of: (a) a polynucleotide comprising the nucleotide sequence of SEQ ID NO: 5 from nucleotide 76 to nucleotide 474; (b) a polynucleotide comprising a fragment of the nucleotide sequence of SEQ ID NO: 5 which codes for a protein having biological activity; (c) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO: 6; (d) a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID NO: 6 having biological activity; (e) a polynucleotide that is an allelic variant of SEQ ID NO: 5; and (f) a polynucleotide capable of hybridizing under stringent conditions to any one of the polynucleotides specified in (a) - (e). In another embodiment, the present invention provides a composition comprising an isolated polynucleotide that is selected from the group consisting of: (a) a polynucleotide comprising the nucleotide sequence of SEQ ID NO: 7 from nucleotide 67 to nucleotide 348; (b) a polynucleotide comprising a fragment of the nucleotide sequence of SEQ ID NO: 7 encoding a protein having biological activity; (c) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO: 8; (d) a polynucleotide that encodes a protein comprising a fragment of the amino acid sequence of SEQ ID NO: 8 having biological activity; (e) a polynucleotide that is an allelic variant of SEQ ID NO: 7; and (f) a polynucleotide capable of hybridizing under stringent conditions to any one of the polynucleotides specified in (a) - (e). In another embodiment, the present invention provides a composition comprising an isolated polynucleotide that is selected from the group consisting of: (a) a polynucleotide comprising the nucleotide sequence of SEQ ID NO: 9 from nucleotide 75 to nucleotide 356; (b) a polynucleotide comprising a fragment of the nucleotide sequence of SEQ ID NO: 9 which codes for a protein having biological activity; (c) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO: 10; (d) a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID NO: 10 having biological activity; (e) a polynucleotide that is an allelic variant of SEQ ID NO: 9; and (f) a polynucleotide capable of hybridizing under stringent conditions to any one of the polynucleotides specified in (a) - (e). In another embodiment, the present invention provides a composition comprising an isolated polynucleotide that is selected from the group consisting of: (a) a polynucleotide comprising the nucleotide sequence of SEQ ID NO: 11 from nucleotide 86 to nucleotide 544; (b) a polynucleotide comprising a fragment of the nucleotide sequence of SEQ ID NO: 11 which codes for a protein having biological activity; (c) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO: 12; (d) a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID NO: 12 having biological activity; (e) a polynucleotide that is an allelic variant of SEQ ID NO: 11; and (f) a polynucleotide capable of hybridizing under stringent conditions to any one of the polynucleotides specified in (a) - (e). In certain preferred embodiments, the polynucleotide is operably linked to an expression control sequence. The invention also provides a host cell, including bacterial, yeast, insect and mammalian cells, transformed with said polynucleotide compositions. Processes for producing a protein are also provided, which comprise: (a) growing a culture of the host cell transformed with said polynucleotide compositions in an appropriate culture medium; and (b) purifying the protein from the culture medium. The protein produced according to said methods is also provided by the present invention. Also described are compositions comprising a biological activity of protein. In preferred embodiments the protein comprises an amino acid sequence selected from the group consisting of: (a) the amino acid sequence of SEQ ID NO: 2; (b) fragments of the amino acid sequence of SEQ ID NO: 2; (c) the amino acid sequence of SEQ ID NO: 4; (d) fragments of the amino acid sequence of SEQ ID NO: 4; (e) the amino acid sequence of SEQ ID NO: 6; (f) fragments of the amino acid sequence of SEQ ID NO: 6; (g) the amino acid sequence of SEQ ID NO: 8; (h) fragments of the amino acid sequence of SEQ ID NO: 8; (i) the amino acid sequence of SEQ ID NO: 12; (j) fragments of the amino acid sequence of SEQ ID NO: 12; the protein being substantially free of other mammalian proteins. Said compositions may further comprise a pharmaceutically acceptable carrier. Compositions comprising an antibody that specifically reacts with said protein are also provided by the present invention. Methods for preventing, treating or alleviating a medical condition are also provided, which comprise administering to a mammalian subject a therapeutically effective amount of a composition comprising a protein of the present invention and a pharmaceutically acceptable carrier.

Detailed Description of the Preferred Modalities. Proteins and Isolated Polynucleotides The sequence of a polynucleotide encoding a protein of the present invention is set forth in SEQ ID NO: 1, with the coding region extending from nucleotide 38 to 1447. This polynucleotide has been identified as "clone J5" The amino acid sequence of the protein encoded by clone J5 is set forth in SEQ ID NO: 2. Clone J5 was deposited at the Acan Type Culture Collection on August 11, 1995 and granted accession number ATCC 69885. SEQ ID NO: 1 represents a spliced combination of the sequence obtained from an isolated clone identified as "J5_3_fl", with the additional 5 'sequence obtained from a second double-stranded clone. Clone J5 was isolated from a library of human activated peripheral blood mononuclear cells (PBMC) using a trap that selects nucleotides that encode secreted proteins; therefore, clone J5 encodes a secreted factor: Clone J5 codes for a novel protein; The BLASTN / BLASTX or FASTA searches did not reveal exact sequence matches. However, a BLASTX search revealed homology between the J5 protein (in the approximate region of amino acids 62-129 of SEQ ID NO: 2), apical testicular proteins (including without limitation, precursor I of apical testicular protein. fascicularis) (access X66139)) and various viper venom hemorrhagic peptides (disintegrins) (including without limitation those assigned accession numbers U01235-1237, X68251 and M89784). Analysis of the full length J5 sequences revealed that the disintegrin domain was incomplete and that this clone did not contain an EGF domain, as with some of the other members of the disintegrin family. Clone J5 does not contain a conserved meta-proteinase domain. Based on these homologies, J5 and these homologous proteins are expected to share at least some activities.

The sequence of a polynucleotide encoding another protein of the present invention is set forth in SEQ ID NO: 3, with the coding region extending from nucleotide 52 to 2030. This polynucleotide has been identified as "clone J422". The amino acid sequence of the protein encoded by clone J422 is set forth in SEQ ID NO: 4. Clone J422 was deposited at the Acan Type Culture Collection on August 11, 1995 and granted accession number ATCC 69884. SEQ ID NO: 3 represents a spliced combination of the sequence obtained from an isolated clone identified as "J422_fl", with the additional 5 'sequence obtained from a second double-stranded clone. Clone J422 was isolated from a library of human activated peripheral blood mononuclear cells (PBMC) using a trap that selects nucleotides that encode secreted proteins; therefore, clone J422 encodes a secreted factor: Clone J422 codes for a novel protein; BLASTN / BLASTX or FASTA searches did not reveal exact sequence matches. However, a FASTA search revealed homology between the J422 protein (in the approximate region of amino acids 34-156 of SEQ ID NO: 4) and a number of Drosophila repeat proteins rich in leucine (LRR). Analysis of the full-length J422 sequences revealed that the conserved EGF domain that was found in a number of members of the LRR family was not present in J422. Based on these homologies, J422 and these homologous proteins are expected to share at least some activities. The sequence of a polynucleotide encoding another protein of the present invention is set forth in SEQ ID NO: 5, with the coding region extending from nucleotide 76 to 474. This polynucleotide has been identified as "clone L105". The amino acid sequence of the protein encoded by clone L105 is set forth in SEQ ID NO: 6. Clone L105 was deposited at the Acan Type Culture Collection on August 11, 1995 and granted accession number ATCC 69883. Clone L105 was isolated from an adult murine thymus library using a trap that selects nucleotides that encode secreted proteins; therefore, clone L105 encodes a secreted factor: Clone L105 codes for a novel protein. The BLASTN / BLASTX or FASTA searches did not reveal exact sequence matches. However, a BLASTX search revealed homology between the L105 protein (particularly in the approximate region of amino acids 73-91 of SEQ ID NO: 6), various monocytes and other chemoattractant proteins (including without limitation those to which they were assigned). accesses M577441, X71087, X72308, X14768 and M24545) and a chicken cytokine (Gallus gallus) (access L34553). Based on these homologies, L105 and these homologous proteins are expected to share at least some activities. The polynucleotide sequence encoding another protein of the present invention is set forth in SEQ ID NO: 7 and SEQ ID NO: 9, with the coding regions extending from nucleotide 67 to 348 and nucleotides 75 to 356, respectively. These polynucleotides have been identified as "clone H174-10" and "clone H-174-43", respectively (collectively referred to herein as "H174"). The amino acid sequence of the protein encoded by clones H174 is set forth in SEQ ID NO: 8 and SEQ ID NO: 10. Clone H174 was deposited at the American Type Culture Collection on August 11, 1995 and was given the accession number ATCC 69882. H174 clones were isolated from a library of human activated peripheral blood mononuclear cells (PBMC) using a trap that selects nucleotides that encode secreted proteins; therefore, clone H174 encodes a secreted factor: Clone H174 codes for a novel protein. The BLASTN / BLASTX or FASTA searches did not reveal exact sequence matches. However, a BLASTX search revealed homology between the H174 protein, human IP-10 (access M33266) and murine CRG-2 (access M86820) (homologues of species). Based on these homologies, H174 and these homologous proteins are expected to share at least some activities. The sequence of a polynucleotide encoding another protein of the present invention is set forth in SEQ ID NO: 11, with the coding region extending from nucleotide 86 to 544. This polynucleotide has been identified as "B18". The amino acid sequence of the protein encoded by clone B18 is set forth in SEQ ID NO: 12. Clone B18 was deposited at the American Type Culture Collection on July 6, 1995 and granted accession number ATCC 69868. Clone B18 was isolated from a library of activated human peripheral blood mononuclear cells (PBMC) using a trap that selects nucleotides that encode secreted proteins; therefore, clone B18 encodes a secreted factor: Clone B18 codes for a novel protein. The BLASTN / BLASTX or FASTA searches did not reveal exact sequence matches. However, a BLASTX search revealed that the region from amino acid 29 to amino acid 163 of B18 (SEQ ID NO: 12) shows marked homology with the portions of murine CTLA-8 (amino acids 18 to 150, access L13839) and the Saimiri herpes virus. ORF13 ("Herpes CTLA-8") (amino acids 19 to 151, access X64346). Based on these homologies, B18 is believed to be the human homolog of murine CTLA-8 and herpes (ie, "human CTLA-8"). B18 can demonstrate pro-inflammatory activity, particularly in the development of T cell-dependent immune responses. B18 is also expected to possess other activities specified here. Clones J5, L105, H174 and B18 were each transfected into COS cells labeled with 35S-methionine and the protein was expressed. Also part of the present invention are polynucleotides that hybridize to the polynucleotides of the present invention under stringent conditions and highly astringent conditions. As used herein, "highly stringent conditions" include, for example, at least about 0.2xSSC at 65 ° C; and "astringent conditions" include, for example, at least 4xSSC at 65 ° C or at least about 50% formamide and 4xSSC at 42 ° C. Allelic variations of the polynucleotides of the present invention are also encompassed by the present invention. Also included within the present invention are fragments of the proteins of the present invention that are capable of exhibiting biological activity. Fragments of the protein may be in linear form or may be cyclized using known methods, for example, as described in H.U. Saragovi, et al, Bio / Technology 10, 773-778 (1992) and in R.S. McDowell, et al., J. Amer. Chem. Soc. 114, 9245-9253 (1992), which are incorporated herein by reference. Such fragments can be fused to carrier molecules such as immunoglobulins for many purposes, including the increase of valence of protein binding sites. For example, fragments of the protein can be fused via "linker" sequences to the Fc portion of an immunoglobulin. For a bivalent form of the protein, said fusion could be to the Fc portion of an IgG molecule. Other immunoglobulin isotypes can also be used to generate such fusions. For example, a protein-lgM fusion would generate a decavalent form of the protein of the invention. The isolated polynucleotide of the invention can be operably linked to an expression control sequence such as the pMT2 or pED expression vectors described in Kaufman et al., Nucleic Acids Res. 19, 4485-4490 (1991), for the purpose of recombinantly produce the protein. Many suitable expression control sequences are known in the art. General methods for expressing recombinant proteins are also known and are exemplified in R. Kaufman, Methods in Enzymology 185, 537-566 (1990). As defined herein, "operably linked" means that the isolated polynucleotide of the invention and the expression control sequence are located within a vector or cell, such that the protein is expressed by a host cell that has been transformed ( transfected) with the linked polynucleotide / expression control sequence. A number of cell types can? act as suitable host cells for the expression of the protein. Mammalian host cells include, for example, monkey COS cells, Chinese Hamster Ovary (CHO) cells, 293 human kidney cells, A431 cells of human epidermis, human Colo205 cells, 3T3 cells, CV-1 cells, other transformed primate cell lines, normal diploid cells, cell strains derived from in vitro culture of primary tissue, primary explants, HeLa cells, mouse L cells, BHK, HL-60, U937, HaK or Jukart cells. Alternatively, the protein can be produced in lower eukaryotes such as yeast or in prokaryotes such as bacteria. Suitable strains and yeast potentials include strains of Saccharomyces cerevisiae, Schizosaccharomyces pombe, Kluyveromyces, Candida, or any strain of yeast capable of expressing heterologous proteins. Suitable strains and bacterial potentials include Escherichia coli, Bacillus subtilis, Salmonella typhimurium, or any bacterial strain capable of expressing heterologous proteins. If the protein is made in yeast or bacteria, it may be necessary to modify the protein produced there, for example, by phosphorylation or glycosylation of the appropriate sites, in order to obtain the functional protein. Said covalent attachments can be made using known chemical or enzymatic methods. The protein can also be produced by operably linking the isolated polynucleotide of the invention to appropriate control sequences in one or more insect expression vectors and employing an insect expression system. Materials and methods for insect / virus cell expression systems are commercially available in the form of equipment in, for example, Invitrogen, San Diego, California, E.U.A. (the MaxBac® kit) and such methods are well known in the art, as described in Summers and Smith, Texas Agricultural Experiment Station Bulletin No. 1555 (1987). which is incorporated herein by reference. As used herein, an insect cell capable of expressing a polynucleotide of the present invention is "transformed." The protein of the invention can be prepared by culturing transformed host cells under suitable culture conditions to express the recombinant protein. The resulting expressed protein can then be purified from the culture medium (ie, from the culture medium or cell extracts) using known purification processes, such as by gel filtration and ion exchange chromatography. Purification of the protein may also include an affinity column containing agents that will bind to the protein; one or more column steps on such affinity resins such as concavalin A-agarose, heparin-toyopearl® or Cibacrom blue 3Ga Sepharose®; one or more steps involving chromatography by hydrophobic interaction using resins such as phenyl ether, butyl ether or propyl ether; or immunoaffinity chromatography. Alternatively, the protein of the invention can also be expressed in a form that facilitates purification. For example, it can be expressed as a fusion protein, such as those of maltose binding proteins (MBP), glutathione-S-transferase (GST) proteins or thioredoxin (TRX). Equipment for the expression and purification of such fusion proteins are commercially available from New England BioLab (Beverly, MA), Pharmacia (Piscatawa, NJ) and InVitrogen, respectively. The protein can also be labeled with an epitope and subsequently purified using a specific antibody directed to said epitope. One such epitope ("Flag") is commercially available in Kodak (New Haven, CT). Finally, to further purify the protein one or more high performance reverse phase liquid chromatography (RP-HPLC) steps using hydrophobic RP-HPLC medium, for example silica gel having methyl groups or other aliphatic groups, may be employed. . Some or all of the preceding purification steps may also be employed, in various combinations, to provide an isolated and substantially homogeneous recombinant protein. The protein thus purified is substantially free of other mammalian proteins and is defined according to the present invention as an "isolated protein." The protein of the invention can also be expressed as a product of transgenic animals, for example, as a component of the milk of transgenic cows, goats, pigs or sheep, which are characterized by germ or somatic cells that contain a nucleotide sequence that code for the protein The protein of the invention can also be produced by conventional chemical synthesis techniques. Methods for constructing the proteins of the present invention by synthetic means are known to those skilled in the art. The sequences of synthetically constructed proteins, by virtue of sharing primary, secondary and tertiary structural and / or conformational characteristics with proteins may possess biological properties in common with them, including protein activity. Thus, they can be used as imunological or biologically active substitutes for purified, natural proteins, in the classification of therapeutic compounds and in immunological processes for the development of antibodies. The proteins provided herein also include proteins characterized by amino acid sequences similar to those of purified proteins but within which modifications are provided naturally or by deliberate manipulation. For example, modifications in the peptide or DNA sequences can be made by those skilled in the art using known techniques. Modifications of interest in the protein sequences may include replacement, insertion or deletion of a selected amino acid residue in the coding sequence. For example, one or more of the cysteine residues can be removed or replaced with another amino acid to modify the conformation of the molecule. Mutagenic techniques for such replacement, insertion or deletion are well known to those skilled in the art (see, for example, U.S. Patent No. 4,518,584). Other fragments and derivatives of the protein sequences that would be expected to retain protein activity in whole or in part and which may therefore be useful for classification or other immunological methodologies can also easily be made by those skilled in the art and based on the present description. It is believed that such modifications fall within the present invention.

Uses v Biological Activity It is expected that the polynucleotides of the present invention and the proteins encoded by them will exhibit one or more of the biological uses or activities (including those associated with assays cited herein) identified below. The uses or activities described for the proteins of the present invention may be provided by the administration or use of said proteins or by the administration or use of polynucleotides encoding said proteins (such as, for example, in appropriate gene or vector therapies. for the introduction of DNA).

Utility as a Research Tool The polynucleotides provided by the present invention can be used by the research community for various purposes. The polynucleotides can be used to express recombinant protein for analysis, characterization or therapeutic use; as markers for tissues in which the corresponding protein is preferentially expressed (either constitutively or at a particular stage of tissue differentiation or development or in disease states); as molecular weight markers on Southern gels; as chromosome markers (when tagged) to track related genetic positions; to compare with endogenous DNA sequences in patients to identify potential genetic disorders; as probes to hybridize and thus discover novel related DNA sequences; as a source of information to derive PCR primaries for genetic identification; as a probe for "subtracting" known sequences in the discovery process of other novel polynucleotides; for raising antibodies to antiproteins using DNA immunization techniques; and as an antigen to raise anti-DNA antibodies or to extract another immune response. Where the polynucleotide encodes a protein that binds or potentially binds to another protein (such as, for example, in a receptor-ligand interaction), the polynucleotide can also be used in interaction trap tests (such as, for example, those described in Gyuris et al., Cell 75: 791-803 (1993)) to identify polynucleotides that encode the other protein with which the binding occurs or to identify inhibitors of the binding interaction.

The proteins provided by the present invention can be used in a similar manner to raise antibodies or to extract another immune response; as a reagent (including labeled reagent) in assays designed to quantitatively determine levels of the protein (or its receptor) in biological fluids; as markers for tissues in which the corresponding * protein is expressed preferentially (either constitutively or at a particular stage of tissue differentiation or development or in a disease state); and, of course, to isolate correlative receptors or ligands. Where the protein binds or potentially binds to another protein (such as, for example, in a receptor-ligand interaction), the protein can be used to identify the other protein with which the binding occurs or to identify inhibitors of the union interaction. The proteins involved in these binding interactions can also be used to classify peptides or inhibitors of small molecules or agonists of the binding interaction. Any of these utilities as "research tools" are capable of being developed into a reactive grade or format of equipment for marketing as "products for research." Cytokine Activity and Proliferation / Cell Differentiation A protein of the present invention can exhibit cytokine activity, cell proliferation (either by inducing or inhibiting) or cell differentiation (either by inducing or inhibiting) or it can induce the production of other cytokines in certain cell populations. Many protein factors discovered to date, including all known cytokines, have exhibited activity in one or more factor-dependent cell proliferation assays, hence the assays serve as a convenient confirmation of cytokine activity. The activity of a protein of the present invention is evidenced by any one of a number of routine factor-dependent cell proliferation assays for cell lines including, without limitation, 32D, DA2, DA1 G, T10, B9, B9 / 11 , BaF3, MC9 / G, M + (preB M +) 2E8, RB5, DA1, 123, T1165, HT2, CTLL2, TF-1, Mo7e and CMK. The activity of a protein of the invention may, among other means, be measured by the following methods: Assays for determining T-cell or thymocyte proliferation include without limitation those described in Current Protocols in Immunology, Edited by J. E. Coligan, A.M. Kruisbeek, D.H. Margulies, E.M. Shevach, W. Strober, Published by Greene Publishing Associates and Wiley-Interscience (Chapter 3, In Vitro Assays for Mouse Lymphocyte Function 3.1-3.19; Chapter 7, Immunologic Studies in Humans) Takai et al., J. Immunol. 137: 3494-3500, 1986; Bertagnolli et al., J. Immunol. 145: 1706-1712, 1990; Bertagnolli et al., Cellular Immunology 133: 327-341, 1991; Bertagnolli et al., J. Immunol. 149: 3778-3783, 1992; Bowman et al., J. Immunol. 152: 1756-1761, 1994. Assays for determining cytokine production and / or proliferation of spleen cells, lymph node cells or thymocytes include, without limitation, those described in: Polyclonal T cell stimulation, Kruisbeek, A.M. and Shevach, E.M. In Current Protocols in Immunology. J.E.e.a. Coligan eds. Vol. 1 pp. 3.12.1-3.12.14, John Wiley and Sons, Toronto, 1994; and Measurements of mouse and human Interferon ?, Schreiber, R.D. In Current Protocols in Immunology. J.E.e.a Coligan eds. Vol 1 pp. 6.8.1 -6.8.8, John Wiley and Sons, Toronto. 1994. Tests to determine the proliferation and differentiation of hematopoietic and lymphopoietic cells include, without limitation, those described in: Measurement of Human and Murine Interleukin 2 and Interleukin 4, Bottomly, K., Davis, L.S. and Lipsky, P.E. In Current Protocols in Immunology. J.E.e.a Coligan eds. Vol 1 pp. 6.3.1-6.3.12, John Wiley and Sons, Toronto. 1991; deVries et al., J. Exp. Med. 173: 1205-1211, 1991; Moreau et al., Nature 336: 690-692, 1988; Greenberger et al., Proc. Nati Acad. Sci. U.S.A. 80: 2931 -2938, 1983; Measurement of mouse and human interleukin 6 - Nordan, R. In Current Protocols in Immunology. J.E.e.a Coligan eds. Vol 1 pp. 6.6.1 -6.6.5, John Wiley and Sons, Toronto. 1991; Smith et al., Proc. Nati Acad. Sci. U.S.A. 83: 1857-1861, 1986; Measurement of human Interleukin 11 - Bennett, F. Giannotti, J. Clark, S.C. and Turner, K.J. In Current Protocols in Immunology. J.E.e.a Coligan eds. Vol 1 pp. 6.15, John Wiley and Sons, Toronto. 1991. Measurement of mouse and human Interleukin 9 - Ciarletta, A. Giannotti, J., Clark, S.C. and Turner, K.J. In Current Protocols in Immunology. J.E.e.a Coligan eds. Vol 1 pp. 6.13.1, John Wiley and Sons, Toronto. 1991. Assays to determine the responses of T cell clones to antigens (which will identify, among others, proteins that affect the interactions of APC-T cells as well as the direct effects of T cells by measuring proliferation and cytokine production) include , without limitation, those described in: Current Protocols in Immunology, Ed by JEea Coligan, AM Kruisbeek, D.H. Margulies, E.M. Shevach, W. Strober, Pub. Greene Publishing Associates and Wiley-lnterscience (Chapter 3, In Vitro Assays for Mouse Lymphocyte Function, Chapter 6, Cytokines and their cellular receptors, Chapter 7, Immunological studies in Humans); Weinberger et al., Proc. Nati Acad. Sci. U.S.A. 77: 6091-6095, 1980; Weinberger et al., Eur. J. Immun. 11: 405-411, 1981; Takai et al., J. Immunol. 137: 3494-3500, 1986; Takei et al., J. Immunol. 140: 508-512, 1988.

Immune Stimulation / Suppression Activity A protein of the present invention may also exhibit immunological stimulation or immune suppression activity, including without limitation the activities for which assays have been described herein. A protein may be useful in the treatment of various immune deficiencies and disorders (including severe combined immunodeficiency (SCID), for example, in the regulation (up or down) of the growth and proliferation of T and / or B lymphocytes, as well how to effect the cytolytic activity of NK cells and other cell populations These immunological deficiencies can be genetic or viral (eg HIV) as well as bacterial or fungal infections, or they can result from autoimmune disorders. Infectious diseases caused by viruses, bacteria, fungi or other infection can be treated using a protein of the present invention, including HIV infections, hepatitis viruses, herpes viruses, mycobacteria, lesmania, malaria and various fungal infections such as candida. Of course, in this regard, a protein of the present invention may also be useful in where it is generally indicated to strengthen the immune system, for example, in the treatment of cancer. Autoimmune disorders that can be treated using a protein of the present invention include, for example, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, autoimmune pulmonary inflammation, Guillain-Barre syndrome, autoimmune thyroiditis, insulin-dependent diabetes mellitus, myasthenia gravis , graft versus host disease and eye inflammation disease by autoimmunity. Said protein of the present invention may also be useful in the treatment of reactions and allergic conditions, such as asthma and other respiratory problems. Other conditions, in which immunological suppression is desired (including, for example, asthma and related respiratory conditions) can also be treated using a protein of the present invention. A protein of the present invention can also suppress chronic or acute inflammation, such as, for example, that associated with infections (such as septic shock or systemic inflammatory response syndrome (SIRS), inflammatory bowel disease, Crohn's disease). or that results from the overproduction of cytokines such as TNF or IL-1 (such as the effect demonstrated by IL-11.) The activity of a protein of the invention, among other means, can be measured by the following methods: Suitable assays for determining cytotoxicity of splenocytes or thymocytes include, without limitation, those described in Current Protocols in Immunology, Edited by JE Coligan, AM Kruisbeek, DH Margulies, EM Shevach, W. Strober, Pub. Greene Publishing Associates and Wiley-lnterscience ( Chapter 3, In Vitro Assays for Mouse Lymphocyte Function 3.1.-3.19; Chapter 7, Immunologic Studies in Humans); Herrmann et al., Proc. Nati. Acad. Sci. USA 7 8: 2488-2492, 1981; Herrmann et al., J. Immunol. 128: 1968-1974, 1982; Handa et al., J. Immunoi. 135-1564-1572, 1985; Takai et al., J. Immunol. 137: 3494-3500, 1986; Takai et al., J. Immunol. 140: 508-512, 1988; Herrmann et al., Proc.Natl. Acad. Sci. USA 78: 2488-2492, 1981; Herrmann et al., J. Immunol. 128: 1968-1974, 1982; Handa et al., J. Immunol 135: 1564-1572, 1985; Takai et al., J. Immunol. 137-3494-3500, 1986; Bowman et al., Virology 61: 1992-1998; Takai et al., J. Immunol. 140: 508-512, 1988; Bertagnolli et al., Cellular Immunology 133: 327-341, 1991; Brown et al., J. Immunol. 153: 3079-3092, 1994. Trials to determine T cell-dependent immunoglobulin responses and isotype switching (which will identify, among others, proteins that modulate T-cell-dependent antibody responses and that affect Th1 / Th2 profiles. ) include, without limitation, those described in: Maliszewski, J. Immunol. 144: 3028-3033, 1990; and Tests for B cell function: In vitro antibody production, Mond, J.J. and Brunswick, M. In current Protocols in Immunology. J.E.e.a. Coligan eds. Vol 1 pp. 3.8.1-3.8.16, John Wiley and sons, Toronto. 1994. Mixed lymphocyte reaction (MLR) tests (which will identify, among others, proteins that predominantly generate Th1 and CTL responses) include, without limitation, those described in Current Protocols in Immunology, Edited by J.E. Coligan, A.M. Kruisbeek, D.H. Margulies, E.M. Shevach, V \ l ~ Strober, Pub. Greene Publishing Associates and Wiley-lnterscience (Chapter 3, In Vitro Assays for Mouse Lymphocyte Function 3.1.-3.19; Chapter 7, Immunologic studies in Humans); Takai et al., J. Immunol. 137: 3494-3500, 1986; Takai et al., J. Immunol. 140: 508-512, 1988; Bertagnolli et al., J. Immunol. 149: 3778-3783, 1992. Dendritic cell-dependent assays (which will identify, among others, proteins expressed by dendritic cells that activate natural T cells) include, without limitation, those described in: Guery et al., J. Immunol. 134: 536-544, 1995; Inaba et al., Journal of Experimental Medicine 173: 549-559, 1991; Macatonia et al., Journal of Immunology 154: 5071-5079, 1995; Porgador et al., Journal of Experimental Medicine 182: 255-260, 1995; Nair et al., Journal of Virology 67: 4062-4069, 1993; Huang et al., Science 264: 961-965, 1994; Macatonia et al., Journal of Eperimental Medicine 169: 1255-1264, 1989; Bhardwaj et al., Journal of Clinical Investigation 94: 797-807, 1994; and Inaba et al., Journal of Experimental Medicine 172: 631-640, 1990. Tests to determine the survival / apoptosis of lymphocytes (which will identify, among others, the proteins that prevent apoptosis after superantigen induction and proteins). regulating lymphocyte homeostasis) include, without limitation, those described in: Darzynkiewicz et al., Cytometry 13: 795-808, 1992; Gorczyca et al., Leukemiaa 7: 659-670, 1993 Gorczyca et al, Cancer Research 53: 1945-1951, 1993; Itoh et al., Cell 66: 233-243, 1991; Zacharchuk, Journal of Immunology 145: 4037-4045, 1990; Zamai et al., Cytometry 14: 891-897, 1993; Gorczyca et al., International Journal of Oncology 1: 639-648, 1992. Tests for proteins that influence early stages of T cell development and confinement include, without limitation, those described in Antica et al., Blood 84; 111 -117, 1994; Fine et al., Cellular Immunology 155: 111-122, 1994; Galy et al., Blood 85: 2770-2778, 1995; Toki et al., Proc. Nat. Acad. Sci. USA 88: 7548-7551, 1991.

Hematopoiesis Regulating Activity A protein of the invention can be useful in the regulation of hematopoiesis and, consequently, in the treatment of deficiencies of myeloid or lymphoid cells. Even a marginal biological activity in support of colony-forming cells or factor-dependent cell lines indicates involvement in the regulation of hematopoiesis, that is, in supporting the growth and proliferation of erythroid progenitor cells alone or in combination with other cytokines. , indicating utility in this way, for example, in the treatment of various anemias or to be used in conjunction with irradiation / chemotherapy to stimulate the production of erythroid precursors and / or erythroid cells; in supporting the growth and proliferation of myeloid cells such as granulocytes and monocytes / macrophages (ie, traditional CSF activity) useful, for example, in conjunction with chemotherapy to prevent or treat consequent myelosuppression; in supporting the growth and proliferation of megakaryocytes and consequently of platelets, thereby allowing the prevention or treatment of various platelet disorders such as thrombocytopenia, and in general to be used in place or in a complementary manner to platelet transfusions; and / or supporting the growth and proliferation of hematopoietic progenitor cells, which are capable of maturing each and every one of the aforementioned hematopoietic cells and therefore find therapeutic utility in various progenitor cell disorders (such as those usually treated with transplants, including, without limitation, aplastic anemia and paroxysmal nocturnal hemoglobinuria) as well as in the repopulation of the division of progenitor cells that results from irradiation / chemotherapy, either in vivo or ex vivo (that is, in conjunction with transplantation of bone marrow) as normal cells or genetically engineered by gene therapy. The activity of a protein of the invention can, among other means, be measured by the following methods: Appropriate tests to determine the proliferation and differentiation of several hematopoietic lines have been cited above. Tests for the differentiation of embryonic progenitor cells (which will identify, among others, proteins that influence the hematopoiesis of embryonic differentiation) include, without limitation, those described in Johansson et al. Cellular Biology 15: 141-151, 1995; Keller et al., Molecular and Cellular Biology 13: 473-486, 1993; McCIanahan et al., Blood 81: 2903-2915, 1993. Tests to determine the survival and differentiation of progenitor cells (which will identify, among others, proteins that regulate lympho-hematopoiesis) include, without limitation, those described in: Methylcellulose colony forming assays, Freshney, MG In Culture of Hematopoietic Cells, R.I. Freshney, et al. Vol pp 265-268, Wiley-Liss, Inc., New York, NY 1994; Hirayama et al., Proc Nati. Acad. Sci. USA 89: 5907-5911, 1992; Primitive hematopoietic colony forming cells with high proliferative potential, McNiece, I.K. and Briddell, R.A. In Culture of Hematopoietic Cells. R.l. Freshney, et al. eds. Vol pp. 23-39, Wiley-Liss, Inc. New York, NY 1994; Neben et al., Experimental Hematology 22: 353-359, 1994; Cobblestone area forming cell assay, Ploemacher, R.E. In Culture of Hematopoietic Cells. R.l. Freshney et al., Eds. Vol pp. 1-21, Wiley-Liss, Inc. New York, NY 1994; Long term bone cultures in the presence of stromal cells, Spooncer, E., Dexter, M. and Alien, T. In Culture of Hematopoietic Cells. R.l. Freshney et al., Eds. Vol pp. 163-179, Wiley-Liss, Inc., New York, NY 1994; Long term culture initiating cell assay, Sutherland, H.J. In Culture of Hematopietic Cells, R.l. Freshney et al., Eds. Vol pp. 139-162, Wiley-Liss, Inc. New York, NY. 1994 Tissue Generation / Regeneration Activity A protein of the present invention may have utility in compositions used for growth or regeneration of bone, cartilage, tendon, ligament and / or nerve tissue, as well as for healing hepates and tissue repair; and in the treatment of burns, cuts and ulcers. A protein of the present invention, which induces the growth of cartilage and / or bone in circumstances where the bone is not normally formed, has application in the healing of bone fractures and damages or cartilage defects in humans and other animals. Such a preparation employing a protein of the invention can have prophylactic use in the reduction of both closed and open fractures and also in the improved fixation of artificial joints. The formation of new bone induced by an osteogenic agent contributes to the repair of congenital craniofacial defects, induced by trauma or induced by oncological shortening; and it is also useful in cosmetic plastic surgery. A protein of this invention may also be useful in the treatment of periodental disease and other dental repair processes. Such agents can provide an environment for attracting bone-forming cells, stimulating the growth of bone-forming cells or inducing differentiation or progenitors of bone-forming cells. A protein of the invention may also be useful in the treatment of osteoporosis or osteoarthritis, such as through the stimulation of bone and / or cartilage repair or by blocking inflammation or tissue destruction processes (collagenase activity, osteoclastic activity , etc.) mediated by inflammatory processes. Another category of tissue regeneration activity that may be attributable to the protein of the present invention is tendon / ligament formation. A protein of the present invention, which induces tissue similar to tendon / ligament or other formation of in circumstances where said tissue is not normally formed, has application in the healing of tendon or ligament tears, deformities and other tendon defects or ligament in humans and other animals. Such a preparation employing a tendon / ligament-like tissue induction protein may have prophylactic use in preventing damage to tendon or ligament tissue, as well as use in the improved fixation of tendon or ligament to bone or other tissues, and in the repair of tendon and ligament tissue defects. The formation of new tissue similar to tendon / ligament that is induced by a composition of the present invention contributes to the repair of tendon or ligament defects due to congenital causes, induced by trauma or with another origin; and it is also useful in cosmetic plastic surgery for fixation or repair of tendons or ligaments. The compositions of the present invention can provide an environment for attracting tendon or ligament forming cells, stimulating the growth of tendon or ligament forming cells, inducing differentiation of progenitors of tendon or ligament forming cells, or inducing cell growth. or progenitors of tendon / ligament ex vivo for in vivo return to perform tissue repair. The compositions of the invention may also be useful in the treatment of tendonitis, carpel tunnel syndrome and other tendon or ligament defects. The compositions may also include an appropriate matrix and / or sequestering agent as a carrier as is well known in the art.

The protein of the present invention can also be useful for the proliferation of nerve cells and for the regeneration of nervous and cerebral tissue, that is, for the treatment of diseases of the central and peripheral nervous system and neuropathies, as well as in mechanical and traumatic disorders , which involve the degeneration, death or trauma to nerve cells or nerve tissue. More specifically, a protein can be used in the treatment of diseases of the peripheral nervous system, such as peripheral nerve wounds, peripheral neuropathy and localized neuropathies; and diseases of the central nervous system such as Alzheimer's and Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and Shy-Drager syndrome. Additional conditions that can be treated in accordance with the present invention include mechanical and traumatic disorders, such as spinal cord disorders, head trauma and cerebrovascular diseases such as seizure. Peripheral neuropathies resulting from chemotherapy or other medical therapies may also be treatable using a protein of the invention It is expected that a protein of the present invention may also exhibit activity for the generation of other tissues, such as organ tissue (including, for example, pancreas, liver, intestine, kidney, skin, endothelium), muscle tissue (soft, skeletal or cardiac) and vascular tissue (including vascular endothelium), or to promote the growth of cells comprising said tissues. Part of the desired effects may be the inhibition of fibrotic healing to allow normal tissue to regenerate. A protein of the present invention may also be useful in the protection or regeneration of the intestine and in the treatment of pulmonary or hepatic fibrosis, reperfusion injury in various tissues; and conditions resulting from systemic cytokine damage. The activity of a protein of the invention can, among other means, be measured by the following methods: Tests to determine tissue generation activity include, without limitation, those described in International Patent Publication No.

WO95 / 16035 (bone, cartilage, tendon); International Patent Publication No.

WO95 / 05846 (nerve, neuronal); International Patent Publication No. WO91 / 07491 (skin, endothelium).

Activity of Activin / lnhibin A protein of the present invention may also exhibit activities related to activin or inhibin. Inhibins are characterized by their ability to inhibit the release of follicle-stimulating hormones (FSH), while activins are characterized by their ability to stimulate the release of follicle-stimulating hormones (FSH). Thus, a protein of the present invention, alone or in heterodimers with a member of the inhibin family, can be useful as a contraceptive based on the ability of inhibins to decrease fertility in female mammals and decrease sperm generation in male mammals The administration of sufficient amounts of other inhibins can induce infertility in these mammals. Alternatively, the protein of the invention, as a homodimer or as a heterodimer with other protein subunits of the inhibin β group, may be useful as a fertility-inducing therapeutic, based on the ability of the activin molecules to stimulate the release of FSH from cells of the anterior pituitary. See, for example, Patent of the United States of America 4,798,885. A protein of the invention may also be useful to advance the impetus of fertility in sexually immature mammals, in order to increase the reproductive life behavior of domestic animals such as cows, sheep and pigs. The activity of a protein of the invention can, among other means, be measured by the following methods: Assays for determining activia / inhibin activity include, without limitation, those described in: Vale et al., Endocrinology 91: 562- 572, 1972; Ling et al., Nature 321: 779-782, 1986; Vale et al., Nature 321: 776-779, 1986; Mason et al., Nature 318: 659-663, 1985; Forage et al. , Proc. Nati Acad. Sci. USA 83: 3091-3095, 1986.

Chemotactic Activity Chemokinetic A protein of the present invention may have chemoattractant or chemokinetic activity (eg, act as a chemokine) for mammalian cells, including, for example, monocytes, neutrophils, T cells, mast cells, eosinophils and / or endothelial cells. The chemotactic or chemokinetic proteins can be used to mobilize or attract a desired population of cells to a desired site of action. Chemotactic or chemokinetic proteins provide particular advantages in the treatment of wounds and other traumas to tissues, as well as in the treatment of localized infections. For example, the attraction of lymphocytes, monocytes or neutrophils to tumors or sites of infection can result in improved immune responses against tumors or infectious agents. A protein or peptide has chemotactic activity for a particular population of cells if it can stimulate, directly or indirectly, the movement or targeting of said population of cells. Preferably, the protein or peptide has the ability to directly stimulate the directed movement of cells. The fact that a particular protein has chemotactic activity for a population of cells can be easily determined by employing such a protein or peptide in any known assay for cell chemotaxis. The activity of a protein of the present invention can, among other means, be measured by the following methods: Tests to determine chemotactic activity (which will identify proteins that induce or prevent chemotaxis) consist of tests that measure the capacity of a protein to induce the migration of cells through a membrane as well as the ability of a protein to induce the adhesion of a population of cells to another population of cells. Suitable tests for determining movement and adhesion include, without limitation, those described in: Current Protocols in Immunology, edited by J.E. Coligan, A.M. Krisbeek, D.H. Margulies, E.M. Shevach, W.Strober, Pub. Greene Publishing Associates and Wiley-Interscience (Chapter 6.12, Measurements of alpha and beta Chemokines 6.12.1 -6.12.28; Taub et al., J. Clin. Invest. 95: 1370-1376, 1995; Lind et al., APMIS 103: 140-146, 1995; Muller et al., J. Immunol., 25: 1744-1748; Gruber et al., J. of Immunol., 152: 5860-5967, 1994; Johnson; et al., J. of Immunol., 153: 1762-1768, 1994.

Hemostatic Activity and Thrombolytic A protein of the invention also exhibits haemostatic or thrombolytic activity. As a result of this, it is expected that said protein be useful in the treatment of various coagulation disorders (including hereditary disorders, such as hemophilia) or to improve coagulation and other hemostatic events in the treatment of wounds resulting from trauma, surgeries or other causes A protein of the invention may also be useful for dissolving or inhibiting the formation of thrombosis and for the treatment and prevention of conditions resulting therefrom (such as, for example, infarction or attack). The activity of a protein of the present invention may, among other means, be measured by the following methods: Assays for determining haemostatic and thrombolytic activity include, without limitation, those described in: Linet et al. , J. Clin. Pharmacol. 26: 131-140, 1986; Burdick et al. , Thrombosis Res. 45: 413-41 9, 1987; Humphrey et al. , Fibrinolysis 5:71 -79 (1991); Schaub, Prostaglandins 35: 467-474, 1988.

Receptor / Ligand Activity A protein of the present invention can also demonstrate activity as a receptor, ligand of receptors or inhibitors or agonists of receptor / ligand interactions. Examples of such receptors and ligands include, without limitation, cytokine receptors and their ligands, kinase receptors and their ligands, phosphatase receptors and their ligands, receptors involved in cell-cell interactions and their ligands (including, without limitation, cell adhesion molecules (such as selectins, integrins and their ligands) and receptor / ligand pairs involved in antigen presentation, antigen recognition and development of cellular and humoral immune responses). The receptors and ligands are also useful for the classification of potential peptide or small molecule inhibitors of the relevant receptor / ligand interaction. A protein of the present invention (including, without limitation, fragments of receptors and ligands) may itself be useful as an inhibitor of receptor / ligand interactions. The activity of a protein of the present invention can, among other means, be measured by the following methods: Appropriate assays for determining receptor-ligand activity include, without limitation those described in: Current Protocols in Immunology, edited by J.E. Coligan, A.M. Kruisbeek, D.H. Margulies, E.M. Shevach, W.Strober, Pub. Greene Publishing Associates and Wiley-lnterscience (Chapter 7.28, Measurements of Celular Adhesion under static conditions 7.28.1 -7.28.22), Takai et al., Proc. Nati Acad. Sci. USA 84: 6864-6868, 1987; Bierer et al., J. Exp. Med. 168: 1145-1156, 1988; Rosenstein et al., J. Exp. Med 169: 149-160 1989; Stoltenborg et al., J. Immunol. Methods 175: 59-68, 1994; Stitt et al., Cell 80: 661-670, 1995.

Other Activities A protein of the invention may also exhibit one or more of the following activities or effects: killing of infectious agents, including, without limitation, bacteria, viruses, fungi or other parasites; effect (suppression or improvement) bodily characteristics, including, without limitation, height, weight, hair color, eye color, pigmentation of skin or other tissues, or size of organs (such as, for example, breast augmentation or decrease); effect the processing of fat, protein or carbohydrates from the diet; effect behavioral characteristics, including, without limitation, appetite, libido, stress, perception (including perceptual disorders), depression (including depressive disorders) and violent behaviors; provision of analgesic effects or other pain-reducing effects; promotion of the differentiation and growth of embryonic progenitor cells in lineages other than hematopoietic lineages; and in the case of enzymes, correct deficiencies of the enzymes and the treatment of related diseases.

Administration v Dosage A protein of the present invention (from any source that has been obtained, including without limitation, from recombinant and non-recombinant sources) can be used in a pharmaceutical composition when combined with a pharmaceutically acceptable carrier. Said composition may also contain (in addition to a protein and a carrier) diluents, fillers, salts, regulators, stabilizers, solubilizers, and other materials that are well known in the art. The term "pharmaceutically acceptable" means a non-toxic material that does not interfere with the effectiveness of the biological activity of the active ingredient (s). The characteristics of the carrier will depend on the administration route. The pharmaceutical composition of the invention may also contain cytokines, lymphokines, or other hematopoietic factors such as M-CSF, GM-CSF, TNF, IL-1, IL-2, IL-3, IL-4, IL-5, IL -6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IFN, TNFO, TNF1, TNF2, G-CSF , Meg-CSF, thrombopoietin, progenitor cell factor and erythropoietin. The pharmaceutical composition may further contain other agents that, either, improve the activity of the protein or complement its activity or use in the treatment. Said factors and / or additional agents can be included in the pharmaceutical composition to produce a synergistic effect with the protein of the invention, or to minimize side effects. Conversely, the protein of the present invention can be included in formulations of the particular cytokine, lymphokine, other hematopoietic factor, thrombolytic or anti-thrombotic factor, or anti-inflammatory agent to minimize side effects of the cytokine, lymphokine, another factor hematopoietic, thrombolytic or anti-thrombotic factor, or anti-inflammatory agent.

A protein of the present invention may be active in multimers (e.g., heterodimers or homodimers) or complexes with themselves or other proteins. As a result, the pharmaceutical compositions of the invention may comprise a protein of the invention in said multimeric or complex form. The pharmaceutical composition of the invention may be in the form of a protein complex (s) of the present invention in conjunction with protein or peptide antigens. The protein and / or peptide antigen will release a stimulating signal to both B and T lymphocytes. B lymphocytes will respond to the antigen through their surface immunoglobulin receptors. The T lymphocytes will respond to the antigen through the T cell receptor (TCR) following the presentation of the antigen by the MHC proteins. MHC proteins and structurally related proteins including those encoded by the MHC class I and class II genes in host cells will serve to present the peptide antigen (s) for T lymphocytes. The antigen components could also be supplied as complexes. purified from MHC-peptide alone or with co-stimulant molecules that can directly signal T cells. Alternatively, antibodies capable of binding immunoglobulin and other molecules in B cells, as well as antibodies capable of binding TCR and other molecules in T cells can be combined with the pharmaceutical composition of the invention. The pharmaceutical composition of the invention may be in the form of a liposome in which the protein of the present invention is combined, in addition to other pharmaceutically acceptable carriers, with amphipathic agents such as lipids that exist in aggregate form such as miscella, insoluble monolayers, liquid crystals, or laminar layers that are in aqueous solution. Suitable lipids for liposomal formulation include, without limitation, monoglycerides, diglycerides, sulfatides, lsolecyctin, phospholipids, saponins, bile acids, and the like. The preparation of such liposomal formulations is within the skill of the art, as described, for example, in U.S. Pat. No. 4,235,871; Patent of the U.S.A. No. 4,501, 728; Patent of the U.S.A.

No. 4,837,028 and U.S. Pat. No. 4,737, 323; all of which is incorporated herein by reference. As used herein, the term "therapeutically effective amount" means the total amount of each active component of the pharmaceutical composition or method that is sufficient to show a significant benefit to the patient, ie, treatment, cure, prevention or improvement of the condition relevant medical condition, or an increase in the speed of treatment, cure, prevention or improvement of said conditions. When an active ingredient is applied to an individual, administered alone, the term refers to that ingredient alone. When a combination is applied, the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, sep- arally or simultaneously. In practicing the method of treatment or use of the present invention, a therapeutically effective amount of the present invention is administered to a mammal having a condition to be treated. The protein of the present invention can be administered according to the method of the invention, either alone or in combination with other therapies such as treatments employing cytokines, lymphokines or other hematopoietic factors. When co-administered with one or more cytokines, lymphokines, or other hematopoietic factors, the protein of the present invention can be administered either simultaneously with cytokine (s), lymphokine (s), other hematopoietic factor (s) (s), thrombolytic or antithrombotic factors, or sequentially. If administered sequentially, the attending physician will decide on the appropriate sequence of administration of the protein of the present invention in combination with cytokine (s), lymphokine (s), other hematopoietic factor (s), factors thrombolytics or anti-thrombotic. The administration of the protein of the present invention used in the pharmaceutical composition or to carry out the method of the present invention can be carried out in a variety of conventional ways, such as oral ingestion, inhalation, cutaneous injection, subcutaneous or intravenous: Intravenous administration to the patient is the most preferred.

When a therapeutically effective amount of the protein of the present invention is administered orally, the protein of the present invention will be in the form of a tablet, capsule, powder, solution or elixir. When administered in tablet form, the pharmaceutical composition of the invention may additionally contain a solid carrier such as gelatin or an adjuvant. The tablet, capsule and powder contains from about 5 to 95% of the protein of the present invention and preferably from about 25 to 90% of the protein of the present invention. When administered in liquid form, a liquid carrier such as water, petroleum, animal or vegetable oils such as peanut oil, mineral oil, soybean oil, sesame oil, or synthetic oils can be added. The liquid form of the pharmaceutical composition may further contain physiological saline, dextrose or other saccharide solution, or glycols such as ethylene glycol, propylene glycol or polyethylene glycol. When administered in liquid form, the pharmaceutical composition contains from about 0.5 to 90% by weight of the protein of the present invention and preferably from about 1 to 50% of the protein of the present invention. When a therapeutically effective amount of the protein of the present invention is administered by intravenous, cutaneous or subcutaneous injection, the protein of the present invention will be in the form of a parenterally acceptable and pyrogen-free aqueous solution. It is within the skill of the art to prepare such parenterally acceptable protein solutions, with due regard to the pH, isotonicity, stability and the like. A pharmaceutically preferred composition for intravenous, cutaneous or subcutaneous injection must contain, in addition to the protein of the present invention, an isotonic vehicle such as Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose Injection and Sodium Chloride, Ringer Injection with Lactate, or other vehicle as is known in the art. The pharmaceutical composition of the present invention may also contain stabilizers, preservatives, regulators, antioxidants, or other additives known to those skilled in the art.

The amount of the protein of the present invention in the pharmaceutical composition of the present invention will depend on the nature and severity of the condition being treated, and on the nature of previous treatments the patient has had. Finally, the attending physician will decide the amount of the protein of the present invention with which he will treat each individual patient. Initially, the attending physician will administer low doses of the protein of the present invention and observe the patient's response. Higher doses of protein of the present invention can be administered until the optimal therapeutic effect is obtained for the patient, and at that point generally the dose will not be increased further. It is contemplated that the various pharmaceutical compositions used in the practice of the method of the present invention should contain from about 0.01 μg to about 100 mg (preferably from about 0.1 μg to about 10 mg, more preferably from about 0.1 μg to about 1 mg) of protein of the present invention per kilogram of body weight. The duration of intravenous therapy using the pharmaceutical composition of the present invention will vary depending on the severity of the disease being treated and the potential idiosyncratic condition and response of each individual patient. It is contemplated that the duration of each application of the protein of the present invention will be in the range of 12 to 24 hours of continuous intravenous administration. Finally the attending physician will decide about the appropriate duration of the intravenous therapy using the pharmaceutical composition of the present invention. The protein of the present invention can also be used to immunize animals to obtain polyclonal and monoclonal antibodies that specifically react with the protein. Such antibodies can be obtained using either the entire protein or fragments thereof as an immunogen. The peptide immunogens may additionally contain a cysteine residue at the carboxyl terminus, and be conjugated to a hapten such as keyhole limpet hemocyanin (KLH). Methods for synthesizing such peptides are known in the art, for example, as in R.P. Merrifield, J. Amer. Chem. Soc. 85, 2149-2154 (1963); J.L. Krstenansky, et al. FEBS Lett. 211, 10 (1987). The monoclonal antibodies that bind to the protein of the present invention can also be useful diagnostic agents for the immunodetection of the protein. Neutralizing monoclonal antibodies that bind to the protein can also be useful therapeutics for both conditions associated with the protein as well as in the treatment of some forms of cancer where abnormal expression of the protein is involved. In the case of cancer cells or leukemia cells, monoclonal antibodies neutralizing against the protein may be useful in detecting and preventing the metastatic spread of cancer cells, which may be mediated by the protein. For the compositions of the present invention that are useful for the regeneration of bone, cartilage, tendon or ligament, the therapeutic method includes administration of the composition topically, systemically or locally as an implant or device. When administered, the therapeutic composition for use in this invention is, of course, in a physiologically acceptable and pyrogen-free form. In addition, the composition may be desirably encapsulated or injected in a viscous form to release it at the site of bone, cartilage or tissue damage. Topical administration may be adequate to heal wounds and repair tissue. Therapeutically useful agents other than the protein of the present invention and which may also be optionally included in the composition as described above, may alternatively or additionally, be administered simultaneously or sequentially with the composition in the methods of the invention. Preferably for the formation of bone and / or cartilage, the composition would include a matrix capable of releasing the protein-containing composition at the site of bone and / or cartilage damage, providing a structure for the development of bone and cartilage; and optimally capable of being reabsorbed by the body. Said matrices may be formed from materials currently in use for other medical implant applications.

The choice of matrix material is based on biocompatibility, biodrectability, mechanical properties, cosmetic appearance and interface properties. The particular application of the composition will define the appropriate formulation. Potential matrices for the compositions may be calcium sulfate, tricalcium phosphate, hydroxyapatite, polylactic acid, polyglycolic acid and chemically well-defined and biodegradable polyanhydrides. Other potential materials are biodegradable and biologically well defined, such as bone or dermal collagen. Additional matrices are composed of pure proteins or extracellular matrix components. Other potential matrices are non-biodegradable and chemically defined, such as hydroxyapatite, biocrystal, aluminates or other ceramics. The matrices may be composed of combinations of any of the above mentioned types of materials, such as polylactic acid and hydroxyapatite or collagen and tricalcium phosphate. Bioceramics can be altered in their composition, such as in calcium-aluminate-phosphate and processed to modify their pore size, particle size, particle shape and biodegradability. A 50:50 copolymer (mol weight) of lactic acid and glycolic acid in the form of porous particles with diameters ranging from 150 to 800 microns is currently preferred. In some applications, it will be useful to employ a sequestering agent, such as carboxymethyl cellulose or autologous blood clots, to prevent protein compositions from dissociating from the matrix. A preferred family of sequestering agents is that of cellulosic materials such as alkylcelluloses (including hydroxyalkylcelluloses), including methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and carboxymethylcellulose, most preferred being cationic salts of carboxymethylcellulose (CMC). Other preferred sequestering agents include hyaluronic acid, sodium alginate, poly (ethylene glycol), polyoxyethylene oxide, carboxyvinyl polymer and poly (vinyl alcohol). The amount of sequestering agent useful herein is 0.5-20% by weight, preferably 1-10% by weight based on the total weight of the formulation, which represents the amount necessary to prevent desorption of the protein from the polymer matrix and to provide proper management of the composition, and yet not so much so that the progenitor cells are prevented from infiltrating into the matrix, thus giving the protein the opportunity to aid the osteogenic activity of the progenitor cells. In additional compositions, the proteins of the invention can be combined with other beneficial agents for the treatment of the defect of bone and / or cartilage, wound or tissue in question. These agents include various growth factors such as epidermal growth factor (EGF), platelet derived growth factor (PDGF), transforming growth factors (TGF-α and TGF-β) and insulin-like growth factor ( IGF). The therapeutic compositions are also currently valuable for veterinary applications. Particularly domestic animals and thoroughbred horses, in addition to humans, are desirable patients for such protein treatments of the present invention. The dosage regimen of a pharmaceutical composition containing protein, to be used in the regeneration of tissue will be determined by the attending physician and in consideration of several factors that will modify the action of the proteins, for example, the amount of tissue weight which is desired to be formed, the site of the damage, the condition of the damaged tissue, the size of the wound, the type of tissue damaged (eg, bone), the age, sex and diet of the patient, the severity of any infection , the time of administration and other clinical factors. The dosage may vary with the type of matrix used in the reconstitution and with the inclusion of other proteins in the pharmaceutical composition. For example, the addition of other known growth factors may also affect the dose, such as IGFI (insulin-like growth factor I) to the final composition. Progress can be monitored by periodic evaluations of tissue / bone growth and / or repair, for example, by X-ray determinations, histomorphometric determinations and tetracycline labeling.

The polynucleotides of the present invention can also be used for gene therapy. Such polynucleotides can be introduced either in vivo or ex vivo into cells for expression in a mammalian subject. The polynucleotides of the invention can also be administered by other known methods for the introduction of nucleic acid into a cell or organism (including, without limitation, in the form of viral vectors or naked DNA). The cells may also be cultured ex vivo in the presence of proteins of the present invention for the purpose of proliferating or producing a desired effect or activity in said cells. The treated cells can then be introduced in vivo for therapeutic purposes.

The patent and literature references cited here are incorporated as references as they were fully disclosed.

LIST OF SEQUENCES (1) GENERAL INFORMATION (i) APPLICANTS: Jacobs, Kenneth MeCoy, John Kelleher, Kerry Carlin, McKeough (ii) TITLE OF THE INVENTION: DNA SEQUENCES AND SECRETED PROTEINS THAT ARE CODED BY THESE (iii) NUMBER OF SEQUENCES : 12 (iv) ADDRESS FOR CORRESPONDENCE: (A) RECIPIENT: Genetics Institute, Inc., Legal Matters (B) STREET: 87 CambridgePark Drive (C) CITY: Cambridge (D) STATE: Massachusetts (E) COUNTRY: USA (F) C.P. : 02140 (v) COMPUTER LEADABLE FORM: (A) TYPE OF MEDIA: Floppy disk (B) COMPUTER: IBM PC compatible (C) OPERATING SYSTEM: PC-DOS / MS-DOS (D) SOFTWARE: Patentln Relay # 1.0, Version # 1.25 (vi) CURRENT DATA OF THE APPLICATION: (A) NUMBER OF APPLICATION: (B) DATE OF PRESENTATION: (C) CLASSIFICATION: (viii) INFORMATION OF THE POWDER / AGENT: (A) NAME: Brown, Scott A. (B) REGISTRATION NUMBER: 32,724 (C) REFERENCE NUMBER / RECORD: GI6000 (ix) INFORMATION FOR TELECOMMUNICATIONS: (A) PHONE: (617) 498-8224 (B) TELEFAX: (617) 876-5851 (2) INFORMATION FOR SEQ ID NO: 1: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 2209 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: double (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: cDNA (iii) HYPOTHETIC: NO (ix) CHARACTERISTICS: (A) NAME / KEY: CDS (B) LOCATION: 38..1447 (i) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 1: GAGAAGATAA AACTGGACAC TGGGGAGACA CAACTTC ATG CTG CGT GGG ATC TCC 55 Met Leu Arg Gly lie Ser 1 5 CAG CTA CCT GCA GTG GCC ACC ATG TCT TGG GTC CTG CTG CCT GTA CTT 103 Gln Leu Pro Wing Val Wing Thr Met Ser Trp Val Leu Leu Pro Val Leu 10 15 20 TGG CTC ATT GTT CAA ACT CAA GCA ATA GCC ATA AAG CAA ACÁ CCT GAA 151 Trp Leu lie Val Gln Thr Gln Ala lie Ala lie Lys Gln Thr Pro Glu 25 30 35 TTA ACG CTC CAT GAA ATA GTT TGT CCT AAA AAA CTT CAC ATT TTA CAC 199 Leu Thr Leu His Glu lie Val Cys Pro Lys Lys Leu His lie Leu His 40 45 50 AAA AGA GAG ATC AAG AAC AAC CAG ACA GAA AAG CAT GGC AAA GAG GAA 247 Lys Arg Glu lie Lys Asn Asn Gln Thr Glu Lys His Gly Lys Glu Glu 55 60 65 70 AGG TAT GAA CCT GAA GTT CAA TAT CAG ATG ATC TTA AAT GGA GAA GAA 295 Arg Tyr Glu Pro Glu Val Gln Tyr Gln Met He Leu Asn Gly Glu Glu 75 80 85 ATC ATT CTC TCC CTA CAA AAA ACC AAG CAC CTC CTG GGG CCA GAC TAC 343 He He Leu Be Leu Gln Lys Thr Lys His Leu Leu Gly Pro Asp Tyr 90 95 100 ACT GAA ACA TTG TAC TCA CCC AGA GGA GAG GAA ATT ACC ACG AAA CCT 391 Thr Glu Thr Leu Tyr Ser Pro Arg Gly Glu Glu He Thr Thr Lys Pro 105 110 115 GAG AAC ATG GAA CAC TGT TAC TAT AAA GGA AAC ATC CTA AAT GAA AAG 439 Glu Asn Met Glu His Cys Tyr Tyr Lys Gly Asn He Leu Asn Glu Lys 120 125 130 AAT TCT GTT GCC AGC ATC AGT ACT TGT GAC GGG TTG AGA GGA TAC TTC 487 Asn Ser Val Ala Ser Be Thr Cys Asp Gly Leu Arg Gly Tyr Phe 135 140 145 150 ACÁ CAT CAT CAC CAA AGA TAC CAG ATA AAA CCT CTG AAA AGC ACÁ GAC 535 Thr His His His Gln Arg Tyr Gln He Lys Pro Leu Lys Ser Thr Asp 155 160 165 GAG AAA GAA CAT GCC GTC TTT ACÁ TCT AAC CAG GAG GAA CAA GAC CCA 583 Glu Lys Glu His Wing Val Phe Thr Ser Asn Gln Glu Glu Gln Asp Pro 170 175 '180 GCT AAC CAC ACA TGT GGT GTG AAG AGC ACT GAC GGG AAA CAA GGC CCA 631 Wing Asn His Thr Cys Gly Val Lys Ser Thr Asp Gly Lys Gln Gly Pro 185 190 195 ATT CGA ATC TCT AGA TCA CTC AAA AGC CCA GAG AAA GAA GAC TTT CTT 679 He Arg He Ser Arg Ser Leu Lys Ser Pro Glu Lys Glu Asp Phe Leu 200 205 210 CGG GCA CAG AAA TAC ATT GAT CTC TAT TTG GTG CTG GAT AAT GCC TTT 727 Arg Ala Gln Lys Tyr He Asp Leu Tyr Leu Val Leu Asp Asn Wing Phe 215 220 225 230 TAT AAG AAC TAT AAT GAG AAT CTA ACT CTG ATA AGA AGC TTT GTG TTT 775 Tyr Lys Asn Tyr Asn Glu Asn Leu Thr Leu He Arg Ser Phe Val Phe 235 240 245 GAT GTG ATG AAC CTA CTC AAT GTG ATA TAT AAC ACC ATA GAT GTT CAA 823 Asp Val Met Asn Leu Leu Asn Val He Tyr Asn Thr He Asp Val Gln 250 255 260 GTG GCC TTG GTA GGT ATG GAA ATC TGG TCT GAT GGG GAT AAG ATA AAG 871 Val Ala Leu Val Gly Met Glu He Trp Ser Asp Gly Asp Lys He Lys 265 270 275 GTG GTG CCC AGC GCA AGC ACC ACG TTT GAC AAC TTC CTG AGA TGG CAC 919 Val Val Pro Ser Wing Ser Thr Thr Phe Asp Asn Phe Leu Arg Trp His 280 285 290 AGT TCT AAC CTG GGG AAA AAG ATC CAC GAC CAT GCT CAG CTT CTC AGC 967 Being Ser Asn Leu Gly Lys Lys He His Asp His Wing Gln Leu Leu Ser 295 300 305 310 GGG ATT AGC TTC AAC AAT CGA CGT GTG GGA CTG GCA GCT TCA AAT TCC 1015 Gly He Ser Phe Asn Asn Arg Arg Val Gly Leu Wing Wing Ser Asn Ser 315 320 325 TTG TGT TCC CCA TCT TCG GTT GCT GTT ATT GAG GCT AAA AAA AAG AAT 1063 Leu Cys Ser Pro Ser Ser Val Wing Val He Glu Wing Lys Lys Lys Asn 330 335 340 AAT GTG GCT CTT GTA GGA GTG ATG TCA CAT GAG CTG GGC CAT GTC CTT 1111 Asn Val Ala Leu Val Gly Val Met Ser His Glu Leu Gly His Val Leu 345 350 355 GGT ATG CCT GAT GTT CCA TTC AAC ACC AAG TGT CCC TCT GGC AGT TGT 1159 Gly Met Pro Asp Val Pro Phe Asn Thr Lys Cys Pro Ser Gly Ser Cys 360 365 370 GTG ATG AAT CAG TAT CTG AGT TCA AAA TTC CCA AAG GAT TTC AGT ACÁ 1207 Val Met Asn Gln Tyr Leu Ser Ser Lys Phe Pro Lys Asp Phe Ser Thr 375 380 385 390 TCT TGC CGT GCA CAT TTT GAA AGA TAC CTT TTA TCT CAG AAA CCA AAG 1255 Ser Cys Arg Ala His Phe Glu Arg Tyr Leu Leu Ser Gln Lys Pro Lys 395 400 405 TGC CTG CAG GCA CCT ATT CCT ACÁ AAT ATA ATG ACÁ ACÁ CÁ GTG 1303 Cys Leu Leu Gln Ala Pro He Pro Thr Asn He Met Thr Thr Pro Val 410 415 420 TGT GGG AAC CAC CTT CTA GAA GTG GGA GAA GAC TGT GAT TGT GGC TCT 1351 Cys Gly Asn His Leu Leu Glu Val Gly Glu Asp Cys Asp Cys Gly Ser 425 430 435 CCT AAG GAG TGT ACC AAT CTC TGC TGT GAA GCC CTA ACG TGT AAA CTG 1399 Pro Lys Glu Cys Thr Asn Leu Cys Cys Glu Ala Leu Thr Cys Lys Leu 440 445 450 AAG CCT GGA ACT GAT TGC GGA GGA GAT GCT CCA AAC CAT ACC ACÁ GAG 1447 Lys Pro Gly Thr Asp Cys Gly Gly Asp Ala Pro Asn His Thr Thr Glu 455 460 465 470 TGAATCCAAA AGTCTGCTTC ACTGAGATGC TACCTTGCCA GGACAAGAAC CAAGAACTCT 1507 AACTGTCCCA GGAATCTTGT GAATTTTCAC CCATAATGGT CTTTCACTTG TCATTCTACT 1567 TTCTATATTG TTATCAGTCC AGGAAACAGG TAAACAGATG TAATTAGAGA CATTGGCTCT 1627 TTGTTTAGGC CTAATCTTTC TTTTTACTTT TTTTTTTCTT TTTTCTTTTT TTTTAAAGAT 1687 CATGAATTTG TGACTTAGTT CTGCCCTTTG GAGAACAAAA GAAAGCAGTC TTCCATCAAA 1747 TCACCTTAAA ATGCACGGCT AAACTATTCA GAGTTAACAC TCCAGAATTG TTAAATTACA 1807 AGTACTATGC TTTAATGCTT CTTTCATCTT ACTAGTATGG CCTATAAAAA AAATAATACC 1867 ACTTGATGGG TGAAGGCTTT GGCAATAGAA AGAAGAATAG AATTCAGGTT TTATGTTATT 1927 CCTCTGTGTT CACTTCGCCT TGCTCTTGAA AGTGCAGTAT TTTTCTACAT CATGTCGAGA 1987 ATGATTCAAT GTAAATATTT TTCATTTTAT CATGTATATC CTATACACAC ATCTCCTTCA 2047 TCATCATATA TGAAGTTTAT TTTGAGAAGT CTACATTGCT TACATTTTAA TTGAGCCAGC 2107 AAAGAAGGCT TAATGATTTA TTGAACCATA ATGTCAATAA AAACACAACT TTTGAGGCAA 2167 'AAAAAAAAAA AAAAAAAAAA AAAAAAAAAA AAAAAAAAAA AA 2209 (2) INFORMATION FOR SEQ ID NO: 2: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 470 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: protein (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 2: Met Leu Arg Gly He Ser Gln Leu Pro Ala Val Ala Thr Met Ser Trp 1 5 10 15 Val Leu Leu Pro Val Leu Trp Leu He Val Gln Thr Gln Ala He Ala 20 25 30 He Lys Gln Thr Pro Glu Leu Thr Leu His Glu He Val Cys Pro Lys 35 40 45 Lys Leu His He Leu His Lys Arg Glu He Lys Asn Asn Gln Thr Glu 50 55 60 Lys His Gly Lys Glu Glu Arg Tyr Glu Pro Glu Val Gln Tyr Gln Met 65 70 75 80 He Leu Asn Gly Glu Glu He He Leu Ser Leu Gln Lys Thr Lys His 85 90 95 Leu Leu Gly Pro Asp Tyr Thr Glu Thr Leu Tyr Ser Pro Arg Gly Glu 100 105 110 Glu He Thr Thr Lys Pro Glu Asn Met Glu His Cys Tyr Tyr Lys Gly 115 120 125 Asn He Leu Asn Glu Lys Asn Ser Val Ala Be Ser Thr Cys Asp 130 135 140 Gly Leu Arg Gly Tyr Phe Thr His His His Gln Arg Tyr Gln He Lys 145 150 155 160 Pro Leu Lys Ser Thr Asp Glu Lys Glu His Wing Val Phe Thr Ser Asn 165 170 175 Gln Glu Glu Gln Asp Pro Wing Asn His Thr Cys Gly Val Lys Ser Thr 180 185 190 Asp Gly Lys Gln Gly Pro He Arg He Ser Arg Ser Leu Lys Ser Pro 195 200 205 Glu Lys Glu Asp Phe Leu Arg Wing Gln Lys Tyr He Asp Leu Tyr Leu 210 215 220 Val Leu Asp Asn Wing Phe Tyr Lys Asn Tyr Asn Glu Asn Leu Thr Leu 225 230 235 240 He Arg Being Phe Val Phe Asp Val Met Asn Leu Leu Asn Val He Tyr 245 250 255 Asn Thr He Asp Val Gln Val Wing Leu Val Gly Met Glu He Trp Ser 260 265 270 Asp Gly Asp Lys He Lys Val Val Pro Ser Wing Ser Thr Thr Phe Asp 275 280 285 Asn Phe Leu Arg Trp His Ser Ser Asn Leu Gly Lys Lys He His Asp 290 295 300 His Wing Gln Leu Leu Ser Gly He Ser Phe Asn Asn Arg Arg Val Gly 305 310 315 320 Leu Ala Ala Ser Asn Ser Leu Cys Ser Pro Ser Ser Val Ala Val He 325 330 335 Glu Ala Lys Lys Lys Asn Asn Val Ala Leu Val Gly Val Met Ser His 340 345 350 Glu Leu Gly His Val Leu Gly Met Pro Asp Val Pro Phe Asn Thr Lys 355 360 365 Cys Pro Ser Gly Ser Cys Val Met Asn Gln Tyr Leu Ser Ser Lys Phe 370 375 380 Pro Lys Asp Phe Ser Thr Ser Cys Arg Ala His Phe Glu Arg Tyr Leu 385 390 395 400 Leu Ser Gln Lys Pro Lys Cys Leu Leu Gln Wing Pro Pro Thr Asn 405 410 415 He Met Thr Thr Pro Val Cys Gly Asn His Leu Leu Glu Val Gly Glu 420 425 430 Asp Cys Asp Cys Gly Ser Pro Lys Glu Cys Thr Asn Leu Cys Cys Glu 435 440 445 Wing Leu Thr Cys Lys Leu Lys Pro Gly Thr Asp Cys Gly Gly Asp Ala 450 455 460 Pro Asn His Thr Thr Glu 465 470 (2) INFORMATION FOR SEQ ID NO: 3: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 2582 base pairs (B) TYPE: nucleic acid (C) CHAIN TYPE: double (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: cDNA (iii) HYPOTHETIC: No (ix) CHARACTERISTICS: (A) NAME / KEY: CDS (B) LOCATION: 52..2034 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 3: ATTTCTCAGC TCCAAGCATT AGGTAAACCC ACCAAGCAAT CCTAGCCTGT G ATG GCG 57 Met Wing 1 TTT GAC GTC AGC TGC TTC TTT TGG GTG GTG CTG TTT TCT GCC GGC TGT 105 Phe Asp Val Ser Cys Phe Phe Trp Val Val Leu Phe Ser Wing Gly Cys 5 10 15 AAA GTC ATC ACC TCC TGG GAT CAG ATG TGC ATT GAG AAA GAA GCC AAC 153 Lys Val He Thr Ser Trp Asp Gln Met Cys He Glu Lys Glu Ala Asn 20 25 30 AAA ACA TAT AAC TGT GAA AAT TTA GGT CTC AGT GAA ATC CCT GAC ACT 201 Lys Thr Tyr Asn Cys Glu Asn Leu Gly Leu Ser Glu He Pro Asp Thr 35 40 45 50 CTA CCA AAC ACÁ GAA TTT TTG GAA TTC AGC TTT AAT TTT TTG CCT 249 Leu Pro Asn Thr Thr Glu Phe Leu Glu Phe Ser Phe Asn Phe Leu Pro 55 60 65 ACÁ ATT CAC AAT AGA ACC TTC AGC AGA CTC ATG AAT CTT ACC TTT TTG 297 Thr He His Asn Arg Thr Phe Ser Arg Leu Met Asn Leu Thr Phe Leu 70 75 80 GAT TTA ACT AGG TGC CAG ATT AAC TGG ATA CAT GAA GAC ACT TTT CAA 345 Asp Leu Thr Arg Cys Gln He Asn Trp He His Glu Asp Thr Phe Gln 85 90 95 AGC CAT CAT CAA TTA AGC ACÁ CTT GTG TTA ACT GGA AAT CCC CTG ATA 393 Ser His His Gln Leu Ser Thr Leu Val Leu Thr Gly Asn Pro Leu He 100 105 110 TTC ATG GCA GAA ACA TCG CTT AAT GGG CCC AAG TCA CTG AAG CAT CTT 441 Phe Met Wing Glu Thr Ser Leu Asn Gly Pro Lys Ser Leu Lys His Leu 115 120 125 130 TTC TTA ATC CAG ACG GGA ATA TCC AAT CTC GAG TTT ATT CCA GTG CAC 489 Phe Leu He Gln Thr Gly He Ser Asn Leu Glu Phe He Pro Val His 135 140 145 AAT CTG GAA AAC TTG GAA AGC TTG TAT CTT GGA AGC AAC CAT ATT TCC 537 Asn Leu Glu Asn Leu Glu Ser Leu Tyr Leu Gly Ser Asn His He Ser 150 155 160 TCC ATT AAG TTC CCC AAA GAC TTC CCA GCA CGG AAT CTG AAA GTA CTG 585 Be He Lys Phe Pro Lys Asp Phe Pro Wing Arg Asn Leu Lys Val Leu 165 170 175 GAT TTT CAG AAT AAT GCT ATA CAC TAC ATC TCT AGA GAA GAC ATG AGG 633 Asp Phe Gln Asn Asn Wing He His Tyr He Ser Arg Glu Asp Met Arg 180 185 190 TCT CTG GAG CAG GCC ATC AAC CTA AGC CTG AAC TTC AAT GGC AAT AAT 681 Ser Leu Glu Gln Ala He Asn Leu Ser Leu Asn Phe Asn Gly Asn Asn 195 200 205 210 GTT AAA GGT ATT GAG CTT GGG GCT TTT GAT TCA ACG GTC TTC CAA AGT 729 Val Lys Gly He Glu Leu Gly Wing Phe Asp Ser Thr Val Phe Gln Ser 215 220 225 TTG AAC TTT GGA GGA ACT CCA AAT TTG TCT GTT ATA TTC AAT GGT CTG 777 Leu Asn Phe Gly Gly Thr Pro Asn Leu Ser Val He Phe Asn Gly Leu 230 235 240 CAG AAC TCT ACT ACT CAG TCT CTC TGG CTG GGA ACA TTT GAG GAC ATT 825 Gln Asn Ser Thr Thr Gln Ser Leu Trp Leu Gly Thr Phe Glu Asp He 245 250 255 GAT GAC GAA GAT ATT AGT TCA GCC ATG CTC AAG GGA CTC TGT GAA ATG 873 Asp Asp Glu Asp Be Ser Be Wing Met Leu Lys Gly Leu Cys Glu Met 260 265 270 TCT GTT GAG AGC CTC AAC CTG CAG GAA CAC CGC TTC TCT GAC ATC TCA 921 Ser Val Glu Ser Leu Asn Leu Gln Glu His Arg Phe Ser Asp He Ser 275 280 285 290 TCC ACC AC TTT CAG TGC TTC ACC CAA CTC CAA GAA TTG GAT CTG ACÁ 969 Be Thr Thr Phe Gln Cys Phe Thr Gln Leu Gln Glu Leu Asp Leu Thr 295 300 305 GCA ACT CAC TTG AAA GGG TTA CCC TCT GGG ATG AAG GGT CTG AAC TTG 1017 Ala Thr His Leu Lys Gly Leu Pro Ser Gly Met Lys Gly Leu Asn Leu 310 315 320 CTC AAG AAA TTA GTT CTC AGT GTA AAT CAT TTC GAT CAA TTG TGT CAA 1065 Leu Lys Lys Leu Val Leu Ser Val Asn His Phe Asp Gln Leu Cys Gln 325 330 335 ATC AGT GCT GCC AAT TTC CCC TCC CTT AC CAC CTC TAC ATC AGA GGC 1113 I Am Ala Ala Asn Phe Pro Ser Leu Thr His Leu Tyr He Arg Gly 340 345 350 AAC GTG AAG AAA CTT CAC CTT GGT GTT GGC TGC TTG GAG AAA CTA GGA 1161 Asn Val Lys Lys Leu His Leu Gly Val Gly Cys Leu Glu Lys Leu Gly 355 360 365 370 AAC CTT CAG ACÁ CTT GAT TTA AGC CAT AAT GAC ATA GAG GCT TCT GAC 1209 Asn Leu Gln Thr Leu Asp Leu Ser His Asn Asp He Glu Wing As Asp 375 380 385 TGC TGC AGT CTG CAA CTC AAA AAC CTG TCC CAC TTG CAA ACC TTA AAC 1257 Cys Cys Ser Leu Gln Leu Lys Asn Leu Ser His Leu Gln Thr Leu Asn 390 395 400 CTG AGC CAC AAT GAG CCT CTT GGT CTC CAG AGT CAG GCA TTC AAA GAA 1305 Leu Ser His Asn Glu Pro Leu Gly Leu Gln Ser Gln Wing Phe Lys Glu 405 410 415 TGT CCT CAG CTA GAA CTC CTC GAT TTG GCA TTT ACC CGC TTA CAC ATT 1353 Cys Pro Gln Leu Glu Leu Leu Asp Leu Wing Phe Thr Arg Leu His He 420 425 430 AAT GCT CCA CAA AGT CCC TTC CAA AAC CTC CAT TTC CTT CAG GTT CTG 1401 Asn Ala Pro Gln Ser Pro Phe Gln Asn Leu His Phe Leu Gln Val Leu 435 440 445 450 AAT CTC ACT TAC TGC TTC CTT GAT ACC AGC AAT CAG CAT CTT CTA GCA 1449 Asn Leu Thr Tyr Cys Phe Leu Asp Thr Ser Asn Gln His Leu Leu Ala 455 460 465 GGC CTA CCA GTT CTC CGG CAT CTC AAC TTA AAA GGG AAT CAC TTT CAA 1497 Gly Leu Pro Val Leu Arg His Leu Asn Leu Lys Gly Asn His Phe Gln 470 475 480 GAT GGG ACT ATC ACG AAG ACC AAC CTA CTT CAG ACC GTG GGC AGC TTG 1545 Asp Gly Thr He Thr Lys Thr Asn Leu Leu Gln Thr Val Gly Ser Leu 485 490 495 GAG GTT CTG ATT TTG TCC TCT TGT GGT CTC CTC TCT ATA GAC CAG CAA 1593 Glu Val Leu He Leu Be Ser Cys Gly Leu Leu Ser He Asp Gln 500 505 510 GCA TTC CAC AGC TTG GGA AAA ATG AGC CAT GTA GAC TTA AGC CAC AAC 1641 Phe Wing His Ser Leu Gly Lys Met Ser His Val Asp Leu Ser His Asn 515 520 525 530 AGC CTG ACA TGC GAC AGC ATT GAT TCT CTT AGC CAT CTT AAG GGA ATC 1689 Ser Leu Thr Cys Asp Ser He Asp Ser Leu Ser His Leu Lys Gly He 535 540 545 TAC CTC AAT CTG GCT GCC AAC AGC ATT AAC ATC ATC TCA CCC CGT CTC 1737 Tyr Leu Asn Leu Wing Wing Asn Ser He Asn He He Ser Pro Arg Leu 550 555 560 CTC CCT ATC TTG TCC CAG CAG AGC ACC ATT AAT TTA AGT CAT AAC CCC 1785 Leu Pro He Leu Ser Gln Gln Ser Thr He Asn Leu Ser His Asn Pro 565 570 575 CTG GAC TGC ACT TGC TCG AAT ATT CAT TTC TTA ATA TGG TAC AAA GAA 1833 Leu Asp Cys Thr Cys Ser Asn He His Phe Leu Thr Trp Tyr Lys Glu 580 585 590 AAC CTG CAC AAA CTT GAA GGC TCG GAG GAG ACC ACG TGT GCA AAC CCG 1881 Asn Leu His Lys Leu Glu Gly Ser Glu Glu Thr Thr Cys Wing Asn Pro 595 600 605 610 CCA TCT CTA AGG GGA GTT AAG CTA TCT GAT GTC AAG CTT TCC TGT GGG 1929 Pro Ser Leu Arg Gly Val Lys Leu Ser Asp Val Lys Leu Ser Cys Gly 615 620 625 ATT ACÁ GCC ATA GGC ATT TTC TTT CTC ATA GTA TTT CTA TTA TTG TTG 1977 He Thr Wing He Gly He Phe Phe Leu He Val Phe Leu Leu Leu Leu 630 635 640 GCT ATT CTG CTA TTT TTT GCA GTT AAA TAC CTT CTC AGG TGG AAA TAC 2025 Wing He Leu Leu Phe Phe Wing Val Lys Tyr Leu Leu Arg Trp Lys Tyr 645 650 655 CAA CAC ATT TAGTGCTGAA GGTTTCCAGA GAAAGCAAAT AAGTGTGCTT 2074 Gln His He 660 AGCAAAATTG CTCTAAGTGA AAGAACTGTC ATCTGCTGGT GACCAGACCA GACTTTTCAG 2134 ATTGCTTCCT GGAACTGGGC AGGGACTCAC TGTGCTTTTC TGAGCTTCTT ACTCCTGTGA 2194 GTCCCAGAGC TAAAGAACCT TCTAGGCAAG TACACCGAAT GACTCAGTCC AGAGGGTCAG 2254 ATGCTGCTGT GAGAGGCACA GAGCCCTTTC CGCATGTGGA AGAGTGGGAG GAAGCAGAGG 2314 GAGGGACTGG GCAGGGACTG CCGGCCCCGG AGTCTCCCAC AGGGAGGCCA TTCCCCTTCT 2374 ACTCACCGAC ATCCCTCCCA GCACCACACA CCCCGCCCCT GAAAGGAGAT CATCAGCCCC 2434 CACAATTTGT CAGAGCTGAA GCCAGCCCAC TACCCACCCC CACTACAGCA TTGTGCTTGG 2494 GTCTGGGTTC TCAGTAATGT AGCCATTTGA GAAACTTACT TGGGGACAAA GTCTCAATCC 2554 TTATTTTAAA TGAAAAAAAA AAAAAAAA 2582 (2) INFORMATION FOR SEQ ID NO: 4: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 661 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: protein (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 4: Met Ala Phe Asp Val Ser Cys Phe Phe Trp Val Val Leu Phe Ser Ala 1 5 10 15 Gly Cys Lys Val He Thr Ser Trp Asp Gln Met Cys He Glu Lys Glu 20 25 30 Wing Asn Lys Thr Tyr Asn Cys Glu Asn Leu Gly Leu Ser Glu He Pro 35 40 45 Asp Thr Leu Pro Asn Thr Thr Glu Phe Leu Glu Phe Ser Phe Asn Phe 50 55 60 Leu Pro Thr He His Asn Arg Thr Phe Ser Arg Leu Met Asn Leu Thr 65 70 75 80 Phe Leu Asp Leu Thr Arg Cys Gln He Asn Trp He His Glu Asp Thr 85 90 95 Phe Gln Ser His His Gln Leu Ser Thr Leu Val Leu Thr Gly Asn Pro 100 105 110 Leu He Phe Met Wing Glu Thr Ser Leu Asn Gly Pro Lys Ser Leu Lys 115 120 125 His Leu Phe Leu He Gln Thr Gly He Ser Asn Leu Glu Phe He Pro 130 135 140 Val His Asn Leu Glu Asn Leu Glu Ser Leu Tyr Leu Gly Ser Asn His 145 150 155 160 He Be Ser He Lys Phe Pro Lys Asp Phe Pro Wing Arg Asn Leu Lys 165 170 175 Val Leu Asp Phe Gln Asn Asn Ala He His Tyr He Ser Arg Glu Asp 180 185 190 Met Arg Ser Leu Glu Gln Wing He Asn Leu Ser Leu Asn Phe Asn Gly 195 200 205 Asn Asn Val Lys Gly He Glu Leu Gly Wing Phe Asp Ser Thr Val Phe 210 215 220 Gln Ser Leu Asn Phe Gly Gly Thr Pro Asn Leu Ser Val He Phe Asn 225 230 235 240 Gly Leu Gln Asn Ser Thr Thr Gln Ser Leu Trp Leu Gly Thr Phe Glu 245 250 255 Asp Asp Asp Asp Glu Asp Be Ser Wing Met Leu Lys Gly Leu Cys 260 265 270 Glu Met Ser Val Glu Ser Leu Asn Leu Gln Glu His Arg Phe Ser Asp 275 280 285 He Be Ser Thr Thr Phe Gln Cys Phe Thr Gln Leu Gln Glu Leu Asp 290 295 300 Leu Thr Ala Thr His Leu Lys Gly Leu Pro Ser Gly Met Lys Gly Leu 305 310 315 320 Asn Leu Leu Lys Lys Leu Val Leu Ser Val Asn His Phe Asp Gln Leu 325 330 335 Cys Gln He Ser Ala Ala Asn Phe Pro Ser Leu Thr His Leu Tyr He 340 345 350 Arg Gly Asn Val Lys Lys Leu His Leu Gly Val Gly Cys Leu Glu Lys 355 360 365 Leu Gly Asn Leu Gln Thr Leu Asp Leu Ser His Asn Asp He Glu Wing 370 375 380 Ser Asp Cys Cys Ser Leu Gln Leu Lys Asn Leu Ser His Leu Gln Thr 385 390 395 400 Leu Asn Leu Ser His Asn Glu Pro Leu Gly Leu Gln Ser Gln Wing Phe 405 410 415 Lys Glu Cys Pro Gln Leu Glu Leu Leu Asp Leu Wing Phe Thr Arg Leu 420 425 430 His He Asn Wing Pro Gln Ser Pro Phe Gln Asn Leu His Phe Leu Gln 435 440 445 Val Leu Asn Leu Thr Tyr Cys Phe Leu Asp Thr Ser Asn Gln His Leu 450 455 460 Leu Wing Gly Leu Pro Val Leu Arg His Leu Asn Leu Lys Gly Asn His 465 470 475 480 Phe Gln Asp Gly Thr He Thr Lys Thr Asn Leu Leu Gln Thr Val Gly 485 490 495 Ser Leu Glu Val Leu He Leu Ser Ser Cys Gly Leu Leu Ser He Asp 500 505 510 Gln Gln Wing Phe His Ser Leu Gly Lys Met Ser His Val Asp Leu Ser 515 520 525 His Asn Ser Leu Thr Cys Asp Ser He Asp Ser Leu Ser His Leu Lys 530 535 540 Gly He Tyr Leu Asn Leu Wing Ala Asn Ser He Asn He He Ser Pro 545 550 555 560 Arg Leu Leu Pro He Leu Ser Gln Gln Ser Thr He Asn Leu Ser His 565 570 575 Asn Pro Leu Asp Cys Thr Cys Ser Asn He His Phe Leu Thr Trp Tyr 580 585 590 Lys Glu Asn Leu His Lys Leu Glu Gly Ser Glu Glu Thr Thr Cys Ala 595 600 605 Asn Pro Pro Ser Leu Arg Gly Val Lys Leu Ser Asp Val Lys Leu Ser 610 615 620 Cys Gly He Thr Wing He Gly He Phe Phe Leu He Val Phe Leu Leu 625 630 635 640 Leu Leu Ala He Leu Leu Phe Phe Ala Val Lys Tyr Leu Leu Arg Trp 645 650 655 Lys Tyr Gln His He 660 (2) INFORMATION FOR SEQ ID NO: 5: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 588 base pairs (B) TYPE: nucleic acid (C) CHAIN TYPE: double (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: cDNA (iii) HYPOTHETIC: NO (ix) CHARACTERISTICS: (A) NAME / KEY: CDS (B) LOCATION: 76..474 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 5 : CGGCCAAAGA GGCCTAAACT TGCGGCTGTC CATCTCACCT ACAGCTCTGG TCTCATCCTC 60CAATC ATG GCT CAG ATG ATG ACT CTG AGC CTC CTT AGC CTG 11 Met Wing Gln Met Met Thr Leu Ser Leu Leu Ser Leu 1 5 10 GTC CTG GCT CTC TGC ATC CCC TGG ACC CAA GGC AGT GAT GGA GGG GGT 159 Val Leu Wing Leu Cys He Pro Trp Thr Gln Gly Ser Asp Gly Gly Gly 15 20 25 CAG GAC TGC CTT AAG TAC AGC CAG AAA AAA ATT CCC TAC AGT ATT 207 Gln Asp Cys Cys Leu Lys Tyr Ser Gln Lys Lys He Pro Tyr Ser He 30 35 40 GTC CGA GGC TAT AGG AAG CAA GAA CCA AGT TTA GGC TGT CCC ATC CCG 255 Val Arg Gly Tyr Arg Lys Gln Glu Pro Ser Leu Gly Cys Pro He Pro 45 50 55 60 GCA ATC CTG TTC TCA CCC CGG AAG CAC TCT AAG CCT GAG CTA TGT GCA 303 Ala He Leu Phe Ser Pro Arg Lys His Ser Lys Pro Glu Leu Cys Wing 65 70 75 AAC CCT GAG GAA GGC TGG GTG CAG AAC CTG ATG CGC CGC CTG GAC CAG 351 Asn Pro Glu Glu Gly Trp Val Gln Asn Leu Met Arg Arg Leu Asp Gln 80 85 90 CCT CCA GCC CCA GGG AAA CAA AGC CCC GGC TGC AGG AAG AAC CGG GGA 399 Pro Pro Pro Wing Gly Lys Gln Pro Pro Gly Cys Arg Lys Asn Arg Gly 95 100 105 ACC TCT AAG TCT GGA AAG AAA GGA AAG GGC TCC AAG GGC TGC AAG AGA 447 Thr Ser Lys Ser Gly Lys Lys Gly Lys Gly Ser Lys Gly Cys Lys Arg 110 115 120 ACT GAA CAG ACÁ CAG CCC TCA AGA GGA TAGCCCAGTA GCCCGCCTGG 494 Thr Glu Gln Thr Gln Pro Ser Arg Gly 125 130 AGCCCAGGAG ATCCCCCACG AACTTCAAGC TGGGTGGTTC ACGGTCCAAC TCACAGGCAA 554 AGAGGGAGCT AGAAAACAGA CTCAGGAGCC GCTA '588 (2) INFORMATION FOR SEQ ID NO: 6: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 133 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: protein (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 6: Met Wing Gln Met Met Thr Leu Ser Leu Leu Ser Leu Val Leu Ala Leu 1 5 10 15 Cys He Pro Trp Thr Gln Gly Ser Asp Gly Gly Gln Gln Asp Cys Cys 20 25 30 Leu Lys Tyr Ser Gln Lys Lys He Pro Tyr Ser He Val Arg Gly Tyr 35 40 45 Arg Lys Gln Glu Pro Ser Leu Gly Cys Pro He Pro Wing He Leu Phe 50 55 60 Ser Pro Arg Lys His Ser Lys Pro Glu Leu Cys Ala Asn Pro Glu Glu 65 70 75 80 Gly Trp Val Gln Asn Leu Met Arg Arg Leu Asp Gln Pro Pro Pro Wing 85 90 95 Gly Lys Gln Ser Pro Gly Cys Arg Lys Asn Arg Gly Thr Ser Lys Ser 100 105 110 Gly Lys Lys Gly Lys Gly Ser Lys Gly Cys Lys Arg Thr Glu Gln Thr 115 120 125 Gln Pro Ser Arg Gly 130 (2) INFORMATION FOR SEQ ID NO: 7: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 966 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: double (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: cDNA (iii) HYPOTHETIC: NO (ix) CHARACTERISTICS: (A) NAME / KEY: CDS (B) LOCATION: 67..348 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 7: CTTCCAAGAA GAGCAGCAAA GCTGAAGTAG CAGCAACAGC ACCAGCAGCA ACAGCAAAAA 60 ACAAAC ATG AGT GTG AAG GGC ATG GCT ATA GCC TTG GCT GTG ATA TTG 108 Met Ser Val Lys Gly Met Wing Wing Wing Leu Wing Val He Leu 1 5 10 TGT GCT ACE GTT GTT CAA GGC TTC CCC ATG TTC AAA AGA GGA CGC TGT 156 Cys Ala Thr Val Val Gln Gly Phe Pro Met Phe Lys Arg Gly Arg Cys 15 20 25 30 CTT TGC ATA GGC CCT GGG GTA AAA GCA GTG AAA GTG GCA GAT ATT GAG 204 Leu Cys He Gly Pro Gly Val Lys Wing Val Lys Val Wing Asp He Glu 35 40 45 AAA GCC TCC ATA ATG TAC CCA AGT AAC AAC TGT GAC AAA ATA GAA GTG 252 Lys Wing Ser Met Met Tyr Pro Ser Asn Asn Cys Asp Lys He Glu Val 50 55 60 ATT ATT ACC CTG AAA GAA AAT AAA GGA CAGA CGA TGC CTA AAT CCC AAA 300 He He Thr Leu Lys Glu Asn Lys Gly Gln Arg Cys Leu Asn Pro Lys 65 70 75 TCG AAG CAA GCA AGG CTT ATA ATC AAA AAA GTT GAA AGA AAG AAT TTT 348 Ser Lys Gln Wing Arg Leu He He Lys Lys Val Glu Arg Lys Asn Phe 80 85 90 TAAAAATATC AAAACATATG AAGTCCTGGA AAAGGGCATC TGAAAAACCT AGAACAAGTT 408 TAACTGTGAC TACTGAAATG ACAAGAATTC TACAGTAGGA AACTGAGACT TTTCTATGGT 468 TTTGTGACTT TCAACTTTTG TACAGTTATG TGAAGGATGA AAGGTGGGTG AAAGGACCAA 528 AAACAGAAAT ACAGTCTTCC TGAATGAATG ACAATCAGAA TTCCACTGCC CAAAGGAGTC 588 CAACAATTAA ATGGATTTCT AGGAAAAGCT ACCTTAAGAA AGGCTGGTTA CCATCGGAGT 648 TTACAAAGTG CTTTCACGTT CTTACTTGTT GTATTATACA TTCATGCATT TCTAGGCTAG_708_AGAACCTTCT AGATTTGATG CTTACAACTA TTCTGTTGTG ACTATGAGAA CATTTCTGTC 768 TCTAGAAGTT ATCTGTCTGT ATTGATCTTT ATGCTATATT ACTATCTGTG GTTACAGTGG 828 AGACATTGAC ATTATTACTG GAGTCAAGCC CTTATAAGTC AAAAGCACCT ATGTGTCGTA 888 AAGCATTCCT CAAACATTTA AAAAAAAAAA AAAAAAAAAA AAAAAAAAAA AAAAAAAAAAA 948 AAAAAAAAAA AAAAAAAA 966 (2) INFORMATION FOR SEQ ID NO: 8: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 94 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: protein (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 8: Met Ser Val Lys Gly Met Ala He Ala Leu Ala Val He Leu Cys Ala 1 5 10 15 Thr Val Val Gln Gly Phe Pro Met Phe Lys Arg Gly Arg Cys Leu Cys 20 25 30 He Gly Pro Gly Val Lys Wing Val Lys Val Wing Asp He Glu Lys Wing 35 40 45 Ser He Met Tyr Pro Ser Asn Asn Cys Asp Lys He Glu Val He He 50 55 60 Thr Leu Lys Glu Asn Lys Gly Gln Arg Cys Leu Asn Pro Lys Ser Lys 65 70 75 80 Gln Ala Arg Leu He He Lys Lys Val Glu Arg Lys Asn Phe 85 90 (2) INFORMATION FOR SEQ ID NO: 9: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 1354 base pairs (B) TYPE: nucleic acid (C) CHAIN TYPE: double (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: cDNA (iii) HYPOTHETIC: NO (ix) CHARACTERISTICS: (A) NAME / KEY: CDS (B) LOCATION: 75..356 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 9: TTCTACTCCT TCCAAGAAGA GCAGCAAAGC TGAAGTAGCA GCAACAGCAC CAGCAGCAAC 60 AGCAAAAAAC AAAC ATG AGT GTG AAG GGC ATG GCT ATA GCC TTG GCT GTG 110 Met Ser Val Lys Gly Met Ala He Ala Leu Ala Val 1 5 10 ATA TTG TGT GCT ACA GTT GTT CAA GGC TTC CCC ATG TTC AAA AGA GGA 158 He Leu Cys Wing Thr Val Val Gln Gly Phe Pro Met Phe Lys Arg Gly 15 20 25 CGC TGT CTT TGC ATA GGC CCT GGG GTA AAA GCA GTG AAA GTG GCA GAT 206 Arg Cys Leu Cys He Gly Pro Gly Val Lys Wing Val Lys Val Wing Asp 30 35 40 ATT GAG AAA GCC TCC ATA ATG TAC CCA AGT AAC AAC TGT GAC AAA ATA 254 He Glu Lys Wing Being He Met Tyr Pro Being Asn Asn Cys Asp Lys He 45 50 55 60 GAA GTG ATT ATT ACC CTG AAA GAA AAT AAA GGA CAA CGA TGC CTA AAT 302 Glu Val He He Thr Leu Lys Glu Asn Lys Gly Gln Arg Cys Leu Asn 65 70 75 CCC AAA TCG AAG CAA GCA AGG CTT ATA ATC AAA AAA GTT GAA AGA AAG 350 Pro Lys Ser Lys Gln Wing Arg Leu He He Lys Lys Val Glu Arg Lys 80 85 90 AAT TTT TAAAAATATC AAAACATATG AAGTCCTGGA AAAGGGCATC TGAAAAACCT 406 Asn Phe AGAACAAGTT TAACTGTGAC TACTGAAATG ACAAGAATTC TACAGTAGGA AACTGAGACT 466 TTTCTATGGT TTTGTGACTT TCAACTTTTG TACAGTTATG TGAAGGATGA AAGGTGGGTG 526 AAAGGACCAA AAACAGAAAT ACAGTCTTCC TGAATGAATG ACAATCAGAA TTCCACTGCC 586 CAAAGGAGTC CAACAATTAA ATGGATTTCT AGGAAAAGCT ACCTTAAGAA AGGCTGGTTA 646 CCATCGGAGT TTACAAAGTG CTTTCACGTT CTTACTTGTT GTATTATACA TTCATGCATT 706 TCTAGGCTAG AGAACCTTCT AGATTTGATG CTTACAACTA TTCTGTTGTG ACTATGAGAA 766 CATTTCTGTC TCTAGAAGTT ATCTGTCTGT ATTGATCTTT ATGCTATATT ACTATCTGTG 826 GTTACAGTGG AGACATTGAC ATTATTACTG GAGTCAAGCC CTTATAAGTC AAAAGCACCT 886 ATGTGTCGTA AAGCATTCCT CAAACATTTT TTCATGCAAA TACACACTTC TTTCCCCAAA 946 TATCATGTAG CACATCAATA TGTAGGGAAA CATTCTTATG CATCATTTGG TTTGTTTTAT 1006 AACCAATTCA TTAAATGTAA TTCATAAAAT GTACTATGAA AAAAATTATA CGCTATGGGA 1066 TACTGGCAAC AGTGCACATA TTTCATAACC AAATTAGCAG CACCGGTCTT AATTTGATGT 1126 TTTTCAACTT TTATTCATTG AGATGTTTTG AAGCAATTAG GATATGTGTG TTTACTGTAC 1186 TTTTTTTTTTT GATCCGTTTG TATAAATGAT AGCAATATCT TGGACACATT TGAAATACAA 1246 AATGTTTTTG TCTACCAAAG AAAAATGTTG AAAAATAAGC AAATGTATAC CTAGCAATCA 1306 CTTTTTACTTT TTGTAATTCT GTCTCTTAGA AAAATACATA ATCTAATT 1354 (2) INFORMATION FOR THE SEQUENCE SEQ ID NO: 10: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 94 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: protein (xi) ) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 10: Met Ser Val Lys Gly Met Ala He Ala Leu Ala Val He Leu Cys Ala 1 5 10 15 Thr Val Val Gln Gly Phe Pro Met Phe Lys Arg Gly Arg Cys Leu Cys 20 25 30 He Gly Pro Gly Val Lys Wing Val Lys Val Wing Asp He Glu Lys Wing 35 40 45 Ser He Met Tyr Pro Ser Asn Asn Cys Asp Lys He Glu Val He He 50 55 60 Thr Leu Lys Glu Asn Lys Gly Gln Arg Cys Leu Asn Pro Lys Ser Lys 65 70 75 80 Gln Ala Arg Leu He He Lys Lys Val Glu Arg Lys Asn Phe 85 90 (2) INFORMATION FOR SEQ ID NO: 11: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 813 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: double (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: cDNA (iii) HYPOTHETIC: NO (ix) CHARACTERISTICS: (A) NAME / KEY: CDS (B) LOCATION: 86.544 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 11: GGGAAGATAC ATTCACAGAA AGAGCTTCCT GCACX "GTA AGCCACCAGC GCAACATGAC 60 AGTGAAGACC CTGCATGGCC CAGCC ATG GTC AAG TAC TTG CTG CTG TCG ATA 112 Met Val Lys Tyr Leu Leu Leu Ser He 1 5 TTG GGG CTT GCC TTT CTG AGT GAG GCG GCA GCT CGG AAA ATC CCC AAA 160 Leu Gly Leu Wing Phe Leu Ser Glu Wing Wing Arg Lys He Pro Lys 10 15 20 25 GTA GGA CAT ACT TTT TTC CAA AAG CCT GAG AGT TGC CCG CCT GTG CCA 208 Val Gly His Thr Phe Phe Gln Lys Pro Glu Ser Cys Pro Pro Val Pro 30 35 40 GGA GGT AGT ATG AAG CTT GAC ATT GGC ATC ATC AAT GAA AAC CAG CGC 256 Gly Gly Ser Met Lys Leu Asp He Gly He He Asn Glu Asn Gln Arg 45 50 55 GTT TCC ATG TCA CGT AAC ATC GAG AGC CGC TCC ACC TCC CCC TGG AAT 304 Val Ser Met Ser Arg Asn He Glu Ser Arg Ser Thr Ser Pro Trp Asn 60 65 70 TAC ACT GTC ACT TGG GAC CCC AAC CGG TAC CCC TCG GAA GTT GTA CAG 352 Tyr Thr Val Thr Trp Asp Pro Asn Arg Tyr Pro Ser Glu Val Val Gln 75 80 85 GCC CAG TGT AGG AAC TTG GGC TGC ATC AAT GCT CAA GGA AAG GAA GAC 400 Wing Gln Cys Arg Asn Leu Gly Cys He Asn Wing Gln Gly Lys Glu Asp 90 95 100 105 ATC TCC ATG AAT TCC GTT CCC ATC CAG CAA GAG ACC CTG GTC GTC CGG 448 He Ser Met Asn Ser Val Pro He Gln Gln Glu Thr Leu Val Val Arg 110 115 120 AGG AAG CAC CAA GGC TGC TCT GTT TCT TTC CAG TTG GAG AAG GTG CTG 496 Arg Lys His Gln Gly Cys Ser Val Ser Phe Gln Leu Glu Lys Val Leu 125 130 135 GTG ACT GTT GGC TGC ACC TGC GTC ACC CCT GTC ATC CAC CAT GTG CAG 544 Val Thr Val Gly Cys Thr Cys Val Thr Pro Val He His His Val Gln 140 145 150 TAAGAGGTGC ATATCCACTC AGCTGAAGAA GCTGTAGAAA TGCCACTCCT TACCCAGTGC 604 TCTGCAACAA GTCCTGTCTG ACCCCCAATT CCCTCCACTT CACAGGACTC TTAATAAGAC 664 CTGCACGGAT GGAAACAGAA AATATTCACA ATGTATGTGT GTATGTACTA CACTTTATAT 724 TTGATATCTA AAATGTTAGG AGAAAAATTA ATATATTCAG TGCTAATATA ATAAAGTATT 784 AATAATTTAA AAATAAAAAA AAAAAAAAA 813 (2) INFORMATION FOR SEQ ID NO: 12: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 153 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: protein (xi) DESCRIPTION OF SEQUENCE: SEQ ID NO: 12: Met Val Lys Tyr Leu Leu Leu Ser He Leu Gly Leu Ala Phe Leu Ser 1 5 10 15 Glu Ala Ala Ala Arg Lys He Pro Lys Val Gly His Thr Phe Phe Gln 20 25 30 Lys Pro Glu Ser Cys Pro Pro Val Pro Gly Gly Ser Met Lys Leu Asp 35 40 45 He Gly He He Asn Glu Asn Gln Arg Val Ser Met Ser Arg Asn He 50 55 60 Glu Ser Arg Ser Thr Ser Pro Trp Asn Tyr Thr Val Thr Trp Asp Pro 65 70 75 80 Asn Arg Tyr Pro Ser Glu Val Val Gln Wing Gln Cys Arg Asn Leu Gly 85 90 95 Cys He Asn Wing Gln Gly Lys Glu Asp He Ser Met Asn Ser Val Pro 100 105 110 He Gln Gln Glu Thr Leu Val Val Arg Arg Lys His Gln Gly Cys Ser 115 120 125 Val Ser Phe Gln Leu Glu Lys Val Leu Val Thr Val Gly Cys Thr Cys 130 135 140 Val Thr Pro Val He His His Val Gln 145 150

Claims (60)

1. Novelty of the Invention 1. A composition comprising an isolated polynucleotide, selected from the group consisting of: (a) a polynucleotide comprising the nucleotide sequence of SEQ ID NO: 1 from nucleotide 38 to nucleotide 1447; (b) a polynucleotide comprising a fragment of the nucleotide sequence of SEQ ID NO: 1 encoding a protein having biological activity; (c) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO: 2; (d) a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID NO: 2 having biological activity; (e) a polynucleotide that is an allelic variant of SEQ ID NO: 1; and (f) a polynucleotide capable of hybridizing under stringent conditions to any one of the polynucleotides specified in (a) - (e).
2. 2. A composition of claim 1, wherein said polynucleotide is operably linked to an expression control sequence.
3. 3. A host cell transformed with a composition of claim 2.
4. 4. The host cell of claim 3, wherein said cell is a mammalian cell.
5. 5. A process for producing a protein, wherein said process comprises the steps of: (a) growing a culture of the host cell of claim 3 in an appropriate culture medium; and (b) purifying the protein from said culture medium.
6. 6. A protein produced according to the process of claim 5.
7. 7. A composition comprising a protein, wherein said protein comprises an amino acid sequence selected from the group consisting of: (a) the amino acid sequence of SEQ ID NO: 2; (b) fragments of the amino acid sequence of SEQ ID NO: 2; the protein being substantially free of other mammalian proteins.
8. 8. The composition of claim 7, further comprising a pharmaceutically acceptable carrier.
9. 9. A composition comprising an antibody that specifically reacts with the protein of claim 7.
10. 10. A method for preventing, treating or ameliorating a medical condition, which comprises administering to a mammalian subject a therapeutically effective amount of a composition of claim 8.
11. 11. A composition comprising an isolated polynucleotide, selected from the group consisting of: (a) a polynucleotide comprising the nucleotide sequence of SEQ ID NO: 3 from nucleotide 52 to nucleotide 2034; (b) a polynucleotide comprising a fragment of the nucleotide sequence of SEQ ID NO: 3 encoding a protein having biological activity; (c) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO: 4; (d) a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID NO: 4 having biological activity; (e) a polynucleotide that is an allelic variant of SEQ ID NO: 4; and (f) a polynucleotide capable of hybridizing under stringent conditions to any one of the polynucleotides specified in (a) - (e).
12. 12. A composition of claim 11, wherein said polynucleotide is operably linked to an expression control sequence.
13. 13. A host cell transformed with a composition of claim 12.
14. 14. The host cell of claim 13, wherein said cell is a mammalian cell.
15. 15. A process for producing a protein, wherein said process comprises the steps of: (a) growing a culture of the host cell of claim 13 in an appropriate culture medium; and (b) purifying the protein from said culture medium.
16. 16. A protein produced in accordance with the process of claim 15.
17. 17. A composition comprising a protein, wherein said protein comprises an amino acid sequence selected from the group consisting of: (a) the amino acid sequence of SEQ ID NO: 4; and (b) fragments of the amino acid sequence of SEQ ID NO: 4; the protein being substantially free of other mammalian proteins.
18. 18. The composition of claim 17, further comprising a pharmaceutically acceptable carrier.
19. 19. A composition comprising an antibody that specifically reacts with the protein of claim 17.
20. 20. A method for preventing, treating or improving a medical condition, which comprises administering to a mammalian subject a therapeutically effective amount of a composition of claim 18.
21. 21. A composition comprising an isolated polynucleotide, selected from the group consisting of: (a) a polynucleotide comprising the nucleotide sequence of SEQ ID NO: 5 from nucleotide 76 to nucleotide 474; (b) a polynucleotide comprising a fragment of the nucleotide sequence of SEQ ID NO: 5 which codes for a protein having biological activity; (c) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO: 6; (d) a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID NO: 6 having biological activity; (e) a polynucleotide that is an allelic variant of SEQ ID NO: 5; and (f) a polynucleotide capable of hybridizing under stringent conditions to any one of the polynucleotides specified in (a) - (e).
22. 22. A composition of claim 21, wherein said polynucleotide is operatively linked to an expression control sequence.
23. 23. A host cell transformed with a composition of claim 22.
24. 24. The host cell of claim 23, wherein said cell is a mammalian cell.
25. 25. A process for producing a protein, wherein said process comprises the steps of: (a) growing a culture of the host cell of claim 23 in an appropriate culture medium; and (b) purifying the protein from said culture medium.
26. 26. A protein produced according to the process of claim 25.
27. 27. A composition comprising a protein, wherein said protein comprises an amino acid sequence selected from the group consisting of: (a) the amino acid sequence of SEQ ID NO: 6; (b) fragments of the amino acid sequence of SEQ ID NO: 6; the protein being substantially free of other mammalian proteins.
28. 28. The composition of claim 27, further comprising a pharmaceutically acceptable carrier.
29. 29. A composition comprising an antibody that specifically reacts with the protein of claim 27.
30. 30. A method for preventing, treating or ameliorating a medical condition, which comprises administering to a mammalian subject a therapeutically effective amount of a composition of claim 28.
31. 31. A composition comprising an isolated polynucleotide, selected from the group consisting of: (a) a polynucleotide comprising the nucleotide sequence of SEQ ID NO: 7 from nucleotide 67 to nucleotide 348; (b) a polynucleotide comprising a fragment of the nucleotide sequence of SEQ ID NO: 7 encoding a protein having biological activity; (c) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO: 8; (d) a polynucleotide that encodes a protein comprising a fragment of the amino acid sequence of SEQ ID NO: 8 having biological activity; (e) a polynucleotide that is an allelic variant of SEQ ID NO: 7; and (f) a polynucleotide capable of hybridizing under stringent conditions to any one of the polynucleotides specified in (a) - (e).
32. 32. A composition of claim 31, wherein said polynucleotide is operably linked to an expression control sequence.
33. 33. A host cell transformed with a composition of claim 32.
34. 34. The host cell of claim 33, wherein said cell is a mammalian cell.
35. 35. A process for producing a protein, wherein said process comprises the steps of: (a) growing a culture of the host cell of claim 33 in an appropriate culture medium; and (b) purifying the protein from said culture medium.
36. 36. A protein produced according to the process of claim 35.
37. 37. A composition comprising a protein, wherein said protein comprises an amino acid sequence selected from the group consisting of: (a) the amino acid sequence of SEQ ID NO: 8; (b) fragments of the amino acid sequence of SEQ ID NO: 8; the protein being substantially free of other mammalian proteins.
38. 38. The composition of claim 37, further comprising a pharmaceutically acceptable carrier.
39. 39. A composition comprising an antibody that specifically reacts with the protein of claim 37.
40. 40. A method for preventing, treating or ameliorating a medical condition, which comprises administering to a mammalian subject a therapeutically effective amount of a composition of claim 38.
41. 41. A composition comprising an isolated polynucleotide, selected from the group consisting of: (a) a polynucleotide comprising the nucleotide sequence of SEQ ID NO: 9 from nucleotide 75 to nucleotide 356; (b) a polynucleotide comprising a fragment of the nucleotide sequence of SEQ ID NO: 9 which codes for a protein having biological activity; (c) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO: 10; (d) a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID NO: 10 having biological activity; (e) a polynucleotide that is an allelic variant of SEQ ID NO: 9; and (f) a polynucleotide capable of hybridizing under stringent conditions to any one of the polynucleotides specified in (a) - (e).
42. 42. A composition of claim 41, wherein said polynucleotide is operatively linked to an expression control sequence.
43. 43. A host cell transformed with a composition of claim 42.
44. 44. The host cell of claim 43, wherein said cell is a mammalian cell.
45. 45. A process for producing a protein, wherein said process comprises the steps of: (a) growing a culture of the host cell of claim 43 in an appropriate culture medium; and (b) purifying the protein from said culture medium.
46. 46. A protein produced according to the process of claim 45.
47. 47. A composition comprising a protein, wherein said protein comprises an amino acid sequence selected from the group consisting of: (a) the amino acid sequence of SEQ ID NO: 10; (b) fragments of the amino acid sequence of SEQ ID NO: 10; the protein being substantially free of other mammalian proteins.
48. 48. The composition of claim 47, further comprising a pharmaceutically acceptable carrier.
49. 49. A composition comprising an antibody that specifically reacts with the protein of claim 47.
50. 50. A method for preventing, treating or ameliorating a medical condition, which comprises administering to a mammalian subject a therapeutically effective amount of a composition of claim 48.
51. 51. A composition comprising an isolated polynucleotide, selected from the group consisting of: (a) a polynucleotide comprising the nucleotide sequence of SEQ ID NO: 11 from nucleotide 86 to nucleotide 544; (b) a polynucleotide comprising a fragment of the nucleotide sequence of SEQ ID NO: 11 which codes for a protein having biological activity; (c) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO: 12; (d) a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID NO: 12 having biological activity; (e) a polynucleotide that is an allelic variant of SEQ ID NO: 11; and (f) a polynucleotide capable of hybridizing under stringent conditions to any one of the polynucleotides specified in (a) - (e).
52. 52. A composition of claim 51, wherein said polynucleotide is operatively linked to an expression control sequence.
53. 53. A host cell transformed with a composition of claim 52.
54. 54. The host cell of claim 53, wherein said cell is a mammalian cell.
55. 55. A process for producing a protein, wherein said process comprises the steps of: (a) growing a culture of the host cell of claim 53 in an appropriate culture medium; and (b) purifying the protein from said culture medium.
56. 56. A protein produced according to the process of claim 55.
57. ..57. A composition comprising a protein, wherein said protein comprises an amino acid sequence selected from the group consisting of: (a) the amino acid sequence of SEQ ID NO: 12; (b) fragments of the amino acid sequence of SEQ ID NO: 12; the protein being substantially free of other mammalian proteins.
58. 58. The composition of claim 57, further comprising a pharmaceutically acceptable carrier.
59. 59. A composition comprising an antibody that specifically reacts with the protein of claim 57.
60. 60. A method for preventing, treating or ameliorating a medical condition, which comprises administering to a mammalian subject a therapeutically effective amount of a composition of claim 58. Extract of the Description New polynucleotides and proteins encoded by said polynucleotides are disclosed and provided; together with therapeutic, diagnostic and research utilities for and of such polynucleotides and proteins.