NUCLEOTIDE AND PROTEIN SEQUENCES OF LATS GENES AND METHODS BASED THEREON

Abstract: The present invention relates to a tumor suppressor gene, termed large tumor suppressor (lats), and methods for identifying tumor suppressor genes. The method provides nucleotide sequences of lats genes, and amino acid sequences of their encoded proteins, as well as derivatives (e.g., fragments) and analogs thereof. In a specific embodiment, the lats protein is a human protein. The invention further relates to fragments (and derivatives and analogs thereof) of lats which comprise one or more domains of a lats protein. Antibodies to lats, its derivatives and analogs, are additionally provided. Methods of production of the lats proteins, derivatives and analogs, e.g., by recombinant means, are also provided. Therapeutic and diagnostic methods and pharmaceutical compositions are provided. The invention also relates to recombinant plants and animals and methods of increasing the growth of edible plants and animals. In specific examples, isolated lats genes, from Drosophila, mouse, and human, and the sequences thereof, are provided.

Description: NUCLEOTIDE AND PROTEIN SEQUENCES OF LATS GENES AND METHODS BASED THEREON 1. INTRODUCTION This application is a continuation-in-part of copending application Serial No. 08/411,111 filed March 27, 1995, which is incorporated by reference herein in its entirety. The present invention relates to tumor suppressor genes, in particular to "lats" genes (large tumor suppressor) and their encoded protein products, as well as derivatives and analogs thereof. Production of lats proteins, derivatives, and antibodies is also provided. The invention further relates to therapeutic compositions and methods of diagnosis and therapy. 2. BACKGROUND OF THE INVENTION Tumorigenesis in humans is a complex process involving activation of oncogenes and inactivation of tumor suppressor genes (Bishop, 1991, Cell 64:235-248). Tumor suppressor genes in humans have been identified through studies of genetic changes occurring in cancer cells (Ponder, 1990, Trends Genet. 6:213-218; Weinberg, 1991, Science 254:1138-1146). In Drosophila , tumor suppressor genes have been previously identified by recessive overproliferation mutations that cause late larval and pupal lethality (Gateff, 1978, Science 200:1448-1459; Gateff and Mechler, 1989, CRC Crit. Rev. Oncogen 1:221-245; Bryant, 1993, Trends Cell Biol. 3:31-35; Tόrόk et al., 1993, Genetics 135:71-80). Mutations of interest were identified when dissection of dead larvae and pupae revealed certain overproliferated tissues. Several genes identified in homozygous mutants have been cloned including 1 (1) discs large-l (dlg ; Woods and Bryant, 1991, Cell 66:451-464; Woods and Bryant, 1993, Mechanisms of Development 44:85-89), fat (Mahoney et al., 1991, Cell 67:853-868), 1 (2) giant larvae (lgl . Lϋtzelschwab et al., 1987, EMBO J. 6:1791-1797; Jacob et al., 1987, Cell 50:215-225), expanded (ex; Boedigheimer and Laughon, 1993, Development 118:1291-1301; Boedigheimer et al., 1993, Mechanisms of Development 44:83-84), hyperplastic discs (hyd; Mansfield et al., 1994, Developmental Biology 165:507-526) and the gene encoding the S6 ribosomal protein (Watson et al., 1992, Proc. Natl. Acad. Sci. USA 89:11302-11306; Stewart and Denell, 1993, Mol. Cell. Biol. 13:2524-2535). Although examining homozygous mutant animals has allowed the successful identification of overproliferation mutations that cause late larval and pupal lethality, mutations that cause lethality at early developmental stages are unlikely to be recovered by this approach. The present invention solves this problem by providing a method for identifying tumor suppressor genes that does not exclude genes that when mutated cause lethality in early developmental stages, and provides genes thus identified with a fundamental role in regulation of cell proliferation. The cessation of proliferative capacity by cells in culture is termed cellular senescence. Cellular senescence is used as an experimental model for cellular aging. Normal vertebrate cells in culture have a finite lifespan in that they undergo a characteristic maximum number of population doublings. The maximum number of population doublings that a cell can undergo inversely correlates with the age of the human donor. Cells from many human tumors are immortal cell lines when grown in tissue culture, i.e., they exhibit infinite or continuous cell growth, suggesting that overcoming senescence is part of carcinogenesis. (For the foregoing see Hubbard and Ozer, 1995, "Senescence and immortalization of human cells," in Cell Growth and Apoptosis. A Practical Approach, C . 12, Studzinski, G.P. (ed.) , Oxford University Press Inc., New York, NY, pp. 229-248; Hubbard-S ith et al., 1992, Mol. Cell. Biol. 12:2273-2281) . A comparative study of preimmortalized and immortalized human fibroblasts transformed with a defective SV40 genome has led to the suggestion that a chromosomal region at and/or distal to 6q21 plays a role in immortalization of cells (Hubbard-Smith et al., 1992, Mol. Cell. Biol. 12:2273-2281). Citation of references hereinabove shall not be construed as an admission that such references are prior art to the present invention. 3. SUMMARY OF THE INVENTION The present invention relates to nucleotide sequences of lats genes (Drosophila, human, and mouse lats and lats homologs of other species) , and amino acid sequences of their encoded proteins, as well as derivatives (e . g . , fragments) and analogs thereof. Nucleic acids hybridizable to or complementary to the foregoing nucleotide sequences are also provided. In a specific embodiment, the lats protein is a human protein. The invention also relates to a method of identifying tumor suppressor genes that does not exclude from identification genes that cause lethality at early developmental stages, thus overcoming the limitations of prior art methods. The method thus allows the identification of genes that regulate cell proliferation and that act at early developmental stages. The genes which thus can be identified play a fundamental role in regulation of cell proliferation such that their dysfunction (e.g., by lack of expression or mutation) leads to overproliferation and cancer. Lats is a gene provided by the present invention, identified by the method of the invention, that acts to inhibit cell proliferation, and that plays a crucial role throughout development. The invention also relates to lats derivatives and analogs of the invention which are functionally active, i.e., they are capable of displaying one or more known functional activities associated with a full-length (wild-type) lats protein. Such functional activities include but are not limited to kinase activity, antigenicity [ability to bind (or compete with lats for binding) to an anti-lats antibody] , immunogenicity (ability to generate antibody which binds to lats) , and ability to bind (or compete with lats for binding) to a receptor/ligand for lats (e . g . , a SH3 domain-containing protein) . The invention further relates to fragments (and derivatives and analogs thereof) of lats which comprise one or more domains of a lats protein. Antibodies to lats, and lats derivatives and analogs, are additionally provided. Methods of production of the lats proteins, derivatives and analogs, e . g . , by recombinant means, are also provided. The present invention also relates to therapeutic and diagnostic methods and compositions based on lats proteins and nucleic acids. Therapeutic compounds of the invention include but are not limited to lats proteins and analogs and derivatives (including fragments) thereof; antibodies thereto; nucleic acids encoding the lats proteins, analogs, or derivatives; and lats antisense nucleic acids. The invention provides for treatment of disorders of overproliferation (e.g., cancer and hyperproliferative disorders) by administering compounds that promote lats activity (e . g . , lats, an agonist of lats; nucleic acids that encode lats) . The invention also provides methods of treatment of disorders involving deficient cell proliferation (growth) or in which cell proliferation is otherwise desired (e.g., degenerative disorders, growth deficiencies, lesions, physical trauma) by administering compounds that antagonize, (inhibit) lats function (e.g., antibodies, antisense nucleic acids) . In a specific embodiment, lats function is antagonized in order to inhibit cellular senescence, in vivo or in vitro . Antagonizing lats function can also be done to grow larger animals and plants, e . g . , those used as food or material sources. Animal models, diagnostic methods and screening methods for predisposition to disorders, and methods to identify lats agonists and antagonists, are also provided by the invention. 3.1. DEFINITIONS As used herein, underscoring or italicizing the name of a gene shall indicate the gene, in contrast to its encoded protein product which is indicated by the name of the gene in the absence of any underscoring or italicizing. For example, "lats" shall mean the lats gene, whereas "lats" shall indicate the protein product of the lats gene. 4. DESCRIPTION OF THE FIGURES Figure 1. Identifying overproliferation mutations in mosaic flies. (A) Although animals that are homozygous for a lethal mutation could die at an early developmental stage, mosaic flies carrying clones of cells that are homozygous for the same mutation could live. One can identify potential tumor suppressors by generating and examining clones of overproliferated mutant cells in mosaic animals. The genetic constitution of these mosaic flies is similar to the mosaicism of the tumor patients. (B) Genetic scheme. The P-element insertions carrying the FLP recombinase (hsFLP; Golic and Lindquist, 1989, Cell 59:499-509), its target site, FRT (solid arrows, Xu and Rubin, 1993, Development 117:1223-1237), the yellow* and mini-white* marker genes (y + and mini-w + , open arrows) are indicated. Mutagenized males were crossed to females to produce heterozygous embryos. Clones of cells homozygous for the induced mutations were generated in developing first-instar larvae by mitotic recombination at the FRT sites induced with the FLP recombinase. Mosaic adults were examined for overproliferated mutant patches (w ~ , y ~ ) . Individuals carrying clones of interest were then mated to recover the mutations of interest in the next generation (Xu and Rubin, 1993, Development 117:1223-1237; Xu and Harrison, 1994; Methods in Cell Biology 44:655-682). Clones of ommatidia derived from fast proliferating mutant cells were identified since they were larger than their darkly pigmented wt (wild- type) twin-spot clones (mini-w* /mini-w + ) . Figure 2. Mutant phenotypes. (A) A clone of unpatterned, overproliferated lats mutant cells in the eye. (B) Induced at the same stage, the 93B mutant cells formed a less overproliferated clone. (C) A third instar lats' 26 ' 1 larva (right) was much larger than a wt sibling (left; at 18°C) . (D) Wing discs from the larva in (C) (wt, top; lats' 26 ' 1 , bottom) . (E) Dissected central nervous systems (wt, top; lats e26~ ' , bottom) . (F) A SEM (scanning electron microscope) view of a lats clone near the eye. (G) A closer view of a region in (F) showing the irregularity of the sizes and shapes of the mutant cells. (H) A plastic section of a mutant clone similar to the one in (F) . Cells seem to be "budding" out of the surface to form new proliferating lobes (arrows) . (I) A lats clone on the back. The boxed area is shown in (J) . The bristles in the mutant clone are short, bent and often split (arrows) . (K) A closer view of the hairs in a lats clone on the body showing enlarged bases and bent tips. (L) A section of a lats clone on the back showing extra cuticle deposits (arrows) . All the mutant clones were induced with lats*' unless stated differently. Figure 3. Organization of the Drosophila lats gene. The genomic restriction map of the lats region is aligned with the lats 5.7 kb transcript unit. The direction of transcription is indicated with large arrows. The sizes of the lats introns are as follows: intron 1 (5.0 kb) , intron 2 (5.8 kb) , intron 3 (68 bp) , intron 4 (63 bp) , intron 5 (64 bp) , intron 6 (61 bp) , intron 7 (62 bp) . The genomic DNA from +7.5 (Bglll) to -4.2 (_3coRI) was used to screen a total imaginal disc cDNA library, which isolated three groups of cDNAs: lats , Tl, T2. The introns in the T2 transcript are not labeled. Only parts of the zfh-1 (Fortini et al., 1991, Mechan. Dev. 34:113-122) and Tl transcripts are indicated. The locations of the P-element insertion (lats pl ) , the deletions in the five excision alleles (i a ts e7 - 2 - e7S e,00 - eU9 e148 ) and in lats"' , lats" 4 are indicated at the bottom. The slash indicates a gap in the genomic map. Restriction sites: EcόRI (small open arrow) , Bglll (open box) and BamHI (open circle). The Bglll site at the -0.5 position of the CLT-52 clone is not present in other genomic DNA. A scale is labeled under the restriction map. Figure 4. RNA blot analysis of the Drosophila lats mRNA. Five μg of poly(A) + RNA isolated from various developmental stages was separated on a 1% agarose gel, and hybridized with 32 P-labeled 5' end 1 kb probe from the Drosophila lats cDNA. E0-2 hrs, E2-4 hrs, E4-6 hrs, E6-8 hrs, E8-16 hrs and E16-24 hrs indicate the age of the embryos in hours. RNA from first, second and third instar larvae is denoted by LI, L2, and L3, respectively. The numbers and arrows on the right correspond to the size and location of the RNA standards. A 5.7 kb RNA was found in all the developmental stages, whereas a 4.7 kb RNA was predominantly present in 0 to 4 hour old embryos. The blot was also hybridized with DNA from the ribosomal protein gene, RNA1. Figure 5. Composite cDNA sequence of the Drosophila lats gene. The entire cDNA sequence (SEQ ID NO:l) corresponding to the 5.7 kb lats RNA is shown. This nucleotide sequence is a composite of two cDNA clones (nucleotide 1-191 from cDNA 9 and the rest from cDNA A2) . The sequence of the corresponding genomic DNA has been determined and is identical to the cDNA sequence except where indicated (above the cDNA sequence) . The predicted amino acid sequence (SEQ ID NO:2) is shown below the cDNA sequence. The opa repeat is indicated by the heavy bar. The location of the putative SH3 binding site and the RERDQ peptides are designated by dashed lines. The two sites that match the polyadenylation signal consensus sequence are underlined. The second site is located at 12 bp away from the 3 ' end of the cDNA. The locations of the introns are indicated by vertical arrows. The underlined 141 bp sequence at the 3' end of the lats transcript is identical to the 5' end untranslated sequence of the class I transcript of the Drosophila phospholipase C gene, plc-21 . The location of the 446 bp deletion in the lats"' allele is also indicated. Figure 6. Schematic of the Drosophila lats predicted protein (SEQ ID NO:2) and the related proteins (A) and sequence comparison of the proteins homologous to lats (B) . In Fig. 6A, solid, hatched, open and shaded boxes denote putative SH3 binding site, opa repeat, RERDQ peptide and kinase domain in the lats protein, respectively. The Dbf20, Dbf2 and COT-1 proteins are illustrated at the bottom. The regions that are homologous to lats are indicated by shaded boxes. The degrees of sequence similarity (percentage of identical sequences inside parentheses; percentage of identical or conservative substitutions outside parentheses) between lats and the three related proteins are indicated above the corresponding regions of these proteins. In Fig. 6B, the carboxy-terminal half of lats is compared to the six most related proteins that are revealed by blastp (a software program that searches for protein sequence homologies) search as of Sept. 1, 1994. Neurospora cot-1 (SEQ ID NO:ll); tobacco PKTL7 (SEQ ID NO:12); common ice plant protein kinase (SEQ ID NO:13); spinach protein kinase (SEQ ID NO:14); yeast Dbf-20 (SEQ ID NO:15); yeast Dbf2 (SEQ ID NO:16). Amino acid residues identical to lats are highlighted. Numbers at the beginning of every sequence refer to the position of that amino acid within the total protein sequence. The boundary of the kinase domain is defined according to Hanks et al. (1988, Science 241:42-52). The location of a region of about 40 amino acid residues that is not conserved among the proteins is indicated by the heavy bar above the sequence. The sequence of PKTL7 from tobacco, Nicotiana tabacu , was submitted to Genbank by Huang,Y. (X71057) . Both the sequence of the protein kinase from spinach, Spinacia oleracea , and the sequence of the protein kinase from common ice plant, Mesembryanthemum crystallinum , were submitted to Genbank by Baur, B., Winter, K. , Fischer, K. and Dietz, K. (Z30329 and Z30330) . Figure 7. cDNA sequence (SEQ ID NO:5) and deduced protein sequence (SEQ ID NO:6) of a mouse lats homolog, m-lats. Figure 8. cDNA sequence (SEQ ID NO:7) and deduced protein sequence (SEQ ID NO:8) of a mouse lats homolog, m-lats2. Figure 9. cDNA sequence (SEQ ID NO:3) and deduced protein sequence (SEQ ID NO:4) of a human lats homolog, h-lats. Figure 10. Schematic diagram of plasmid pBS(KS)-h-lats, containing the full length coding sequence of the h-lats cDNA. Figure 11. Alignment of the h-lats protein sequence (SEQ ID NO:4) (upper case letters) with the m-lats protein sequence (SEQ ID NO:6) (lower case letters). A dot indicates amino acid identity; a dash indicates a deletion relative to the sequence on the line above. The a ino- terminal portion of the m-lats protein is not shown due to the missing 5' end of the m-lats cDNA coding region. Figure 12. Alignment of the h-lats protein sequence (SEQ ID NO:4) (upper case letters) with the m-lats2 protein sequence (SEQ ID NO:8) (lower case letters) . A dot indicates amino acid identity; a dash indicates a deletion relative to the sequence on the line above. The amino- terminal portion of the m-lats2 protein is not shown due to the missing 5' end of the m-lats2 cDNA coding region. Figure 13. Alignment of the h-lats protein sequence (SEQ ID NO:4) (upper case letters) with the Drosophila lats protein sequence (SEQ ID NO:2) (lower case letters) . A dot indicates amino acid identity; a dash indicates a deletion relative to the sequence on the line above. Insertions in the Drosophila sequence relative to the human sequence are indicated below the sequence line. Conserved domains are indicated. LSD2 = lats split domain 2; LSD2a = LSD2 anterior portion; LSD2p = LSD2 posterior portion. The putative SH3-binding domain and the kinase domain are shown. LSD1 = lats split domain l; LSDla = LSD1 anterior portion; LSDlp = LSD1 posterior portion. LFD = lats flanking domain. LCD1 = lats C-terminal domain 1; LCD2 = lats C-terminal domain 2; LCD3 - lats C-terminal domain 3. Figure 14. Schematic diagram of plasmid pCaSpeR-hs-h-lats, an expression vector containing the full length coding sequence of the h-lats cDNA. Figure 15. Northern blot analysis of h-lats expression in normal human tissues. A 32 P-labeled BamHI fragment of h-lats was used as a probe for hybridization to polyA 4 RNA from the normal human fetal and adult tissues indicated for each lane. The positions of standard molecular weight markers are shown at right. The positions of the h-lats RNA and of 3-actin RNA (used as a standard) are shown. 5. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to nucleotide sequences of lats genes, and amino acid sequences of their encoded proteins. The invention further relates to fragments and other derivatives, and analogs, of lats proteins. Nucleic acids encoding such fragments or derivatives are also within the scope of the invention. The invention provides lats genes and their encoded proteins of many different species. The lats genes of the invention include Drosophila , human, and mouse lats and related genes (homologs) in other species. In specific embodiments, the lats genes and proteins are from vertebrates, or more particularly, mammals. In a preferred embodiment of the invention, the lats genes and proteins are of human origin. Production of the foregoing proteins and derivatives, e.g., by recombinant methods, is provided. The invention also relates to a method of identifying tumor suppressor genes that does not exclude from identification genes that cause lethality at early developmental stages, thus overcoming the limitations of prior art methods. The method thus allows the identification of genes that regulate cell proliferation and that act at early developmental stages. The genes which thus can be identified play a fundamental role in regulation of cell proliferation such that their dysfunction (e.g., due to lack of expression or mutation) leads to overproliferation and cancer. Lats is a gene provided by the present invention, identified by the method of the invention, that acts to inhibit cell proliferation, and that plays a crucial role throughout development. The invention also relates to lats derivatives and analogs of the invention which are functionally active, i.e., they are capable of displaying one or more known functional activities associated with a full-length (wild-type) lats protein. Such functional activities include but are not limited to kinase activity, antigenicity [ability to bind (or compete with lats for binding) to an anti-lats antibody] , immunogenicity (ability to generate antibody which binds to lats) , ability to bind (or compete with lats for binding) to an SH3-domain-containing protein or other ligand, ability to inhibit cell proliferation, tumor inhibition, etc. The invention further relates to fragments (and derivatives and analogs thereof) of lats which comprise one or more domains of the lats protein. Antibodies to lats, its derivatives and analogs, are additionally provided. The present invention also relates to therapeutic and diagnostic methods and compositions based on lats proteins and nucleic acids and anti-lats antibodies. The invention provides for treatment of disorders of overproliferation (e . g . , cancer and hyperproliferative disorders) by administering compounds that promote lats activity (e.g., lats proteins and functionally active analogs and derivatives (including fragments) thereof; nucleic acids encoding the lats proteins, analogs, or derivatives, agonists of lats) . The invention also provides methods of treatment of disorders involving deficient cell proliferation or in which cell proliferation (growth) is otherwise desirable (e.g., growth deficiencies, degenerative disorders, lesions, physical trauma) by administering compounds that antagonize, or inhibit, lats function (e.g., antibodies, lats antisense nucleic acids, lats derivatives that are dominant-negative protein kinases) . In a specific embodiment, lats function is antagonized in order to inhibit cellular senescence, in vivo or in vitro. Inhibition of lats function can also be done to grow larger farm animals and plants. Animal models, diagnostic methods and screening methods for predisposition to disorders are also provided by the invention. The invention is illustrated by way of examples infra which disclose, inter alia , the cloning and characterization of D. melanogaster lats (Section 6) ; the cloning and characterization of mouse and human lats homologs (Section 7) ; the sequence and domain conservation among the lats homologs (Section 8) ; the functional interchangeability of the human and Drosophila lats homologs (Section 9) ; and the differentially decreased expression of human lats in human tumor cell lines (Section 10) . For clarity of disclosure, and not by way of limitation, the detailed description of the invention is divided into the subsections which follow. 5.1. ISOLATION OF THE LATS GENES The invention relates to the nucleotide sequences of lats nucleic acids. In specific embodiments, lats nucleic acids comprise the cDNA sequences of SEQ ID NO:l, 3, 5, or 7, or the coding regions thereof, or nucleotide sequences acids encoding a lats protein (e . g . , a protein having the sequence of SEQ ID NO:2, 4, 6, or 8). The invention provides purified nucleic acids consisting of at least 8 nucleotides ( i . e . , a hybridizable portion) of a lats sequence; in other embodiments, the nucleic acids consist of at least 25 (continuous) nucleotides, 50 nucleotides, 100 nucleotides, 150 nucleotides, or 200 nucleotides of a lats sequence, or a full-length lats coding sequence. In another embodiment, the nucleic acids are smaller than 35, 200 or 500 nucleotides in length. Nucleic acids can be single or double stranded. The invention also relates to nucleic acids hybridizable to or complementary to the foregoing sequences. In specific aspects, nucleic acids are provided which comprise a sequence complementary to at least 10, 25, 50, 100, or 200 nucleotides or the entire coding region of a lats gene. In a specific embodiment, a nucleic acid which is hybridizable to a lats nucleic acid (e . g . , having sequence SEQ ID NO:3 or 7) , or to a nucleic acid encoding a lats derivative, under conditions of low stringency is provided. By way of example and not limitation, procedures using such conditions of low stringency are as follows (see also Shilo and Weinberg, 1981, Proc. Natl. Acad. Sci. USA 78:6789-6792): Filters containing DNA are pretreated for 6 h at 40°C in a solution containing 35% formamide, 5X SSC, 50 mM Tris-HCl (pH 7.5), 5 mM EDTA, 0.1% PVP, 0.1% Ficoll, 1% BSA, and 500 μg/ml denatured salmon sperm DNA. Hybridizations are carried out in the same solution with the following modifications: 0.02% PVP, 0.02% Ficoll, 0.2% BSA, 100 μg/ml salmon sperm DNA, 10% (wt/vol) dextran sulfate, and 5-20 X 10 6 cpm 32 P-labeled probe is used. Filters are incubated in hybridization mixture for 18-20 h at 40°C, and then washed for 1.5 h at 55°C in a solution containing 2X SSC, 25 mM Tris-HCl (pH 7.4), 5 mM EDTA, and 0.1% SDS. The wash solution is replaced with fresh solution and incubated an additional 1.5 h at 60°C. Filters are blotted dry and exposed for autoradiography. If necessary, filters are washed for a third time at 65-68°C and reexposed to film. Other conditions of low stringency which may be used are well known in the art (e.g., as employed for cross- species hybridizations) . In another specific embodiment, a nucleic acid which is hybridizable to a lats nucleic acid under conditions of high stringency is provided. By way of example and not limitation, procedures using such conditions of high stringency are as follows: Prehybridization of filters containing DNA is carried out for 8 h to overnight at 65°C in buffer composed of 6X SSC, 50 mM Tris-HCl (pH 7.5), 1 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.02% BSA, and 500 μg/ml denatured salmon sperm DNA. Filters are hybridized for 48 h at 65°C in prehybridization mixture containing 100 μg/ml denatured salmon sperm DNA and 5-20 X 10 6 cpm of 32 P-labeled probe. Washing of filters is done at 37°C for 1 h in a solution containing 2X SSC, 0.01% PVP, 0.01% Ficoll, and 0.01% BSA. This is followed by a wash in 0.1X SSC at 50°C for 45 min before autoradiography. Other conditions of high stringency which may be used are well known in the art. In another specific embodiment, a nucleic acid, which is hybridizable to a lats nucleic acid under conditions of moderate stringency is provided (see, e.g., Section 7.2). Nucleic acids encoding derivatives and analogs of lats proteins (see Sections 5.6 and 5.6.1), and lats antisense nucleic acids (see Section 5.8.2.2.1) are additionally provided. As is readily apparent, as used herein, a "nucleic acid encoding a fragment or portion of a lats protein" shall be construed as referring to a nucleic acid encoding only the recited fragment or portion of the lats protein and not the other contiguous portions of the lats protein as a continuous sequence. Fragments of lats nucleic acids comprising regions conserved between (with homology to) other lats nucleic acids, of the same or different species, are also provided. Nucleic acids encoding one or more lats domains are provided. Specific embodiments for the cloning of a lats gene, presented as a particular example but not by way of limitation, follows: For expression cloning (a technique commonly known in the art) , an expression library is constructed by methods known in the art. For example, mRNA (e.g., human) is isolated, cDNA is made and ligated into an expression vector (e.g., a bacteriophage derivative) such that it is capable of being expressed by the host cell into which it is then introduced. Various screening assays can then be used to select for the expressed lats product. In one embodiment, anti-lats antibodies can be used for selection. In another embodiment, polymerase chain reaction (PCR) is used to amplify the desired sequence in a genomic or cDNA library, prior to selection. Oligonucleotide primers representing known lats sequences can be used as primers in PCR. In a preferred aspect, the oligonucleotide primers represent at least part of the lats conserved segments of strong homology between lats of different species (e . g . , LCDl, LCD2, kinase domain, LFD, SH3 binding domain, LSDl, and LSD2 domains; see, e.g., Section 8 infra . ) The synthetic oligonucleotides may be utilized as primers to amplify by PCR sequences from a source (RNA or DNA) , preferably a cDNA library, of potential interest. PCR can be carried out, e.g., by use of a Perkin-Elmer Cetus thermal cycler and Taq polymerase (Gene Amp"') . The DNA being amplified can include mRNA or cDNA or genomic DNA from any eukaryotic species. One can choose to synthesize several different degenerate primers, for use in the PCR reactions. It is also possible to vary the stringency of hybridization conditions used in priming the PCR reactions, to allow for greater or lesser degrees of nucleotide sequence similarity between the known lats nucleotide sequence and the nucleic acid homolog being isolated. For cross species hybridization, low stringency conditions are preferred. For same species hybridization, moderately stringent conditions are preferred. After successful amplification of a segment of a lats homolog, that segment may be molecularly cloned and sequenced, and utilized as a probe to isolate a complete cDNA or genomic clone. This, in turn, will permit the determination of the gene's complete nucleotide sequence, the analysis of its expression, and the production of its protein product for functional analysis, as described infra . In this fashion, additional genes encoding lats proteins and lats analogs may be identified. The above-methods are not meant to limit the following general description of methods by which clones of lats may be obtained. Any eukaryotic cell potentially can serve as the nucleic acid source for the molecular cloning of the lats gene. The nucleic acid sequences encoding lats can be isolated from vertebrate, mammalian, human, porcine, bovine, feline, avian, equine, canine, as well as additional primate sources, insects, plants, etc. The DNA may be obtained by standard procedures known in the art from cloned DNA (e . g . , a DNA "library"), by chemical synthesis, by cDNA cloning, or by the cloning of genomic DNA, or fragments thereof, purified from the desired cell. (See, for example, Sambrook et al., 1989, Molecular Cloning, A Laboratory Manual, 2d Ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York; Glover, D.M. (ed.), 1985, DNA Cloning: A Practical Approach, MRL Press, Ltd., Oxford, U.K. Vol. I, II.) Clones derived from genomic DNA may contain regulatory and intron DNA regions in addition to coding regions; clones derived from cDNA will contain only exon sequences. Whatever the source, the gene should be molecularly cloned into a suitable vector for propagation of the gene. In the molecular cloning of the gene from genomic DNA, DNA fragments are generated, some of which will encode the desired gene. The DNA may be cleaved at specific sites using various restriction enzymes. Alternatively, one may use DNAse in the presence of manganese to fragment the DNA, or the DNA can be physically sheared, as for example, by sonication. The linear DNA fragments can then be separated according to size by standard techniques, including but not limited to, agarose and polyacrylamide gel electrophoresis and column chromatography. Once the DNA fragments are generated, identification of the specific DNA fragment containing the desired gene may be accomplished in a number of ways. For example, if an amount of a portion of a lats (of any species) gene or its specific RNA, or a fragment thereof (see Section 5.6), is available and can be purified and labeled, the generated DNA fragments may be screened by nucleic acid hybridization to the labeled probe (Benton, W. and Davis, R. , 1977, Science 196:180; Grunstein, M. And Hogness, D. , 1975, Proc. Natl. Acad. Sci. U.S.A. 72:3961). Such a procedure is presented by way of example in Section 7 infra . Those DNA fragments with substantial homology to the probe will hybridize. It is also possible to identify the appropriate fragment by restriction enzyme digestion(s) and comparison of fragment sizes with those expected according to a known restriction map if such is available. Further selection can be carried out on the basis of the properties of the gene. Alternatively, the presence of the gene may be detected by assays based on the physical, chemical, or immunological properties of its expressed product. For example, cDNA clones, or DNA clones which hybrid-select the proper mRNAs, can be selected which produce a protein that, e . g . , has similar or identical electrophoretic migration, isolectric focusing behavior, proteolytic digestion maps, kinase activity, inhibition of cell proliferation activity, substrate binding activity, or antigenic properties as known for lats. If an antibody to lats is available, the lats protein may be identified by binding of labeled antibody to the putatively lats synthesizing clones, in an ELISA (enzyme- linked immunosorbent assay)-type procedure. The lats gene can also be identified by mRNA selection by nucleic acid hybridization followed by in vitro translation. In this procedure, fragments are used to isolate complementary mRNAs by hybridization. Such DNA fragments may represent available, purified lats DNA of another species (e . g . , Drosophila , mouse, human). Immunoprecipitation analysis or functional assays (e.g., aggregation ability in vitro ; binding to receptor; see infra ) of the in vitro translation products of the isolated products of the isolated mRNAs identifies the mRNA and, therefore, the complementary DNA fragments that contain the desired sequences. In addition, specific mRNAs may be selected by adsorption of polyso es isolated from cells to immobilized antibodies specifically directed against lats protein. A radiolabelled lats cDNA can be synthesized using the selected mRNA (from the adsorbed polysomes) as a template. The radiolabelled mRNA or cDNA may then be used as a probe to identify the lats DNA fragments from among other genomic DNA fragments. Alternatives to isolating the lats genomic DNA include, but are not limited to, chemically synthesizing the gene sequence itself from a known sequence or making cDNA to the mRNA which encodes the lats protein. For example, RNA for cDNA cloning of the lats gene can be isolated from cells which express lats . Other methods are possible and within the scope of the invention. The identified and isolated gene can then be inserted into an appropriate cloning vector. A large number of vector-host systems known in the art may be used. Possible vectors include, but are not limited to, plasmids or modified viruses, but the vector system must be compatible with the host cell used. Such vectors include, but are not limited to, bacteriophages such as lambda derivatives, or plasmids such as PBR322 or pUC plasmid derivatives or the Bluescript vector (Stratagene) . The insertion into a cloning vector can, for example, be accomplished by ligating the DNA fragment into a cloning vector which has complementary cohesive termini. However, if the complementary restriction sites used to fragment the DNA are not present in the cloning vector, the ends of the DNA molecules may be enzymatically modified. Alternatively, any site desired may be produced by ligating nucleotide sequences (linkers) onto the DNA termini; these ligated linkers may comprise specific chemically synthesized oligonucleotides encoding restriction endonuclease recognition sequences. In an alternative method, the cleaved vector and lats gene may be modified by homopolymeric tailing. Recombinant molecules can be introduced into host cells via transformation, transfection, infection, electroporation, etc., so that many copies of the gene sequence are generated. In an alternative method, the desired gene may be identified and isolated after insertion into a suitable cloning vector in a "shot gun" approach. Enrichment for the desired gene, for example, by size fractionization, can be done before insertion into the cloning vector. In specific embodiments, transformation of host cells with recombinant DNA molecules that incorporate the isolated lats gene, cDNA, or synthesized DNA sequence enables generation of multiple copies of the gene. Thus, the gene may be obtained in large quantities by growing transformants, isolating the recombinant DNA molecules from the transformants and, when necessary, retrieving the inserted gene from the isolated recombinant DNA. The lats sequences provided by the instant invention include those nucleotide sequences encoding substantially the same amino acid sequences as found in native lats proteins, and those encoded amino acid sequences with functionally equivalent amino acids, as well as those encoding other lats derivatives or analogs, as described in Sections 5.6 and 5.6.1 infra for lats derivatives and analogs. 5.2. EXPRESSION OF THE LATS GENES The nucleotide sequence coding for a lats protein or a functionally active analog or fragment or other derivative thereof (see Section 5.6), can be inserted into an appropriate expression vector, i.e., a vector which contains the necessary elements for the transcription and translation of the inserted protein-coding sequence. The necessary transcriptional and translational signals can also be supplied by the native lats gene and/or its flanking regions. A variety of host-vector systems may be utilized to express the protein-coding sequence. These include but are not limited to mammalian cell systems infected with virus (e.g., vaccinia virus, adenovirus, etc.); insect cell systems infected with virus (e.g., baculovirus) ; microorganisms such as yeast containing yeast vectors, or bacteria transformed with bacteriophage, DNA, plasmid DNA, or cosmid DNA. The expression elements of vectors vary in their strengths and specificities. Depending on the host-vector system utilized, any one of a number of suitable transcription and translation elements may be used. In specific embodiments, the human lats gene is expressed, or a sequence encoding a functionally active portion of human lats. In yet another embodiment, a fragment of lats comprising a domain of the lats protein is expressed. Any of the methods previously described for the insertion of DNA fragments into a vector may be used to construct expression vectors containing a chimeric gene consisting of appropriate transcriptional/translational control signals and the protein coding sequences. These methods may include in vitro recombinant DNA and synthetic techniques and in vivo recombinants (genetic recombination) . Expression of nucleic acid sequence encoding a lats protein or peptide fragment may be regulated by a second nucleic acid sequence so that the lats protein or peptide is expressed in a host transformed with the recombinant DNA molecule. For example, expression of a lats protein may be controlled by any promoter/enhancer element known in the art. In a specific embodiment, the promoter is not a native lats gene promoter. Promoters which may be used to control lats expression include, but are not limited to, the SV40 early promoter region (Bernoist and Chambon, 1981, Nature 290:304- 310), the promoter contained in the 3' long terminal repeat of Rous sarcoma virus (Yamamoto, et al., 1980, Cell 22:787- 797), the herpes thymidine kinase promoter (Wagner et al., 1981, Proc. Natl. Acad. Sci. U.S.A. 78:1441-1445), the regulatory sequences of the metallothionein gene (Brinster et al., 1982, Nature 296:39-42); prokaryotic expression vectors such as the 3-lactamase promoter (Villa-Kamaroff, et al., 1978, Proc. Natl. Acad. Sci. U.S.A. 75:3727-3731), or the tac promoter (DeBoer, et al., 1983, Proc. Natl. Acad. Sci. U.S.A. 80:21-25); see also "Useful proteins from recombinant bacteria" in Scientific American, 1980, 242:74-94; plant expression vectors comprising the nopaline synthetase promoter region (Herrera-Estrella et al.. Nature 303:209-213) or the cauliflower mosaic virus 35S RNA promoter (Gardner, et al., 1981, Nucl. Acids Res. 9:2871), and the promoter of the photosynthetic enzyme ribulose biphosphate carboxylase (Herrera-Estrella et al., 1984, Nature 310:115-120); promoter elements from yeast or other fungi such as the Gal 4 promoter, the ADC (alcohol dehydrogenase) promoter, PGK (phosphoglycerol kinase) promoter, alkaline phosphatase promoter, and the following animal transcriptional control regions, which exhibit tissue specificity and have been utilized in transgenic animals: elastase I gene control region which is active in pancreatic acinar cells (Swift et al., 1984, Cell 38:639-646; Ornitz et al., 1986, Cold Spring Harbor Symp. Quant. Biol. 50:399-409; MacDonald, 1987, Hepatology 7:425-515); insulin gene control region which is active in pancreatic beta cells (Hanahan, 1985, Nature 315:115-122), immunoglobulin gene control region which is active in lymphoid cells (Grosschedl et al., 1984, Cell 38:647-658; Adames et al., 1985, Nature 318:533-538; Alexander et al., 1987, Mol. Cell. Biol. 7:1436-1444), mouse mammary tumor virus control region which is active in testicular, breast, lymphoid and mast cells (Leder et al., 1986, Cell 45:485-495) , albumin gene control region which iε active in liver (Pinkert et al., 1987, Genes and Devel. 1:268-276), alpha-fetoprotein gene control region which is active in liver (Krumlauf et al., 1985, Mol. Cell. Biol. 5:1639-1648; Hammer et al., 1987, Science 235:53-58; alpha 1- antitrypsin gene control region which is active in the liver (Kelsey et al., 1987, Genes and Devel. 1:161-171), beta- globin gene control region which is active in myeloid cells (Mogram et al., 1985, Nature 315:338-340; Kollias et al., 1986, Cell 46:89-94; myelin basic protein gene control region which is active in oligodendrocyte cells in the brain (Readhead et al., 1987, Cell 48:703-712); myosin light chain- 2 gene control region which is active in skeletal muscle (Sani, 1985, Nature 314:283-286), and gonadotropic releasing hormone gene control region which is active in the hypothalamus (Mason et al., 1986, Science 234:1372-1378). In a specific embodiment, a vector is used that comprises a promoter operably linked to a lats-encoding nucleic acid, one or more origins of replication, and, optionally, one or more selectable markers (e.g., an antibiotic resistance gene) . In a specific embodiment, an expression construct is made by subcloning a lats coding sequence into the EcoRI restriction site of each of the three pGEX vectors (Glutathione S-Transferase expression vectors; Smith and Johnson, 1988, Gene 7:31-40). This allows for the expression of the lats protein product from the subclone in the correct reading frame. Expression vectors containing lats gene inserts can be identified by three general approaches: (a) nucleic acid hybridization, (b) presence or absence of "marker" gene functions, and (c) expression of inserted sequences. In the first approach, the presence of a lats gene inserted in an expression vector can be detected by nucleic acid hybridization using probes comprising sequences that are homologous to an inserted lats gene. In the second approach, the recombinant vector/host system can be identified and selected based upon the presence or absence of certain "marker" gene functions (e.g., thymidine kinase activity, resistance to antibiotics, transformation phenotype, occlusion body formation in baculovirus, etc.) caused by the insertion of a lats gene in the vector. For example, if the lats gene is inserted within the marker gene sequence of the vector, recombinants containing the lats insert can be identified by the absence of the marker gene function. In the third approach, recombinant expression vectors can be identified by assaying the lats product expressed by the recombinant. Such assays can be based, for example, on the physical or functional properties of the lats protein in in vitro assay systems, e.g., kinase activity, binding with anti-lats antibody, inhibition of cell proliferation. Once a particular recombinant DNA molecule is identified and isolated, several methods known in the art may be used to propagate it. Once a suitable host system and growth conditions are established, recombinant expression vectors can be propagated and prepared in quantity. As previously explained, the expression vectors which can be used include, but are not limited to, the following vectors or their derivatives: human or animal viruses such as vaccinia virus or adenovirus; insect viruses such as baculovirus; yeast vectors; bacteriophage vectors (e.g., lambda) , and plasmid and cosmid DNA vectors, to name but a few. In addition, a host cell strain may be chosen which modulates the expression of the inserted sequences, or modifies and processes the gene product in the specific fashion desired. Expression from certain promoters can be elevated in the presence of certain inducers; thus, expression of the genetically engineered lats protein may be controlled. Furthermore, different host cellε have characteristic and specific mechanisms for the translational and post-translational processing and modification (e.g., glycosylation, phosphorylation of proteins. Appropriate cell lines or host systems can be chosen to ensure the desired modification and processing of the foreign protein expressed. For example, expression in a bacterial system can be used to produce an unglycosylated core protein product. Expression in yeast will produce a glycosylated product. Expression in mammalian cells can be used to ensure "native" glycosylation of a heterologous protein. Furthermore, different vector/host expression systems may effect processing reactions to different extents. In other specific embodiments, the lats protein, fragment, analog, or derivative may be expressed as a fusion, or chimeric protein product (comprising the protein, fragment, analog, or derivative joined via a peptide bond to a heterologous protein sequence (of a different protein) ) . Such a chimeric product can be made by ligating the 5 appropriate nucleic acid sequences encoding the desired amino acid sequences to each other by methods known in the art, in the proper coding frame, and expressing the chimeric product by methods commonly known in the art. Alternatively, such a chimeric product may be made by protein synthetic techniques, 10 e.g., by use of a peptide synthesizer. Both cDNA and genomic sequences can be cloned and expressed. 5.3. IDENTIFICATION AND PURIFICATION 15 OF THE LATS GENE PRODUCTS In particular aspects, the invention provides amino acid sequences of lats, preferably human lats, and fragments and derivatives thereof which comprise an antigenic determinant (i.e., can be recognized by an antibody) or which 20 are otherwise functionally active, as well as nucleic acid sequences encoding the foregoing. "Functionally active" lats material as used herein refers to that material displaying one or more known functional activities associated with a full-length (wild-type) lats protein, e.g., kinase activity, _- inhibition of cell proliferation, tumor inhibition, binding to an SH3-domain, binding to a lats substrate or lats binding partner, antigenicity (binding to an anti-lats antibody) , immunogenicity, etc. In specific embodiments, the invention provides fragments of a lats protein consisting of at least 6 amino acids, 10 amino acids, 50 amino acids, or of at least 75 amino acids. In other embodiments, the proteins comprise or consist essentially of a lats carboxy (C)-terminal domain 3 (LCD3) , lats C-terminal domain 2 (LCD2) , lats C-terminal domain 1 (LCDl) , kinase domain, kinase subdomains, lats flanking domain (amino-terminal to the kinase domain) , lats split domain 1 (LSDl), lats split domain 2 (LSD2), SH3-binding domain, and opa repeat domain (see Section 8 infra) , or any combination of the foregoing, of a lats protein. Fragments, or proteins comprising fragments, lacking some or all of the foregoing regions of a lats protein are also provided. Nucleic acids encoding the foregoing are provided. Once a recombinant which expresses the lats gene sequence is identified, the gene product can be analyzed. This is achieved by assays based on the physical or functional properties of the product, including radioactive labelling of the product followed by analysis by gel electrophoresis, immunoassay, etc. Once the lats protein is identified, it may be isolated and purified by standard methods including chromatography (e.g., ion exchange, affinity, and sizing column chromatography) , centrifugation, differential solubility, or by any other standard technique for the purification of proteins. The functional properties may be evaluated using any suitable assay (see Section 5.7). Alternatively, once a lats protein produced by a recombinant is identified, the amino acid sequence of the protein can be deduced from the nucleotide sequence of the chimeric gene contained in the recombinant. As a result, the protein can be synthesized by standard chemical methods known in the art (e.g., see Hunkapiller, M. , et al., 1984, Nature 310:105-111) . In another alternate embodiment, native lats proteins can be purified from natural sources, by standard methods such as those described above (e.g., immunoaffinity purification) . In a specific embodiment of the present invention, such lats proteins, whether produced by recombinant DNA techniques or by chemical synthetic methods or by purification of native proteins, include but are not limited to those containing, as a primary amino acid sequence, all or part of the amino acid sequence substantially as depicted in Figure 9 (SEQ ID NO:4), as well as fragments and other derivatives, and analogs thereof, including proteins homologous thereto. 5.4. STRUCTURE OF THE LATS GENE AND PROTEIN The structure of the lats gene and protein can be analyzed by various methods known in the art. 5.4.1. GENETIC ANALYSIS The cloned DNA or cDNA corresponding to the lats gene can be analyzed by methods including but not limited to Southern hybridization (Southern, E.M. , 1975, J. Mol. Biol. 98:503-517), Northern hybridization (see e.g., Freeman et al., 1983, Proc. Natl. Acad. Sci. U.S.A. 80:4094-4098), restriction endonuclease mapping (Maniatis, T. , 1982, Molecular Cloning, A Laboratory, Cold Spring Harbor, New York) , and DNA sequence analysis. Polymerase chain reaction (PCR; U.S. Patent Nos. 4,683,202, 4,683,195 and 4,889,818; Gyllenstein et al., 1988, Proc. Natl. Acad. Sci. U.S.A. 85:7652-7656; Ochman et al., 1988, Genetics 120:621-623; Loh et al., 1989, Science 243:217-220) followed by Southern hybridization with a lats-specific probe can allow the detection of the lats gene in DNA from various cell types. Methods of amplification other than PCR are commonly known and can also be employed. In one embodiment, Southern hybridization can be used to determine the genetic linkage of lats. Northern hybridization analysis can be used to determine the expression of the lats gene. Various cell types, at various states of development or activity can be tested for lats expression. The stringency of the hybridization conditions for both Southern and Northern hybridization can be manipulated to ensure detection of nucleic acids with the desired degree of relatedness to the specific lats probe used. Modifications of these methods and other methods commonly known in the art can be used. Restriction endonuclease mapping can be used to roughly determine the genetic structure of the lats gene. Restriction maps derived by restriction endonuclease cleavage can be confirmed by DNA sequence analysis. DNA sequence analysis can be performed by any techniques known in the art, including but not limited to the method of Maxam and Gilbert (1980, Meth. Enzymol. 65:499- 560), the Sanger dideoxy method (Sanger, F. , et al., 1977, Proc. Natl. Acad. Sci. U.S.A. 74:5463), the use of T7 DNA polymerase (Tabor and Richardson, U.S. Patent No. 4,795,699), or use of an automated DNA sequenator (e.g.. Applied Biosystems, Foster City, CA) . 5.4.2. PROTEIN ANALYSIS The amino acid sequence of the lats protein can be derived by deduction from the DNA sequence, or alternatively, by direct sequencing of the protein, e.g., with an automated amino acid sequencer. The lats protein sequence can be further characterized by a hydrophilicity analysis (Hopp, T. and Woods, K., 1981, Proc. Natl. Acad. Sci. U.S.A. 78:3824). A hydrophilicity profile can be used to identify the hydrophobic and hydrophilic regions of the lats protein and the corresponding regions of the gene sequence which encode such regions. Secondary, structural analysis (Chou, P. and Fasman, G., 1974, Biochemistry 13:222) can also be done, to identify regions of lats that assume specific secondary structures. Manipulation, translation, and secondary structure prediction, open reading frame prediction and plotting, as well as determination of sequence ho ologies, can also be accomplished using computer software programs available in the art. Other methods of structural analysis can also be employed. These include but are not limited to X-ray crystallography (Engstom, A., 1974, Biochem. Exp. Biol. 11:7- 13) and computer modeling (Fletterick, R. and Zoller, M. (eds.), 1986, Computer Graphics and Molecular Modeling, in Current Communications in Molecular Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York) . 5.5. GENERATION OF ANTIBODIES TO LATS 5 PROTEINS AND DERIVATIVES THEREOF According to the invention, lats protein, its fragments or other derivatives, or analogs thereof, may be used as an immunogen to generate antibodies which immunospecifically bind such an immunogen. Such antibodies , 0 include but are not limited to polyclonal, monoclonal, chimeric, single chain, Fab fragments, and an Fab expression library. In a specific embodiment, antibodies to a human lats protein are produced. In another embodiment, antibodies to a domain (e.g., the SH3-binding domain) of a lats protein ,_ are produced. In a specific embodiment, fragments of a lats protein identified as hydrophilic are used as immunogens for antibody production. Various procedures known in the art may be used for the production of polyclonal antibodies to a lats protein or 20 derivative or analog. In a particular embodiment, rabbit polyclonal antibodies to an epitope of a lats protein encoded by a sequence of SEQ ID NOS:2, 4, 6 or 8, or a subsequence thereof, can be obtained. For the production of antibody, various host animals can be immunized by injection with the 2 _ native lats protein, or a synthetic version, or derivative (e.g., fragment) thereof, including but not limited to rabbits, mice, rats, etc. Various adjuvants may be used to increase the immunological response, depending on the host species, and including but not limited to Freund's (complete and incomplete) , mineral gels such as aluminum hydroxide, surface active substances such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, keyhole limpet hemocyanins, dinitrophenol, and potentially useful human adjuvants such as BCG (bacille Cal ette-Guerin) and corynebacterium parvum. For preparation of monoclonal antibodies directed toward a lats protein sequence or analog thereof, any technique which provides for the production of antibody molecules by continuous cell lines in culture may be used. For example, the hybridoma technique originally developed by Kohler and Milstein (1975, Nature 256:495-497), as well as the trioma technique, the human B-cell hybridoma technique (Kozbor et al., 1983, Immunology Today 4:72), and the EBV- hybridoma technique to produce human monoclonal antibodies (Cole et al., 1985, in Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc. , pp. 77-96) . In an additional embodiment of the invention, monoclonal antibodies can be produced in germ-free animals utilizing recent technology (PCT/US90/02545) . According to the invention, human antibodies may be used and can be obtained by using human hybridomas (Cote et al., 1983, Proc. Natl. Acad. Sci. U.S.A. 80:2026-2030) or by transforming human B cells with EBV virus in vitro (Cole et al., 1985, in Monoclonal Antibodies and Cancer Therapy. Alan R. Liss, pp. 77-96) . In fact, according to the invention, techniques developed for the production of "chimeric antibodies" (Morrison et al., 1984, Proc. Natl. Acad. Sci. U.S.A. 81:6851-6855; Neuberger et al., 1984, Nature 312:604-608; Takeda et al., 1985, Nature 314:452-454) by splicing the genes from a mouse antibody molecule specific for lats together with genes from a human antibody molecule of appropriate biological activity can be used; such antibodies are within the scope of this invention. According to the invention, techniques described for the production of single chain antibodies (U.S. Patent 4,946,778) can be adapted to produce lats-specific single chain antibodies. An additional embodiment of the invention utilizes the techniques described for the construction of Fab expression libraries (Huse et al., 1989, Science 246:1275- 1281) to allow rapid and easy identification of monoclonal Fab fragments with the desired specificity for lats proteins, derivatives, or analogs. Antibody fragments which contain the idiotype of the molecule can be generated by known techniques. For example, such fragments include but are not limited to: the F(ab') 2 fragment which can be produced by pepsin digestion of the antibody molecule; the Fab' fragments which can be generated by reducing the disulfide bridges of the F(ab') 2 fragment, the Fab fragments which can be generated by treating the antibody molecule with papain and a reducing agent, and Fv fragments. In the production of antibodies, screening for the desired antibody can be accomplished by techniques known in the art, e.g. ELISA (enzyme-linked immunosorbent assay) . For example, to select antibodies which recognize a specific domain of a lats protein, one may assay generated hybridomas for a product which binds to a lats fragment containing such domain. For selection of an antibody that specifically binds a first lats homolog but which does not specifically bind a different lats homolog, one can select on the basis of positive binding to the first lats homolog and a lack of binding to the second lats homolog. Antibodies specific to a domain of a lats protein are also provided. The foregoing antibodies can be used in methods known in the art relating to the localization and activity of the lats protein sequences of the invention, e.g., for imaging these proteins, measuring levels thereof in appropriate physiological samples, in diagnostic methods, etc. In another embodiment of the invention (see infra ) , anti-lats antibodies and fragments thereof containing the binding domain are Therapeutics. 5.6. LATS PROTEINS. DERIVATIVES AND ANALOGS The invention further relates to lats proteins, and derivatives (including but not limited to fragments) and analogs of lats proteins. Nucleic acids encoding lats protein derivatives and protein analogs are also provided. In one embodiment, the lats proteins are encoded by the lats nucleic acids described in Section 5.1 supra . In particular aspects, the proteins, derivatives, or analogs are of lats proteins of animals, e.g., fly, frog, mouse, rat, pig, cow, dog, monkey, human, or of plants. The production and use of derivatives and analogs related to lats are within the scope of the present invention. In a specific embodiment, the derivative or analog is functionally active, i.e., capable of exhibiting one or more functional activities associated with a full- length, wild-type lats protein. As one example, such derivatives or analogs which have the desired immunogenicity or antigenicity can be used, for example, in immunoassays, for immunization, for inhibition of lats activity, etc. Aε another example, such derivatives or analogs which have the desired kinase activity, or which are phosphorylated or dephosphorylated, are provided. Derivatives or analogs that retain, or alternatively lack or inhibit, a desired lats property of interest (e.g., binding to an SH3-domain- containing protein or other lats binding partner, kinase activity, inhibition of cell proliferation, tumor inhibition) , can be used as inducers, or inhibitors, respectively, of such property and its physiological correlates. A specific embodiment relates to a lats fragment that can be bound by an anti-lats antibody. Derivatives or analogs of lats can be tested for the desired activity by procedures known in the art, including but not limited to the assays described in Sections 5.7 and 5.9. In particular, lats derivatives can be made by altering lats sequences by substitutions, additions or deletions that provide for functionally equivalent molecules. Due to the degeneracy of nucleotide coding sequenceε, other DNA sequences which encode substantially the same amino acid sequence as a lats gene may be used in the practice of the present invention. These include but are not limited to nucleotide sequences comprising all or portions of lats genes which are altered by the substitution of different codons that encode a functionally equivalent amino acid residue within the sequence, thus producing a silent change. Likewise, the lats derivatives of the invention include, but are not limited to, those containing, as a primary amino acid sequence, all or part of the amino acid sequence of a lats protein including altered sequences in which functionally equivalent amino acid residues are substituted for residues within the sequence resulting in a silent change. For example, one or more amino acid residues within the sequence can be substituted by another amino acid of a similar polarity which acts as a functional equivalent, resulting in a silent alteration. Substitutes for an amino acid within the sequence may be selected from other members of the class to which the amino acid belongs. For example, the nonpolar (hydrophobic) amino acids include alanine, leucine, isoleucine, valine, proline, phenylalanine, tryptophan and methionine. The polar neutral amino acids include glycine, serine, threonine, cysteine, tyrosine, asparagine, and glutamine. The positively charged (basic) amino acids include arginine, lysine and histidine. The negatively charged (acidic) amino acids include aspartic acid and glutamic acid. In a specific embodiment of the invention, proteins consisting of or comprising a fragment of a lats protein consisting of at least 10 (continuous) amino acids of the lats protein is provided. In other embodiments, the fragment consists of at least 20 or 50 amino acids of the lats protein. In specific embodiments, such fragments are not larger than 35, 100 or 200 amino acids. Derivatives or analogs of lats include but are not limited to those molecules comprising regions that are substantially homologous to lats or fragments thereof (e.g., in various embodiments, at least 60% or 70% or 80% or 90% or 95% identity over an amino acid sequence of identical size or when compared to an aligned sequence in which the alignment is done by a computer homology program known in the art) or whose encoding nucleic acid is capable of hybridizing to a coding lats sequence, under stringent, moderately stringent, or nonstringent conditions. The lats derivatives and analogs of the invention can be produced by various methods known in the art. The manipulations which result in their production can occur at the gene or protein level. For example, the cloned lats gene sequence can be modified by any of numerous strategies known in the art (Maniatis, T. , 1990, Molecular Cloning, A Laboratory Manual, 2d ed. , Cold Spring Harbor Laboratory, Cold Spring Harbor, New York) . The sequence can be cleaved at appropriate sites with restriction endonuclease(s) , followed by further enzymatic modification if desired, isolated, and ligated in vitro . In the production of the gene encoding a derivative or analog of lats, care should be taken to ensure that the modified gene remains within the same translational reading frame as lats, uninterrupted by translational stop signals, in the gene region where the desired lats activity is encoded. Additionally, the lats-encoding nucleic acid sequence can be mutated in vitro or in vivo , to create and/or destroy translation, initiation, and/or termination sequences, or to create variations in coding regions and/or form new restriction endonuclease sites or destroy preexisting ones, to facilitate further in vitro modification. Any technique for mutagenesis known in the art can be used, including but not limited to, chemical mutagenesis, in vitro site-directed mutagenesis (Hutchinson, C, et al., 1978, J. Biol. Chem 253:6551), use of TAB® linkers (Pharmacia) , etc. Manipulations of the lats sequence may also be made at the protein level. Included within the scope of the invention are lats protein fragments or other derivatives or analogs which are differentially modified during or after translation, e.g., by glycosylation, acetylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, linkage to an antibody molecule or other cellular ligand, etc. Any of numerous chemical modifications may be carried out by known techniques, including but not limited to specific chemical cleavage by cyanogen bromide, trypsin, chymotrypsin, papain, V8 protease, NaBH 4 ; acetylation, formylation, oxidation, reduction; metabolic synthesis in the presence of tunicamycin; etc. In addition, analogs and derivatives of lats can be chemically synthesized. For example, a peptide corresponding to a portion of a lats protein which comprises the desired domain (see Section 5.6.1), or which mediates the desired activity in vitro, can be synthesized by use of a peptide synthesizer. Furthermore, if desired, nonclassical amino acids or chemical amino acid analogs can be introduced as a substitution or addition into the lats sequence. Non¬ classical amino acids include but are not limited to the D- isomers of the common amino acids, α-amino isobutyric acid, 4-aminobutyric acid, Abu, 2-amino butyric acid, 7-Abu, e-Ahx, 6-amino hexanoic acid, Aib, 2-amino isobutyric acid, 3-amino propionic acid, ornithine, norleucine, norvaline, hydroxyproline, sarcosine, citrulline, cysteic acid, t- butylglycine, t-butylalanine, phenylglycine, cyclohexylalanine, /3-alanine, fluoro-amino acids, designer amino acids such as 3-methyl amino acids, Cα-methyl amino acids, Nα-methyl amino acids, and amino acid analogs in general. Furthermore, the amino acid can be D (dextrorotary) or L (levorotary) . In a specific embodiment, the lats derivative is a chimeric, or fusion, protein comprising a lats protein or fragment thereof (preferably consisting of at least a domain or motif of the lats protein, or at least 10 amino acids of the lats protein) joined at its amino- or carboxy-terminus via a peptide bond to an amino acid sequence of a different protein. In one embodiment, such a chimeric protein is produced by recombinant expression of a nucleic acid encoding the protein (comprising a lats-coding sequence joined in- frame to a coding sequence for a different protein) . Such a chimeric product can be made by ligating the appropriate nucleic acid sequences encoding the desired amino acid sequences to each other by methods known in the art, in the proper coding frame, and expressing the chimeric product by methods commonly known in the art. Alternatively, such a chimeric product may be made by protein synthetic techniques, e.g., by use of a peptide synthesizer. Chimeric genes 5 comprising portions of lats fused to any heterologous protein-encoding sequences may be constructed. A specific embodiment relates to a chimeric protein comprising a fragment of lats of at least six amino acids. In another specific embodiment, the lats derivative 0 is a molecule comprising a region of homology with a lats protein. By way of example, in various embodiments, a first protein region can be considered "homologous" to a second protein region when the amino acid sequence of the first region is at least 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 5 95% identical, when compared to any sequence in the second region of an equal number of amino acids as the number contained in the first region or when compared to an aligned sequence of the second region that has been aligned by a computer homology program known in the art. For example, a 0 molecule can comprise one or more regions homologous to a lats domain (see Section 5.6.1) or a portion thereof. Other specific embodiments of derivatives and analogs are described in the subsection below and examples sections infra . 5 5.6.1. DERIVATIVES OF LATS CONTAINING ONE OR MORE DOMAINS OF THE PROTEIN In a specific embodiment, the invention relates to lats derivatives and analogs, in particular lats fragments _ and derivatives of such fragments, that comprise, or alternatively consist of, one or more domains of a lats protein, including but not limited to a lats C-terminal domain 3 (LCD3) , lats C-terminal domain 2 (LCD2), lats C-terminal domain 1 (LCDl) , kinase domain, kinase subdomains, _ lats flanking domain (LFD) (amino-terminal to the kinase domain) , lats split domain 1 (LSDl) , lats split domain 2 (LSD2) , SH3-binding domain, and opa repeat domain, functional (e.g., binding) fragments of any of the foregoing, or any combination of the foregoing. In particular examples relating to the human, mouse and Drosophila lats proteins, such domains are identified in Examples Sections 6 and 8, and in Figures 6A, 6B, and 13. A specific embodiment relates to molecules comprising specific fragments of lats that are those fragments in the respective lats protein most homologous to specific fragments of a human or mouse lats protein. A fragment comprising a domain of a lats homolog can be identified by protein analysis methods as described in Sections 5.3.2 or 6. In a specific embodiment, a lats protein, derivative or analog is provided that has a kinase domain and has a phosphorylated serine situated within 20 residues upstream of an Ala-Pro-Glu consensus in subdomain eight of its kinase domain. In another embodiment, a lats protein derivative or analog is provided with a kinase domain and with a dephosphorylated serine situated within 20 residues upstream of an Ala-Pro-Glu consensus in subdomain eight of its kinase domain, or in which the serine situated within 20 residues upstream of that consensus has been deleted or substituted by another amino acid. In a specific embodiment, the invention provides various phosphorylated and dephosphorylated forms of the lats protein, derivative, or analog that are active kinase forms. Both phosphorylation and dephosphorylation of lats at different residues could potentially activate lats. In another specific embodiment, the invention provides various phosphorylated and dephosphorylated forms of the lats protein, derivative or analog that are inactive kinase forms. Phosphorylation can be carried out by any methods known in the art, e.g., by use of a kinase. Dephosphorylation can be carried out by use of any methods known in the art, e.g., by use of a phosphatase. Another specific embodiment relates to a derivative or analog of a lats protein that is a dominant-active protein kinase. Such a derivative or analog comprises a lats kinase domain that has been mutated so as to be dominantly active (exhibit constitutively active kinase activity) . It is known that acidic residues such as Glu and Asp sometimes mimic a phosphorylated residue, and changing the phosphorylatable Ser or Thr residue in subdomain eight into a Glu or Asp residue has been previously used to produce constitutively active kinases (Mansour et al., 1994, Science 265:966-970). Thus, changing a serine or threonine residue situated within 20 residues upstream of an Ala-Pro-Glu consensus in subdomain eight of a lats kinase domain into another residue (e.g., Glu, Asp) may be used to make a dominant-active lats protein kinase. For example, changing Ser914 in Drosophila lats, or changing Ser909 in h-lats, into a Glu residue could produce a dominant active lats kinase. Another specific embodiment relates to a derivative or analog of lats that is a dominant-negative protein kinase. Protein kinases can be mutated into dominant negative forms. Expression of a dominant negative protein kinase can suppreεs the activity of the wild-type form of the same kinase. Dominant negative forms of protein kinases are often obtained by expressing an inactive form of a kinase (Milarski and Saltiel, 1994, J. Biol. Chem. 269(33) :21239-21243) or by expressing a noncatalytic domain of a kinase (Lu and Means, 1994, EMBO J. 12:2103-2113; Yarden et al., 1992, EMBO J. 11:2159-2166). Thus, a lats dominant-negative kinase can be obtained by mutating the kinase domain so as to be inactive (e.g., by deletion and/or point mutation). By way of example, a lats derivative that is a dominant-negative kinase is a lats protein that lacks a kinase domain but comprises one or more of the other domains of the lats protein; e.g., a lats protein derivative truncated at about the beginning of the kinase domain (i.e., a lats fragment containing only sequences amino-terminal to the kinase domain) . By way of another example, a lats derivative that is a dominant- negative kinase is a lats protein in which one of the residues conserved among serine/threonine kinases (see Hanks et al., 1988, Science 241:42-52) is mutated (deleted or substituted by a different residue) . In another specific embodiment, a molecule is provided that comprises one or more domains (or functional 5 portion thereof) of a lats protein but that also lacks one or more domains (or functional portion thereof) of a lats protein. In particular examples, lats protein derivatives are provided that lack an opa repeat domain. By way of another example, such a protein may also lack all or a 0 portion of the kinase domain, but retain at least the SH3-binding domain of a lats protein. In another embodiment, a molecule is provided that comprises one or more domains (or functional portion thereof) of a lats protein, and that has one or more mutant (e.g., due to deletion or point 15 mutation(s)) domains of a latε protein (e.g., such that the mutant domain has decreased function) . By way of example, the kinase domain may be mutant so as to have reduced, absent, or increased kinase activity. 20 5.7. ASSAYS OF LATS PROTEINS, DERIVATIVES AND ANALOGS The functional activity of lats proteins, derivatives and analogs can be assayed by various methods. For example, in one embodiment, where one is 2 _ assaying for the ability to bind or compete with wild-type lats for binding to anti-lats antibody, variouε im unoaεεays known in the art can be used, including but not limited to competitive and non-competitive assay systems using techniques such as radioimmunoasεays, ELISA (enzyme linked _ 0 immunosorbent asεay) , "εandwich" immunoassays, immunoradiometric assays, gel diffusion precipitin reactions, immunodiffusion assays, in si tu immunoassays (using colloidal gold, enzyme or radioisotope labels, for example) , western blots, precipitation reactions, agglutination assays (e.g., __ gel agglutination assays, hemagglutination assays) , complement fixation assays, immunofluorescence assays, protein A assays, and immunoelectrophoresis asεays, etc. In one embodiment, antibody binding is detected by detecting a label on the primary antibody. In another embodiment, the primary antibody is detected by detecting binding of a secondary antibody or reagent to the primary antibody. In a further embodiment, the secondary antibody is labelled. Many means are known in the art for detecting binding in an immunoassay and are within the scope of the present invention. In another embodiment, where a lats-binding protein is identified, the binding can be assayed, e.g., by means well-known in the art. In another embodiment, physiological correlates of lats binding to its substrates (signal transduction) can be assayed. In another embodiment, kinase asεays can be used to measure lats kinase activity. Such assays can be carried out by methods well known in the art. By way of example, a lats protein is contacted with a substrate (e.g., a known substrate of serine/threonine kinases) in the presence of a 32 P-labeled phosphate donor, and any phosphorylation of the substrate is detected or measured. In another embodiment, in insect or other model systems, genetic studies can be done to study the phenotypic effect of a lats mutant that is a derivative or analog of wild-type lats (see Section 6, infra) . In addition, assays that can be used to detect or measure the ability to inhibit, or alternatively promote, cell proliferation are described in Section 5.9. Other methods will be known to the skilled artisan and are within the scope of the invention. 5.8. THERAPEUTIC USES The invention provides for treatment or prevention of various diseases and disorderε by adminiεtration of a therapeutic compound (termed herein "Therapeutic") . Such "Therapeutics" include but are not limited to: lats proteins and analogs and derivatives (including fragments) thereof (e.g., as described hereinabove) ; antibodies thereto (as described hereinabove) ; nucleic acids encoding the lats proteins, analogs, or derivatives (e.g., as described hereinabove) ; lats antisense nucleic acids, and lats agonists and antagonists. Disorders involving cell overproliferation 5 are treated or prevented by administration of a Therapeutic that promotes lats function. Disorders in which cell proliferation is deficient or is desired are treated or prevented by administration of a Therapeutic that antagonizes (inhibits) lats function. The above is described in detail 10 in the subsections below. Generally, administration of products of a species origin or species reactivity (in the case of antibodies) that is the same species as that of the patient is preferred. Thus, in a preferred embodiment, a human lats protein, 15 derivative, or analog, or nucleic acid, or an antibody to a human lats protein, is therapeutically or prophylactically administered to a human patient. Additional descriptions and sources of Therapeutics that can be used according to the invention are found in 20 Sections 5.1 through 5.7 herein. 5.8.1. TREATMENT AND PREVENTION OF DISORDERS INVOLVING OVERPROLIFERATION OF CELLS Diseases and disorders involving cell __ overproliferation are treated or prevented by administration of a Therapeutic that promotes (i.e., increases or supplies) lats function. Examples of such a Therapeutic include but are not limited to lats proteins, derivatives, or fragments that are functionally active, particularly that are active in 3 _ inhibiting cell proliferation (e.g., as demonstrated in in vitro assays or in animal models or in Drosophila ) , and nucleic acids encoding a lats protein or functionally active derivative or fragment thereof (e . g . , for use in gene therapy). Other Therapeutics that can be used, e . g . , lats agonists, can be identified using in vitro assays or animal models, or assays in Drosophila , exampleε of which are described infra . In specific embodiments, Therapeutics that promote lats function are administered therapeutically (including prophylactically) : (1) in diseases or disorders involving an absence or decreased (relative to normal or desired) level of lats protein or function, for example, in patients where lats protein is lacking, genetically defective, biologically inactive or underactive, or underexpressed; or (2) in diseases or disorders wherein in vitro (or in vivo) assays (see infra) indicate the utility of lats agonist administration. The absence or decreased level in lats protein or function can be readily detected, e.g., by obtaining a patient tissue sample (e.g., from biopsy tissue) and assaying it in vitro for RNA or protein levels, structure and/or activity of the expressed lats RNA or protein. Many methods standard in the art can be thus employed, including but not limited to kinase assays, immunoassays to detect and/or visualize lats protein (e.g., Western blot, immunoprecipitation followed by sodium dodecyl sulfate polyacrylamide gel electrophoresis, immunocytochemistry, etc.) and/or hybridization assays to detect lats expression by detecting and/or visualizing lats mRNA (e . g . , Northern assays, dot blots, in situ hybridization, etc.), etc. Diseases and disorders involving cell overproliferation that can be treated or prevented include but are not limited to malignancies, premalignant conditions (e.g., hyperplasia, metaplasia, dysplasia) , benign tumors, hyperproliferative disorders, benign dysproliferative disorders, etc. Examples of these are detailed below. In a specific embodiment, the Therapeutic uεed, that promotes lats function, is a lats protein, derivative or analog comprising a lats kinase domain (and optionally also a lats LFD, or the remainder of the lats sequence) in which a serine within 20 residues upstream of the Ala-Pro-Glu consensus in subdomain eight of the kinase domain is phosphorylated or substituted by another residue (e.g., Glu, Asp) . In another specific embodiment, the Therapeutic used, that promotes lats function, is a derivative or analog comprising a kinase domain of a lats protein that has been mutated so as to be dominantly active. 5.8.1.1. MALIGNANCIES Malignancies and related disorders that can be treated or prevented by administration of a Therapeutic that promotes lats function include but are not limited to those listed in Table 1 (for a review of such disorders, see Fishman et al., 1985, Medicine , 2d Ed., J.B. Lippincott Co., Philadelphia) : TABLE 1 MALIGNANCIES AND RELATED DISORDERS Leukemia acute leukemia acute lymphocytic leukemia acute myelocytic leukemia myeloblastic promyelocytic myelomonocytic monocytic erythroleukemia chronic leukemia chronic myelocytic (granulocytic) leukemia chronic lymphocytic leukemia Polycythemia vera Lymphoma Hodgkin's disease non-Hodgkin•s disease Multiple myeloma Waldenstrδm's macroglobulinemia Heavy chain disease Solid tumors sarcomas and carcinomas fibrosarcoma myxosarcoma liposarcoma chondrosarcoma osteogenic sarcoma chordoma angiosarcoma endotheliosarcoma lymphangiosarcoma lymphangioendotheliosarcoma synovioma mesothelioma Ewing's tumor leiomyosarcoma rhabdomyosarcoma colon carcinoma pancreatic cancer breast cancer ovarian cancer prostate cancer squa ous cell carcinoma basal cell carcinoma adenocarcinoma sweat gland carcinoma sebaceous gland carcinoma papillary carcinoma papillary adenocarcinomas cystadenocarcinoma medullary carcinoma bronchogenic carcinoma renal cell carcinoma hepato a bile duct carcinoma choriocarcinoma seminoma embryonal carcinoma Wilms' tumor cervical cancer uterine cancer testicular tumor lung carcinoma small cell lung carcinoma bladder carcinoma epithelial carcinoma glioma astrocytoma medulloblastoma craniopharyngioma ependymoma pinealoma hemangioblastoma acoustic neuroma oligodendroglioma menangioma melanoma neuroblasto a retinoblastoma In specific embodiments, malignancy or dysproliferative changes (such as metaplasias and dysplasias) , or hyperproliferative disorders, are treated or prevented in the bladder, breast, colon, lung, melanoma, pancreas, or uterus. In other specific embodiments, sarcoma, or leukemia is treated or prevented. 5.8.1.2. PREMALIGNANT CONDITIONS The Therapeutics of the invention that promote lats activity can also be administered to treat premalignant conditions and to prevent progression to a neoplastic or malignant state, including but not limited to those disorders listed in Table 1. Such prophylactic or therapeutic use is indicated in conditions known or suspected of preceding progression to neoplasia or cancer, in particular, where non- neoplastic cell growth consisting of hyperplasia, metaplasia, or most particularly, dysplasia has occurred (for review of such abnormal growth conditions, see Robbins and Angel1, 1976, Basic Pathology, 2d Ed., W.B. Saunders Co., Philadelphia, pp. 68-79.) Hyperplasia is a form of controlled cell proliferation involving an increase in cell number in a tissue or organ, without significant alteration in structure or function. As but one example, endometrial hyperplasia often precedes endometrial cancer. Metaplasia is a form of controlled cell growth in which one type of adult or fully differentiated cell substitutes for another type of adult cell. Metaplasia can occur in epithelial or connective tissue cells. Atypical metaplasia involves a somewhat disorderly metaplastic epithelium. Dysplasia is frequently a forerunner of cancer, and is found mainly in the epithelia; it is the most disorderly form of non-neoplastic cell growth, involving a loss in individual cell uniformity and in the architectural orientation of cells. Dysplaεtic cellε often have abnormally large, deeply stained nuclei, and exhibit pleomorphism. Dysplaεia characteristically occurs where there exists chronic irritation or inflammation, and iε often found in the cervix, respiratory passages, oral cavity, and gall bladder. Alternatively or in addition to the presence of abnormal cell growth characterized as hyperplasia, metaplasia, or dysplasia, the presence of one or more characteristics of a transformed phenotype, or of a malignant phenotype, displayed in vivo or displayed in vitro by a cell sample from a patient, can indicate the desirability of prophylactic/therapeutic administration of a Therapeutic that promotes lats function. As mentioned supra , such characteristics of a transformed phenotype include morphology changes, looser substratum attachment, loss of contact inhibition, loss of anchorage dependence, protease release, increased sugar transport, decreased serum requirement, expression of fetal antigens, disappearance of the 250,000 dalton cell surface protein, etc. (see also id . , at pp. 84-90 for characteristics associated with a transformed or malignant phenotype) . In a specific embodiment, leukoplakia, a benign- appearing hyperplastic or dysplastic lesion of the epithelium, or Bowen's disease, a carcinoma in situ , are pre- neoplastic lesions indicative of the desirability of prophylactic intervention. In another embodiment, fibrocystic disease (cystic hyperplasia, mammary dysplasia, particularly adenosis (benign epithelial hyperplasia) ) is indicative of the desirability of prophylactic intervention. In other embodiments, a patient which exhibits one or more of the following predisposing factors for malignancy is treated by administration of an effective amount of a Therapeutic: a chromosomal translocation associated with a malignancy (e.g., the Philadelphia chromosome for chronic myelogenous leukemia, t(14;18) for follicular lymphoma, etc.), familial polyposis or Gardner's syndrome (possible forerunners of colon cancer) , benign monoclonal gam opathy (a possible forerunner of multiple myeloma) , and a first degree kinship with persons having a cancer or precancerous disease showing a Mendelian (genetic) inheritance pattern (e.g., familial polyposis of the colon, Gardner's syndrome, hereditary exostosis, polyendocrine adenomatosis, medullary thyroid carcinoma with amyloid production and pheochromocytoma, Peutz-Jeghers syndrome, neurofibromatosiε of Von Recklinghausen, retinoblastoma, carotid body tumor, 5 cutaneous melanocarcinoma, intraocular melanocarcinoma, xeroderma pigmentosum, ataxia telangiectasia, Chediak-Higashi syndrome, albinism, Fanconi's aplastic anemia, and Bloom's syndrome; see Robbins and Angel1, 1976, Basic Pathology, 2d Ed., W.B. Saunders Co., Philadelphia, pp. 112-113) etc.) 10 In another specific embodiment, a Therapeutic of the invention is administered to a human patient to prevent progression to breast, colon, lung, pancreatic, or uterine cancer, or melanoma or sarcoma. 15 5.8.1.3. HYPERPROLIFERATIVE AND DYSPROLIFERATIVE DISORDERS In another embodiment of the invention, a Therapeutic that promotes lats activity is used to treat or prevent hyperproliferative or benign dysproliferative _ 0 disorders. Specific embodiments are directed to treatment or prevention of cirrhosis of the liver (a condition in which scarring has overtaken normal liver regeneration processes) , treatment of keloid (hypertrophic scar) formation (disfiguring of the skin in which the scarring process _ interferes with normal renewal) , psoriasis (a common skin condition characterized by excessive proliferation of the skin and delay in proper cell fate determination) , benign tumors, fibrocystic conditions, and tisεue hypertrophy (e.g., prostatic hyperplasia) . 30 5.8.1.4. GENE THERAPY In a specific embodiment, nucleic acids comprising a sequence encoding a lats protein or functional derivative thereof, are administered to promote lats function, by way of 35 gene therapy. Gene therapy refers to therapy performed by the administration of a nucleic acid to a subject. In this embodiment of the invention, the nucleic acid produces its encoded protein that mediates a therapeutic effect by promoting lats function. Any of the methods for gene therapy available in the art can be used according to the present invention. 5 Exemplary methods are described below. For general reviews of the methods of gene therapy, see Goldspiel et al., 1993, Clinical Pharmacy 12:488-505; Wu and Wu, 1991, Biotherapy 3:87-95; Tolstoshev, 1993, Ann. Rev. Pharmacol. Toxicol. 32:573-596; Mulligan, 1993, Science 10 260:926-932; and Morgan and Anderson, 1993, Ann. Rev. Biochem. 62:191-217; May, 1993, TIBTECH 11(5) :155-215) . Methods commonly known in the art of recombinant DNA technology which can be used are described in Ausubel et al. (eds.), 1993, Current Protocols in Molecular Biology, John 15 Wiley & Sons, NY; and Kriegler, 1990, Gene Transfer and Expression, A Laboratory Manual, Stockton Press, NY. In a preferred aspect, the Therapeutic comprises a lats nucleic acid that is part of an expression vector that expresses a lats protein or fragment or chimeric protein 20 thereof in a suitable host. In particular, such a nucleic acid has a promoter operably linked to the lats coding region, said promoter being inducible or constitutive, and, optionally, tissue-specific. In another particular embodiment, a nucleic acid molecule is used in which the lats 25 coding sequences and any other desired sequences are flanked by regions that promote homologous recombination at a desired site in the genome, thus providing for intrachromosomal expression of the lats nucleic acid (Koller and Smithies, 1989, Proc. Natl. Acad. Sci. USA 86:8932-8935; Zijlstra et 30 al., 1989, Nature 342:435-438). Delivery of the nucleic acid into a patient may be either direct, in which caεe the patient is directly exposed to the nucleic acid or nucleic acid-carrying vector, or indirect, in which case, cells are first transformed with the 35 nucleic acid in vitro , then transplanted into the patient. These two approaches are known, respectively, as in vivo or ex vivo gene therapy. In a specific embodiment, the nucleic acid is directly administered in vivo , where it is expressed to produce the encoded product. This can be accomplished by any of numerous methods known in the art, e.g., by constructing it as part of an appropriate nucleic acid expression vector and administering it so that it becomes intracellular, e.g., by infection using a defective or attenuated retroviral or other viral vector (see U.S. Patent No. 4,980,286), or by direct injection of naked DNA, or by use of microparticle bombardment (e.g., a gene gun; Biolistic, Dupont) , or coating with lipids or cell-surface receptors or transfecting agents, encapsulation in liposomes, microparticles, or microcapεuleε, or by administering it in linkage to a peptide which is known to enter the nucleus, by administering it in linkage to a ligand subject to receptor-mediated endocytosis (see e.g., Wu and Wu, 1987, J. Biol. Chem. 262:4429-4432) (which can be used to target cell types specifically expressing the receptors) , etc. In another embodiment, a nucleic acid- ligand complex can be formed in which the ligand compriseε a fusogenic viral peptide to disrupt endosomes, allowing the nucleic acid to avoid lysosomal degradation. In yet another embodiment, the nucleic acid can be targeted in vivo for cell specific uptake and expression, by targeting a specific receptor (see, e.g., PCT Publications WO 92/06180 dated April 16, 1992 (Wu et al.); WO 92/22635 dated December 23, 1992 (Wilson et al.); WO92/20316 dated November 26, 1992 (Findeis et al.); W093/14188 dated July 22, 1993 (Clarke et al.), WO 93/20221 dated October 14, 1993 (Young)). Alternatively, the nucleic acid can be introduced intracellularly and incorporated within host cell DNA for expression, by homologous recombination (Koller and Smithies, 1989, Proc. Natl. Acad. Sci. USA 86:8932-8935; Zijlstra et al., 1989, Nature 342:435-438) . In a specific embodiment, a viral vector that contains the lats nucleic acid iε used. For example, a retroviral vector can be used (see Miller et al., 1993, Meth. Enzymol. 217:581-599). These retroviral vectors have been modified to delete retroviral sequences that are not necessary for packaging of the viral genome and integration into host cell DNA. The lats nucleic acid to be used in gene therapy is cloned into the vector, which facilitates delivery of the gene into a patient. More detail about retroviral vectors can be found in Boesen et al., 1994, Biotherapy 6:291-302, which describes the use of a retroviral vector to deliver the mdrl gene to hematopoietic stem cells in order to make the stem cells more resistant to chemotherapy. Other references illustrating the use of retroviral vectors in gene therapy are: Clowes et al., 1994, J. Clin. Invest. 93:644- 651; Kiem et al., 1994, Blood 83:1467-1473; Salmons and Gunzberg, 1993, Human Gene Therapy 4:129-141; and Grossman and Wilson, 1993, Curr. Opin. in Genetics and Devel. 3:110- 114. Adenoviruses are other viral vectors that can be used in gene therapy. Adenoviruses are especially attractive vehicles for delivering genes to respiratory epithelia. Adenoviruses naturally infect respiratory epithelia where they cause a mild disease. Other targets for adenovirus- based delivery systems are liver, the central nervous system, endothelial cells, and muscle. Adenoviruses have the advantage of being capable of infecting non-dividing cells. Kozarsky and Wilson, 1993, Current Opinion in Genetics and Development 3:499-503 present a review of adenovirus-based gene therapy. Bout et al., 1994, Human Gene Therapy 5:3-10 demonstrated the use of adenovirus vectors to transfer genes to the respiratory epithelia of rhesus monkeys. Other instances of the use of adenoviruses in gene therapy can be found in Rosenfeld et al., 1991, Science 252:431-434; Rosenfeld et al., 1992, Cell 68:143-155; and Mastrangeli et al., 1993, J. Clin. Invest. 91:225-234. Adeno-associated virus (AAV) has also been proposed for use in gene therapy (Walsh et al., 1993, Proc. Soc. Exp. Biol. Med. 204:289-300. Another approach to gene therapy involves transferring a gene to cells in tissue culture by such methods as electroporation, lipofection, calcium phosphate mediated transfection, or viral infection. Usually, the method of transfer includes the transfer of a selectable marker to the cells. The cells are then placed under selection to isolate those cells that have taken up and are expressing the transferred gene. Those cells are then delivered to a patient. In this embodiment, the nucleic acid is introduced into a cell prior to administration in vivo of the resulting recombinant cell. Such introduction can be carried out by any method known in the art, including but not limited to transfection, electroporation, microinjection, infection with a viral or bacteriophage vector containing the nucleic acid sequences, cell fusion, chromosome-mediated gene transfer, microcell-mediated gene transfer, spheroplast fusion, etc. Numerous techniques are known in the art for the introduction of foreign genes into cells (see e.g., Loeffler and Behr, 1993, Meth. Enzymol. 217:599-618; Cohen et al., 1993, Meth. Enzymol. 217:618-644; Cline, 1985, Pharmac. Ther. 29:69-92) and may be used in accordance with the present invention, provided that the necessary developmental and physiological functions of the recipient cells are not disrupted. The technique should provide for the stable transfer of the nucleic acid to the cell, so that the nucleic acid is expressible by the cell and preferably heritable and expressible by its cell progeny. The resulting recombinant cells can be delivered to a patient by various methods known in the art. In a preferred embodiment, epithelial cells are injected, e . g . , subcutaneously. In another embodiment, recombinant skin cells may be applied as a εkin graft onto the patient. Recombinant blood cellε (e.g., hematopoietic εtem or progenitor cells) are preferably administered intravenously. The amount of cells envisioned for use depends on the desired effect, patient state, etc., and can be determined by one skilled in the art. Cells into which a nucleic acid can be introduced for purposes of gene therapy encompass any desired, available cell type, and include but are not limited to epithelial cells, endothelial cells, keratinocytes, fibroblasts, muscle cells, hepatocytes; blood cells such as T lymphocytes, B lymphocytes, monocytes, macrophages, neutrophils, eosinophils, megakaryocytes, granulocytes; various stem or progenitor cells, in particular hematopoietic stem or progenitor cells, e.g., as obtained from bone marrow, umbilical cord blood, peripheral blood, fetal liver, etc. In a preferred embodiment, the cell used for gene therapy is autologous to the patient. In an embodiment in which recombinant cells are used in gene therapy, a lats nucleic acid is introduced into the cells such that it is expressible by the cells or their progeny, and the recombinant cells are then administered in vivo for therapeutic effect. In a specific embodiment, stem or progenitor cells are used. Any stem and/or progenitor cells which can be isolated and maintained in vitro can potentially be used in accordance with this embodiment of the present invention. Such stem cells include but are not limited to hematopoietic stem cells (HSC) , εtem cellε of epithelial tissues such as the skin and the lining of the gut, embryonic heart muscle cells, liver stem cells (PCT Publication WO 94/08598, dated April 28, 1994), and neural stem cells (Stemple and Anderson, 1992, Cell 71:973-985). Epithelial stem cells (ESCs) or keratinocytes can be obtained from tissues such as the εkin and the lining of the gut by known procedureε (Rheinwald, 1980, Meth. Cell Bio. 21A:229) . In stratified epithelial tissue such as the skin, renewal occurs by mitosis of stem cells within the germinal layer, the layer closest to the basal lamina. Stem cells within the lining of the gut provide for a rapid renewal rate of this tissue. ESCs or keratinocytes obtained from the skin or lining of the gut of a patient or donor can be grown in tissue culture (Rheinwald, 1980, Meth. Cell Bio. 21A:229; Pittelkow and Scott, 1986, Mayo Clinic Proc. 61:771). If the ESCs are provided by a donor, a method for suppression of host versus graft reactivity (e.g., irradiation, drug or antibody administration to promote moderate immunosuppreεεion) can also be used. With respect to hematopoietic stem cells (HSC) , any technique which provides for the isolation, propagation, and maintenance in vitro of HSC can be used in this embodiment of the invention. Techniques by which this may be accompliεhed include (a) the isolation and establishment of HSC cultures from bone marrow cells isolated from the future host, or a donor, or (b) the use of previously established long-term HSC cultures, which may be allogeneic or xenogeneic. Non- autologous HSC are used preferably in conjunction with a method of suppressing transplantation immune reactions of the future host/patient. In a particular embodiment of the present invention, human bone marrow cells can be obtained from the posterior iliac crest by needle aεpiration (see, e.g., Kodo et al., 1984, J. Clin. Invest. 73:1377-1384). In a preferred embodiment of the present invention, the HSCs can be made highly enriched or in substantially pure form. This enrichment can be accomplished before, during, or after long- term culturing, and can be done by any techniqueε known in the art. Long-term cultureε of bone marrow cellε can be established and maintained by using, for example, modified Dexter cell culture techniques (Dexter et al., 1977, J. Cell Physiol. 91:335) or Witlock-Witte culture techniques (Witlock and Witte, 1982, Proc. Natl. Acad. Sci. USA 79:3608-3612). In a specific embodiment, the nucleic acid to be introduced for purposeε of gene therapy co priεeε an inducible promoter operably linked to the coding region, such that expression of the nucleic acid is controllable by controlling the presence or absence of the appropriate inducer of transcription. Additional methods that can be adapted for use to deliver a nucleic acid encoding a latε protein or functional derivative thereof are deεcribed in Section 5.8.2.2.2. 5.8.2. TREATMENT AND PREVENTION OF DISORDERS IN WHICH CELL PROLIFERATION IS DESIRED Diseases and disorders involving a deficiency in cell proliferation (growth) or in which cell proliferation is _ otherwise desirable for treatment or prevention, are treated or prevented by administration of a Therapeutic that antagonizes (inhibits) lats function (in particular, lats- mediated inhibition of cell proliferation) . Therapeutics that can be used include but are not limited to anti-lats , 0 antibodies (and fragments and derivatives thereof containing the binding region thereof) , lats derivatives or analogs that are dominant-negative kinases, lats antisense nucleic acids, and lats nucleic acids that are dysfunctional (e.g., due to a heterologous (non-lats sequence) insertion within the lats 15 coding sequence) that are used to "knockout" endogenous lats function by homologous recombination (see, e.g., Capecchi, 1989, Science 244:1288-1292). In a specific embodiment of the invention, a nucleic acid containing a portion of a lats gene in which lats sequences flank (are both 5' and 3' to) a 20 different gene sequence, is used, as a lats antagonist, to promote lats inactivation by homologous recombination (see also Koller and Smithies, 1989, Proc. Natl. Acad. Sci. USA 86:8932-8935; Zijlstra et al., 1989, Nature 342:435-438). Other Therapeutics that inhibit lats function can be 2 _ identified by use of known convenient in vitro assays, e.g., based on their ability to inhibit binding of lats to another protein (e.g., an SH3-domain containing protein), or inhibit any known lats function, as preferably assayed in vi tro or in cell culture, although genetic assays (e.g., in Drosophila ) _ may also be employed. Preferably, suitable in vitro or in vivo assayε, are utilized to determine the effect of a specific Therapeutic and whether its administration is indicated for treatment of the affected tissue. In specific embodiments, Therapeutics that inhibit 3 _ lats function are administered therapeutically (including prophylactically) : (1) in diseases or disorderε involving an increased (relative to normal or desired) level of lats protein or function, for example, in patients where lats protein is overactive or overexpressed; or (2) in diseases or disorders wherein in vitro (or in vivo) assays (see infra) indicate the utility of lats antagonist administration. The increased levels in lats protein or function can be readily detected, e.g., by quantifying protein and/or RNA, by obtaining a patient tissue sample (e.g., from biopsy tisεue) and assaying it in vitro for RNA or protein levels, structure and/or activity of the expressed lats RNA or protein. Many methods standard in the art can be thus employed, including but not limited to kinase assays, immunoassays to detect and/or visualize lats protein (e.g., Western blot, immunoprecipitation followed by sodium dodecyl sulfate polyacrylamide gel electrophoresis, immunocytochemiεtry, etc.) and/or hybridization assays to detect lats expression by detecting and/or visualizing respectively lats mRNA (e.g., Northern assays, dot blots, in situ hybridization, etc.), etc. Diεeaεeε and diεorderε involving a deficiency in cell proliferation or in which cell proliferation is desired for treatment or prevention, and that can be treated or prevented by inhibiting lats function, include but are not limited to degenerative disorders, growth deficiencies, hypoproliferative disorders, physical trauma, lesions, and wounds; for example, to promote wound healing, or to promote regeneration in degenerated, lesioned or injured tissues, etc. In a specific embodiment, nervous system disorders are treated. In another specific embodiment, a disorder that is not of the nervous syεtem is treated. Lesions which may be treated according to the present invention include but are not limited to the following lesionε: (i) traumatic leεionε, including leεionε cauεed by phyεical injury or associated with εurgery; (ϋ) ischemic lesionε, in which a lack of oxygen reεultε in cell injury or death, e.g., myocardial or cerebral infarction or ischemia, or spinal cord infarction or ischemia; (iii) malignant lesions, in which cells are destroyed or injured by malignant tissue; (iv) infectious lesions, in which tissue is destroyed or injured as a result of infection, for example, by an abscess or associated with infection by human immunodeficiency virus, herpes zoster, or herpes simplex virus or with Lyme disease, tuberculosis, syphilis; (v) degenerative lesions, in which tisεue iε destroyed or injured as a result of a degenerative process, including but not limited to nervous system degeneration associated with Parkinson's disease, Alzheimer's diseaεe, Huntington's chorea, or amyotrophic lateral scleroεiε; (vi) lesions associated with nutritional diseaεeε or disorders, in which tissue is destroyed or injured by a nutritional disorder or disorder of metabolism including but not limited to, vitamin B12 deficiency, folic acid deficiency, Wernicke disease, tobacco-alcohol amblyopia, Marchiafava-Bignami disease (primary degeneration of the corpus callosum) , and alcoholic cerebellar degeneration; (vii) lesionε associated with syεtemic diseases including but not limited to diabetes or systemic lupus erythematosus; (viii) lesionε cauεed by toxic substances including alcohol, lead, or other toxins; and (ix) demyelinated lesions of the nervous syεtem, in which a portion of the nervouε εyεte iε destroyed or injured by a demyelinating disease including but not limited to multiple sclerosis, human immunodeficiency virus- associated myelopathy, transverεe myelopathy or various etiologies, progressive multifocal leukoencephalopathy, and central pontine myelinolysis. Nervous system lesions which may be treated in a patient (including human and non-human mammalian patients) according to the invention include but are not limited to the lesions of either the central (including spinal cord, brain) or peripheral nervous systems. Therapeutics which are useful according to this embodiment of the invention for treatment of a disorder may be selected by testing for biological activity in promoting the survival or differentiation of cells (see also Section 5.9). For example, in a specific embodiment relating to therapy of the nervous system, a Therapeutic which elicits one of the following effects may be useful according to the invention: (i) increased sprouting of neurons in culture or in vivo; (ii) increased production of a neuron-asεociated molecule in culture or in vivo , e . g . , choline acetyltranεferase or acetylcholinesteraεe with respect to motor neurons; or (iii) decreased εymptomε of neuron dyεfunction in vivo. Such effects may be measured by any method known in the art. In preferred, non-limiting embodiments, increased sprouting of neurons may be detected by methods set forth in Pestronk et al. (1980, Exp. Neurol. 70:65-82) or Brown et al. (1981, Ann. Rev. Neurosci. 4:17-42); and increased production of neuron-associated molecules may be measured by bioassay, enzymatic assay, antibody binding, Northern blot assay, etc., depending on the molecule to be measured. 5.8.2.1. ANTISENSE REGULATION OF LATS EXPRESSION In a specific embodiment, lats function is inhibited by use of lats antisense nucleic acids. The present invention provides the therapeutic or prophylactic use of nucleic acids of at least six nucleotides that are antisense to a gene or cDNA encoding lats or a portion thereof. A lats "antisense" nucleic acid as used herein refers to a nucleic acid capable of hybridizing to a portion of a lats RNA (preferably mRNA) by virtue of some sequence complementarity. The antisense nucleic acid may be complementary to a coding and/or noncoding region of a lats mRNA. Such antisense nucleic acids have utility as Therapeutics that inhibits lats function, and can be used in the treatment or prevention of disorders as described supra in Section 5.8.2 and its subsections. The antisense nucleic acids of the invention can be oligonucleotides that are double-stranded or single-stranded, RNA or DNA or a modification or derivative thereof, which can be directly administered to a cell, or which can be produced intracellularly by transcription of exogenous, introduced sequences. In a specific embodiment, the lats antisense nucleic acids provided by the instant invention can be used to promote regeneration or wound healing or to promote growth (larger size) . The invention further provides pharmaceutical compositions comprising an effective amount of the lats antisense nucleic acids of the invention in a pharmaceutically acceptable carrier, as deεcribed infra . In another embodiment, the invention iε directed to methodε for inhibiting the expreεsion of a lats nucleic acid sequence in a prokaryotic or eukaryotic cell comprising providing the cell with an effective amount of a composition comprising an lats antisense nucleic acid of the invention. Lats antisense nucleic acids and their uses are described in detail below. 5.8.2.1.1. LATS ANTISENSE NUCLEIC ACIDS The lats antisense nucleic acids are of at least six nucleotides and are preferably oligonucleotides (ranging from 6 to about 50 oligonucleotides) . In specific aspects, 5 the oligonucleotide is at least 10 nucleotides, at least 15 nucleotides, at least 100 nucleotides, or at least 200 nucleotides. The oligonucleotides can be DNA or RNA or chimeric mixtures or derivatives or modified versions thereof, single-stranded or double-stranded. The 10 oligonucleotide can be modified at the base moiety, sugar moiety, or phosphate backbone. The oligonucleotide may include other appending groups such as peptides, or agentε facilitating transport across the cell membrane (see, e.g., Letsinger et al., 1989, Proc. Natl. Acad. Sci. U.S.A. 15 86:6553-6556; Lemaitre et al., 1987, Proc. Natl. Acad. Sci. 84:648-652; PCT Publication No. WO 88/09810, published December 15, 1988) or blood-brain barrier (see, e.g., PCT Publication No. WO 89/10134, published April 25, 1988), hybridization-triggered cleavage agentε (see, e.g., Krol et 20 al., 1988, BioTechniques 6:958-976) or intercalating agents (see, e.g., Zon, 1988, Pharm. Res. 5:539-549). In a preferred aspect of the invention, a lats antisense oligonucleotide is provided, preferably of single- stranded DNA. In a most preferred aspect, such an 25 oligonucleotide comprises a sequence antisense to the sequence encoding an SH3 binding domain or a kinase domain of a lats protein, most preferably, of a human lats protein. The oligonucleotide may be modified at any position on its structure with substituents generally known in the art. 30 The lats antisense oligonucleotide may comprise at least one modified base moiety which is εelected from the group including but not limited to 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xantine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 35 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D- galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil , beta-D-mannosylqueosine, 5 , -methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v) , wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil- 5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v) , 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w, and 2,6-diaminopurine. In another embodiment, the oligonucleotide comprises at least one modified sugar moiety selected from the group including but not limited to arabinose, 2-fluoroarabinose, xylulose, and hexose. In yet another embodiment, the oligonucleotide comprises at least one modified phosphate backbone selected from the group consisting of a phosphorothioate, a phosphorodithioate, a phosphoramidothioate, a phosphoramidate, a phosphordiamidate, a methylphosphonate, an alkyl phosphotriester, and a for acetal or analog thereof. In yet another embodiment, the oligonucleotide is an α-anomeric oligonucleotide. An α-anomeric oligonucleotide forms specific double-stranded hybrids with complementary RNA in which, contrary to the usual 3-units, the strands run parallel to each other (Gautier et al., 1987, Nucl. Acids Res. 15:6625-6641) . The oligonucleotide may be conjugated to another molecule, e.g., a peptide, hybridization triggered cross- linking agent, transport agent, hybridization-triggered cleavage agent, etc. Oligonucleotideε of the invention may be synthesized by standard methods known in the art, e.g. by use of an automated DNA synthesizer (such as are commercially available from Biosearch, Applied Bioεyεtemε, etc.). Aε examples, phosphorothioate oligonucleotides may be synthesized by the method of Stein et al. (1988, Nucl. Acids Res. 16:3209), methylphosphonate oligonucleotides can be prepared by use of controlled pore glasε polymer supports (Sarin et al., 1988, Proc. Natl. Acad. Sci. U.S.A. 85:7448- 5 7451) , etc. In a specific embodiment, the lats antisense oligonucleotide comprises catalytic RNA, or a ribozyme (see, e.g., PCT International Publication WO 90/11364, published October 4, 1990; Sarver et al., 1990, Science 247:1222-1225). 0 In another embodiment, the oligonucleotide is a 2'-0- methylribonucleotide (Inoue et al., 1987, Nucl. Acids Res. 15:6131-6148), or a chimeric RNA-DNA analogue (Inoue et al., 1987, FEBS Lett. 215:327-330). In an alternative embodiment, the lats antisenεe 5 nucleic acid of the invention iε produced intracellularly by transcription from an exogenous sequence. For example, a vector can be introduced in vivo such that it is taken up by a cell, within which cell the vector or a portion thereof is transcribed, producing an antisenεe nucleic acid (RNA) of the 0 invention. Such a vector would contain a sequence encoding the lats antisense nucleic acid. Such a vector can remain episomal or become chromosomally integrated, aε long aε it can be transcribed to produce the desired antisense RNA. Such vectors can be constructed by recombinant DNA technology 5 methods standard in the art. Vectors can be plasmid, viral, or others known in the art, used for replication and expression in mammalian cells. Expression of the sequence encoding the lats antisenεe RNA can be by any promoter known in the art to act in mammalian, preferably human, cells. 0 Such promoterε can be inducible or constitutive. Such promoterε include but are not limited to: the SV40 early promoter region (Bernoiεt and Chambon, 1981, Nature 290:304- 310), the promoter contained in the 3' long terminal repeat of Rouε εarcoma viruε (Yamamoto et al., 1980, Cell 22:787- 5 797), the herpes thymidine kinase promoter (Wagner et al., 1981, Proc. Natl. Acad. Sci. U.S.A. 78:1441-1445), the regulatory sequences of the metallothionein gene (Brinster et al., 1982, Nature 296:39-42), etc. The antisense nucleic acids of the invention comprise a sequence complementary to at least a portion of an 5 RNA transcript of a lats gene, preferably a human lats gene. However, absolute complementarity, although preferred, is not required. A sequence "complementary to at least a portion of an RNA," as referred to herein, means a sequence having sufficient complementarity to be able to hybridize with the 0 RNA, forming a stable duplex; in the case of double-stranded lats antisense nucleic acids, a single strand of the duplex DNA may thus be tested, or triplex formation may be assayed. The ability to hybridize will depend on both the degree of complementarity and the length of the antisense nucleic acid. 5 Generally, the longer the hybridizing nucleic acid, the more base mismatches with a lats RNA it may contain and still form a stable duplex (or triplex, as the case may be) . One skilled in the art can ascertain a tolerable degree of mismatch by use of standard procedures to determine the 0 melting point of the hybridized complex. 5.8.2.1.2. THERAPEUTIC USE OF LATS ANTISENSE NUCLEIC ACIDS The lats antisense nucleic acids can be used to _ treat (or prevent) disorders of a cell type that expresses, or preferably overexpresses, lats . In a specific embodiment, such a disorder is a growth deficiency. In a preferred embodiment, a single-stranded DNA antisense lats oligonucleotide is used. 0 Cell types which expresε or overexpress lats RNA can be identified by variouε methodε known in the art. Such methodε include but are not limited to hybridization with a lats-specific nucleic acid (e.g. by Northern hybridization, dot blot hybridization, in situ hybridization) , observing the 5 ability of RNA from the cell type to be translated in vitro into lats, immunoassay, etc. In a preferred aspect, primary tissue from a patient can be assayed for lats expression prior to treatment, e.g., by immunocytochemistry or in situ hybridization. Pharmaceutical compositions of the invention (see Section 5.10), comprising an effective amount of a lats antisense nucleic acid in a pharmaceutically acceptable carrier, can be administered to a patient having a disease or disorder which is of a type that expresses or overexpresses lats RNA or protein. The amount of lats antisense nucleic acid which will be effective in the treatment of a particular disorder or condition will depend on the nature of the disorder or condition, and can be determined by standard clinical techniques. Where possible, it is desirable to determine the antisense cytotoxicity of the tumor type to be treated in vitro, and then in useful animal model syεtemε prior to testing and use in humans. In a specific embodiment, pharmaceutical compositions comprising lats antisense nucleic acids are administered via liposomes, microparticles, or microcapsules. 0 In various embodiments of the invention, it may be useful to use such compositions to achieve sustained release of the lats antisense nucleic acids. In a specific embodiment, it may be desirable to utilize liposomes targeted via antibodies to specific identifiable tumor antigens (Leonetti et al., 5 1990, Proc. Natl. Acad. Sci. U.S.A. 87:2448-2451; Renneisen et al., 1990, J. Biol. Chem. 265:16337-16342). Additional methods that can be adapted for use to deliver a lats antisense nucleic acid are described in Section 5.8.1.4. 0 5.9. DEMONSTRATION OF THERAPEUTIC OR PROPHYLACTIC UTILITY The Therapeutics of the invention are preferably tested in vitro , and then in vivo for the desired therapeutic _ or prophylactic activity, prior to use in humans. For example, In vitro aεεayε which can be uεed to determine whether adminiεtration of a εpecific Therapeutic is indicated, include in vitro cell culture assays in which a patient tissue sample is grown in culture, and exposed to or otherwise administered a Therapeutic, and the effect of such Therapeutic upon the tissue sample is observed. In one embodiment, where the patient has a malignancy, a sample of cells from such malignancy is plated out or grown in culture, and the cells are then exposed to a Therapeutic. A Therapeutic which inhibits survival or growth of the malignant cells is selected for therapeutic use in vivo . Many assays standard in the art can be used to assess such survival and/or growth; for example, cell proliferation can be assayed by measuring 3 H-thymidine incorporation, by direct cell count, by detecting changes in transcriptional activity of known genes such as proto-oncogenes (e.g., fos, myc) or cell cycle markers; cell viability can be assessed by trypan blue staining, differentiation can be asεessed visually based on changes in morphology, etc. In another embodiment, a Therapeutic is indicated for use which exhibits the desired effect, inhibition or promotion of cell growth, upon a patient cell sample from tissue having or suspected of having a hyper- or hypoproliferative disorder, respectively. Such hyper- or hypoproliferative disorders include but are not limited to those described in Sections 5.8.1 through 5.8.3 infra . In another specific embodiment, a Therapeutic is indicated for use in treating cell injury or a degenerative disorder (see Section 5.8.2) which exhibits in vitro promotion of growth/proliferation of cells of the affected patient type. Regarding nervous syεtem diεorders, see also Section 5.8.2.1 for asεays that can be used. In various specific embodiments, in vi tro assays can be carried out with representative cells of cell types involved in a patient's disorder, to determine if a Therapeutic has a desired effect upon such cell types. in another embodiment, cells of a patient tisεue sample suspected of being pre-neoplastic are similarly plated out or grown in vitro , and exposed to a Therapeutic. The Therapeutic which results in a cell phenotype that is more normal (i.e., less representative of a pre-neoplastic state, neoplastic state, malignant state, or transformed phenotype) is selected for therapeutic use. Many assays standard in the art can be used to assess whether a pre-neoplastic state, neoplastic state, or a transformed or malignant phenotype, is present. For example, characteristics associated with a transformed phenotype (a set of in vitro characteristics associated with a tumorigenic ability in vivo) include a more rounded cell morphology, looser subεtratum attachment, loεε of contact inhibition, loss of anchorage dependence, release of proteases such as plasminogen activator, increased sugar transport, decreased serum requirement, expression of fetal antigens, disappearance of the 250,000 dalton surface protein, etc. (see Luria et al., 1978, General Virology, 3d Ed., John Wiley & Sons, New York pp. 436-446). In other specific embodiments, the in vitro assays described supra can be carried out using a cell line, rather than a cell sample derived from the specific patient to be treated, in which the cell line is derived from or displayε characteristic(s) associated with the malignant, neoplastic or pre-neoplastic disorder desired to be treated or prevented, or is derived from the cell type upon which an effect is desired, according to the present invention. Compounds for use in therapy can be tested in suitable animal model systems prior to testing in humans, including but not limited to rats, mice, chicken, cows, monkeys, rabbits, etc. For in vivo testing, prior to administration to humans, any animal model syεtem known in the art may be used. 5.10. THERAPEUTIC/PROPHYLACTIC ADMINISTRATION AND COMPOSITIONS The invention provideε methodε of treatment (and prophylaxiε) by administration to a subject of an effective amount of a Therapeutic of the invention. In a preferred aspect, the Therapeutic is εubεtantially purified. The subject is preferably an animal, including but not limited to animals such as cows, pigs, horses, chickens, cats, dogs, etc., and is preferably a mammal, and most preferably human. In a specific embodiment, a non-human mammal is the subject. Formulations and methods of administration that can be employed when the Therapeutic comprises a nucleic acid are described in Sections 5.8.1.4 and 5.8.2.2 above; additional appropriate formulations and routes of administration can be selected from among those described hereinbelow. Various delivery systems are known and can be used to administer a Therapeutic of the invention, e.g., encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the Therapeutic, receptor-mediated endocytosis (see, e . g . , Wu and Wu, 1987, J. Biol. Chem. 262:4429-4432), construction of a Therapeutic nucleic acid as part of a retroviral or other vector, etc. Methods of introduction include but are not limited to intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The compounds may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents. Administration can be systemic or local. In addition, it may be desirable to introduce the pharmaceutical compositionε of the invention into the central nervous system by any suitable route, including intraventricular and intrathecal injection; intraventricular injection may be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya reservoir. Pulmonary administration can also be employed, e.g., by use of an inhaler or nebulizer, and formulation with an aerosolizing agent. In a specific embodiment, it may be desirable to administer the pharmaceutical compositions of the invention locally to the area in need of treatment; thiε may be achieved by, for example, and not by way of limitation, local infusion during surgery, topical application, e.g., in conjunction with a wound dressing after surgery, by injection, by means of a catheter, by means of a suppository, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers. In one embodiment, administration can be by direct injection at the site (or former site) of a malignant tumor or neoplastic or pre- neoplastic tissue. In another embodiment, the Therapeutic can be delivered in a vesicle, in particular a liposome (see Langer, Science 249:1527-1533 (1990); Treat et al., in Lipoεomeε in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989); Lopez-Berestein, iJid., pp. 317-327; see generally iJid.) In yet another embodiment, the Therapeutic can be delivered in a controlled release system. In one embodiment, a pump may be used (see Langer, supra ; Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989)). In another embodiment, polymeric materials can be used (see Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Florida (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, J. Macromol. Sci. Rev. Macromol. Chem. 23:61 (1983); see also Levy et al., Science 228:190 (1985); During et al., Ann. Neurol. 25:351 (1989); Howard et al., J. Neurosurg. 71:105 (1989)). In yet another embodiment, a controlled release system can be placed in proximity of the therapeutic target, i.e., the brain, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra , vol. 2, pp. 115-138 (1984) ) . Other controlled release systemε are discusεed in the review by Langer (Science 249:1527-1533 (1990)). In a specific embodiment where the Therapeutic is a nucleic acid encoding a protein Therapeutic, the nucleic acid can be administered in vivo to promote expression of its encoded protein, by constructing it as part of an appropriate nucleic acid expression vector and administering it so that it becomes intracellular, e.g., by use of a retroviral vector (see U.S. Patent No. 4,980,286), or by direct injection, or by use of microparticle bombardment (e.g., a gene gun; Biolistic, Dupont) , or coating with lipids or cell-surface receptors or transfecting agents, or by administering it in linkage to a homeobox-like peptide which is known to enter the nucleus (see e.g., Joliot et al., 1991, Proc. Natl. Acad. Sci. USA 88:1864-1868), etc. Alternatively, a nucleic acid Therapeutic can be introduced intracellularly and incorporated within host cell DNA for expresεion, by homologous recombination. The present invention also provides pharmaceutical compositions. Such compositions comprise a therapeutically effective amount of a Therapeutic, and a pharmaceutically acceptable carrier. In a specific embodiment, the term "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred carrier when the pharmaceutical composition is administered intravenously. Saline solutionε and aqueouε dextroεe and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucoεe, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, εodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like. The composition can be formulated as a suppository, with traditional binders and carriers εuch as triglycerides. Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin. Such compositions will contain a therapeutically effective amount of the Therapeutic, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient. The formulation should suit the mode of administration. In a preferred embodiment, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to human beings. Typically, compositionε for intravenous administration are solutionε in sterile isotonic aqueous buffer. Where necesεary, the compoεition may alεo include a solubilizing agent and a local anesthetic such as lignocaine to ease pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit doεage form, for example, aε a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent. Where the composition iε to be adminiεtered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration. The Therapeutics of the invention can be formulated as neutral or salt forms. Pharmaceutically acceptable salts include those formed with free amino groups such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with free carboxyl groups such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine, etc. The amount of the Therapeutic of the invention which will be effective in the treatment of a particular disorder or condition will depend on the nature of the disorder or condition, and can be determined by standard clinical techniques. In addition, in vitro assays may optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the formulation will also depend on the route of administration, and the seriousness of the disease or disorder, and should be decided according to the judgment of the practitioner and each patient's circumstances. However, suitable dosage ranges for intravenous administration are generally about 20-500 micrograms of active compound per kilogram body weight. Suitable dosage ranges for intranasal administration are generally about 0.01 pg/kg body weight to 1 mg/kg body weight. Effective doses may be extrapolated from dose- response curves derived from in vitro or animal model test systems. Suppositories generally contain active ingredient in the range of 0.5% to 10% by weight; oral formulations preferably contain 10% to 95% active ingredient. The invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, uεe or εale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration. 5.11. ADDITIONAL USE OF INHIBITION OF LATS 5 FUNCTION TO PROMOTE INCREASED GROWTH Inhibition of lats function (e.g., by administering a compound that inhibits lats function as described in Sections 5.8.2 through 5.8.2.1.2 above), has utility that is not limited to therapeutic or prophylactic applications. For , 0 example, lats function can be inhibited in order to increase growth of animals (e.g., cows, horεeε, pigε, goatε, deer, chickens) and plants (particularly edible plants, e.g., tomatoes, melons, lettuce, carrots, potatoes, and other vegetables) , particularly those that are food or material sources. For example, antisense inhibition (preferably where the lats antisense nucleic acid is under the control of a tissue-specific promoter) can be used in plants or animals to increase growth where desired (e.g., in the fruit or muscle) . For example, a lats antisense nucleic acid under the control 2 _ of a temperature-sensitive promoter can be administered to a plant or animal, and the desired portion of the (or the entire) plant or animal can be subjected to heat in order to induce antisense nucleic acid production, resulting lats inhibition, and resulting cell proliferation. In other 2 _ embodiments, chemical mutagenesis, or homologous recombination with an insertionally inactivated lats gene (see Capecchi, 1989, Science 244:1288-1292 and Section 5.14 infra) can be carried out to reduce or destroy endogenous lats function, in order to achieve increased growth. Suitable methods, modes of administration and compositions, that can be used to inhibit lats function are described in Sectionε 5.8.2 through 5.8.2.1.2, above. Methodε to make plantε recombinant are commonly known in the art and can be used. Regarding methods of plant tranεfor ation (e.g., for _35_ transformation with a lats antisense nucleic acid or with a sequence encoding a lats derivative that is a dominant- negative kinase) , see e.g., Valvekens et al., 1988, Proc. Natl. Acad. Sci. USA 85:5536-5540. Regarding methods of targeted gene inactivation in plants (e.g., to inactivate lats) , see e.g., Miao and Lam, 1995, The Plant J. 7:359-365. Inhibition of lats function can also have uses in 5 vitro , e .g. , to expand cells in vitro , including but not limited to stem cells, progenitor cells, muscle cells, fibroblasts, liver cells, etc., e.g., to grow cells/tissue in vitro prior to administration to a patient (preferably a patient from which the cells were derived) , etc. 0 5.12. ADDITIONAL USE OF INHIBITION OF LATS FUNCTION TO INHIBIT CELLULAR SENESCENCE Inhibition of lats function (e.g., by ad iniεtering a compound that inhibits lats function as described in Sections 5.8.2 through 5.8.2.1.2 above), also has utility in the inhibition of cellular senescence. Thuε, inhibition of lats function can be carried out to delay or prevent the onset of cellular senescence, in vivo or in vitro . In a specific embodiment, cellular senescence is delayed or 0 prevented without incurring the onset of cell malignancy or its in vitro correlate, a transformed phenotype. Thus, for example, a lats antagonist (e.g., anti- lats antibody, lats derivatives or analogs that are dominant- negative kinases; lats antisense nucleic acids, etc.) can be _ administered to a subject to inhibit or prevent aging or cell death or the effects of aging or cell death (e.g., in the skin, wrinkling, losε of elasticity, less uniform skin tone; in the skin and elsewhere, loss of known characteristicε of proper phyεiological function εuch as expreεεion of Q characteristic antigens, secreted molecules, etc.) In one embodiment, a lats antagonist is applied topically, e.g., in a cream or gel, to the skin of the subject. In another embodiment, a lats antagonist is injected, e.g., intradermally, intraperitoneally, or intramuscularly. 5 In a specific embodiment, a lats antagonist is contacted with cells grown in culture, e.g., by addition of the antagonist to the culture medium or by adsorption of the antagonist to the culture plate or flask prior to seeding of the cells, in order to inhibit or delay senescence in vitro, e.g., to delay "crisis" phase. For example, such a method can be carried out in order to lengthen the time that cells can be kept alive in vitro, e . g . , in order to facilitate conducting studies of the toxicity of a compound (e.g., a lead drug candidate) upon such cells, to study the effect of a molecule upon cell function, and, generally, to study the function of such cells. Such cells include but are not limited to neurons of the central nervous syεtem (e.g., hippocampal, hypothalmic) or peripheral nervous εyεtem, glial cells, fibroblasts, kidney cells, liver cells, heart cells, muscle cells, endothelial cells, melanocyteε, and hematopoietic cells such and T and B lymphocytes, macrophages, granulocytes, and mast cells. In vitro assays of senescence are well known in the art and can be used to screen potential lats antagoniεtε prior to use in this aspect of the invention (see, e . g . , Hubbard and Ozer, 1995, "Senescence and immortalization of human cells," in Cell Growth and Apoptosiε. A Practical Approach. Ch. 12, Studzinski, G.P. (ed.), Oxford University Press, Inc., New York, NY, pp. 229-248. 5.13. DIAGNOSIS AND SCREENING Lats proteins, analogues, derivatives, and subsequences thereof, lats nucleic acids (and sequenceε complementary thereto) , anti-latε antibodieε, have uses in diagnostics. Such molecules can be uεed in aεεayε, εuch as immunoassayε, to detect, prognoεe, diagnoεe, or monitor various conditions, diseaseε, and diεorderε affecting lats expression, or monitor the treatment thereof. In particular, such an immunoassay is carried out by a method comprising contacting a sample derived from a patient with an anti-lats antibody under conditions such that i munospecific binding can occur, and detecting or measuring the amount of any immunospecific binding by the antibody. In a specific aspect, such binding of antibody, in tissue sectionε, can be used to detect aberrant lats localization or aberrant (e.g., low or absent) levels of lats. In a specific embodiment, antibody to lats can be used to assay in a patient tissue or serum sample for the presence of lats where an aberrant level of lats is an indication of a diseased condition. By "aberrant levels," is meant increased or decreased levels relative to that present, or a standard level representing that present, in an analogous sample from a portion of the body or from a subject not having the disorder. The immunoassays which can be used include but are not limited to competitive and non-competitive assay systems using techniques such as western blots, radioimmunoassays, ELISA (enzyme linked immunosorbent assay) , "sandwich" immunoassays, immunoprecipitation assays, precipitin reactions, gel diffusion precipitin reactions, immunodiffusion assays, agglutination assays, complement- fixation assays, immunoradiometric assays, fluorescent immunoassays, protein A immunoassays, to name but a few. Lats geneε and related nucleic acid sequences and subsequences, including complementary sequenceε, can also be used in hybridization assays. Lats nucleic acid sequenceε, or subsequences thereof comprising about at least 8 nucleotides, can be used as hybridization probes. Hybridization assays can be used to detect, prognose, diagnose, or monitor conditions, disorders, or disease states associated with aberrant changes in lats expresεion and/or activity aε deεcribed supra . In particular, εuch a hybridization aεsay is carried out by a method comprising contacting a sample containing nucleic acid with a nucleic acid probe capable of hybridizing to lats DNA or RNA, under conditions such that hybridization can occur, and detecting or measuring any reεulting hybridization. In specific embodiments, diseases and disorders involving overproliferation of cells can be diagnosed, or their suspected presence can be εcreened for, or a predisposition to develop such disorders can be detected, by detecting decreased levels of lats protein, lats RNA, or lats functional activity (e.g., kinase activity, SH3 domain- binding activity, etc.), or by detecting mutations in lats RNA, DNA or protein (e.g., translocations in lats nucleic acids, truncations in the lats gene or protein, changes in nucleotide or amino acid sequence relative to wild-type lats) that cause decreased expression or activity of lats. Such diseases and disorders include but are not limited to those described in Section 5.8.1 and its subsectionε. By way of example, levels of lats protein can be detected by immunoassay, levels of lats RNA can be detected by hybridization assays (e.g., Northern blots, dot blots), lats kinase activity can be measured by kinase assays commonly known in the art, lats binding to an SH3 domain-containing protein can be done by binding assayε commonly known in the art, translocations and point mutations in lats nucleic acids can be detected by Southern blotting, RFLP analysis, PCR using primers that preferably generate a fragment spanning at least most of the lats gene, sequencing of the lats genomic DNA or cDNA obtained from the patient, etc. In a preferred embodiment, levels of lats mRNA or protein in a patient sample are detected or measured, in which decreased levels indicate that the subject has, or has a predisposition to developing, a malignancy or hyperproliferative disorder; in which the decreased levels are relative to the levels present in an analogous sample from a portion of the body or from a εubject not having the malignancy or hyperproliferative diεorder, aε the case may be. In another specific embodiment, diseases and disorders involving a deficiency in cell proliferation or in which cell proliferation is desirable for treatment, are diagnosed, or their suεpected preεence can be εcreened for, or a predisposition to develop such disorders can be detected, by detecting increased levels of lats protein, lats RNA, or lats functional activity (e . g . , kinase activity, SH3 domain binding activity, etc.), or by detecting mutations in lats RNA, DNA or protein (e.g., translocationε in lats nucleic acids, truncations in the gene or protein, changes in nucleotide or amino acid sequence relative to wild-type lats) that cause increased expression or activity of lats. Such diseases and disorders include but are not limited to those described in Section 5.8.2 and its subsections. By way of example, levels of lats protein, levels of lats RNA, lats kinase activity, lats binding activity, and the presence of translocations or point mutations can be determined as described above. In a specific embodiment, levels of lats mRNA or protein in a patient sample are detected or measured, in which increased levels indicate that the subject has, or has a predisposition to developing, a growth deficiency or degenerative or hypoproliferative disorder; in which the increased levels are relative to the levels present in an analogous sample from a portion of the body or from a subject not having the growth deficiency, degenerative, or hypoproliferative disorder, as the case may be. Kits for diagnostic use are also provided, that comprise in one or more containers an anti-lats antibody, and, optionally, a labeled binding partner to the antibody. Alternatively, the anti-lats antibody can be labeled (with a detectable marker, e.g., a chemiluminescent, enzymatic, fluorescent, or radioactive moiety) . A kit is also provided that comprises in one or more containers a nucleic acid probe capable of hybridizing to lats RNA. In a specific embodiment, a kit can comprise in one or more containers a pair of primers (e.g., each in the size range of 6-30 nucleotides) that are capable of priming amplification [e.g., by polymerase chain reaction (see e.g., Inniε et al., 1990, PCR Protocols, Academic Press, Inc., San Diego, CA) , ligase chain reaction (see EP 320,308) use of Qβ replicase, cyclic probe reaction, or other methods known in the art] under appropriate reaction conditions of at least a portion of a lats nucleic acid. A kit can optionally further comprise in a container a predetermined amount of a purified lats protein or nucleic acid, e . g . , for use as a standard or control. 5.14. SCREENING FOR LATS AGONISTS AND ANTAGONISTS Lats nucleic acids, proteins, and derivatives also have uses in screening assays to detect molecules that specifically bind to lats nucleic acids, proteins, or derivatives and thus have potential use as agonists or antagonists of lats, in particular, molecules that thus affect cell proliferation. In a preferred embodiment, such assays are performed to screen for molecules with potential utility as anti-cancer drugs or lead compounds for drug development. The invention thus provides asεayε to detect moleculeε that specifically bind to lats nucleic acids, proteins, or derivatives. For example, recombinant cells expressing lats nucleic acids can be used to recombinantly produce lats proteins in these asεays, to screen for molecules that bind to a lats protein. Molecules (e.g., putative binding partners of lats) are contacted with the lats protein (or fragment thereof) under conditions conducive to binding, and then molecules that specifically bind to the lats protein are identified. Similar methods can be used to screen for molecules that bind to lats derivatives or nucleic acids. Methods that can be uεed to carry out the foregoing are commonly known in the art. By way of example, diverεity librarieε, such as random or combinatorial peptide or nonpeptide libraries can be screened for molecules that specifically bind to lats. Many libraries are known in the art that can be used, e.g., chemically synthesized libraries, recombinant (e.g., phage display libraries) , and in vitro translation-based libraries. Examples of chemically synthesized libraries are described in Fodor et al., 1991, Science 251:767-773; Houghten et al., 1991, Nature 354:84-86; Lam et al., 1991, Nature 354:82-84; Medynski, 1994, Bio/Technology 12:709-710; Gallop et al., 1994, J. Medicinal Chemistry 37 (9) : 1233-1251; Ohlmeyer et al., 1993, Proc. Natl. Acad. Sci. USA 90:10922-10926; Erb et al., 1994, Proc. Natl. Acad. Sci. USA 91:11422-11426; Houghten et al., 1992, Biotechniques 13:412; Jayawickreme et al., 1994, Proc. Natl. Acad. Sci. USA 91:1614-1618; Salmon et al., 1993, Proc. Natl. Acad. Sci. USA 90:11708-11712; PCT Publication No. WO 93/20242; and Brenner and Lerner, 1992, Proc. Natl. Acad. Sci. USA 89:5381-5383. Examples of phage display libraries are described in Scott and Smith, 1990, Science 249:386-390; Devlin et al., 1990, Science, 249:404-406; Christian, R.B., et al., 1992, J. Mol. Biol. 227:711-718) ; Lenstra, 1992, J. Immunol. Meth. 152:149-157; Kay et al., 1993, Gene 128:59-65; and PCT Publication No. WO 94/18318 dated August 18, 1994. In vitro translation-based libraries include but are not limited to those described in PCT Publication No. WO 91/05058 dated April 18, 1991; and Mattheakiε et al., 1994, Proc. Natl. Acad. Sci. USA 91:9022-9026. By way of exampleε of nonpeptide libraries, a benzodiazepine library (see e.g., Bunin et al., 1994, Proc. Natl. Acad. Sci. USA 91:4708-4712) can be adapted for use. Peptoid libraries (Simon et al., 1992, Proc. Natl. Acad. Sci. USA 89:9367-9371) can also be used. Another example of a library that can be used, in which the amide functionalities in peptides have been permethylated to generate a chemically transformed combinatorial library, is described by Ostreεh et al. (1994, Proc. Natl. Acad. Sci. USA 91:11138-11142) . Screening the librarieε can be accomplished by any of a variety of commonly known methods. See, e.g., the following references, which disclose εcreening of peptide libraries: Parmley and Smith, 1989, Adv. Exp. Med. Biol. 251:215-218; Scott and Smith, 1990, Science 249:386-390; Fowlkes et al., 1992; BioTechniques 13:422-427; Oldenburg et al., 1992, Proc. Natl. Acad. Sci. USA 89:5393-5397; Yu et al., 1994, Cell 76:933-945; Staudt et al., 1988, Science 241:577-580; Bock et al., 1992, Nature 355:564-566; Tuerk et al., 1992, Proc. Natl. Acad. Sci. USA 89:6988-6992; Ellington et al., 1992, Nature 355:850-852; U.S. Patent No. 5,096,815, U.S. Patent No. 5,223,409, and U.S. Patent No. 5,198,346, all to Ladner et al.; Rebar and Pabo, 1993, Science 263:671-673; and PCT Publication No. WO 94/18318. In a specific embodiment, screening can be carried out by contacting the library members with a lats protein (or nucleic acid or derivative) immobilized on a solid phase and harvesting those library members that bind to the protein (or nucleic acid or derivative) . Examples of such screening methods, termed "panning" techniques are described by way of example in Parmley and Smith, 1988, Gene 73:305-318; Fowlkes et al., 1992, BioTechniques 13:422-427; PCT Publication No. WO 94/18318; and in references cited hereinabove. In another embodiment, the two-hybrid system for selecting interacting proteins in yeast (Fields and Song, 1989, Nature 340:245-246; Chien et al., 1991, Proc. Natl. Acad. Sci. USA 88:9578-9582) can be used to identify molecules that specifically bind to a lats protein or derivative. In addition, Drosophila can be used as a model system in order to detect genes that phenotypically interact with lats . For example, overexpression of lats in Drosophila eye leads to a smaller and rougher eye. Mutagenesis of the fly genome can be performed, followed by selecting flies in which the mutagenesis has resulted in suppression or enhancement of the small rough eye phenotype; the mutated genes in such flies are likely to encode proteinε that interact/bind with lats. 5.15. ANIMAL MODELS The invention also provides animal models. In one embodiment, animal models for diseaseε and disorders involving cell overproliferation (e.g., as described in Section 5.8.1) are provided. Such an animal can be initially produced by promoting homologous recombination between a lats gene in itε chromosome and an exogenous lats gene that has been rendered biologically inactive (preferably by insertion of a heterologous sequence, e.g., an antibiotic resistance gene) . In a preferred aspect, this homologous recombination is carried out by tranεfor ing embryo-derived stem (ES) cells with a vector containing the insertionally inactivated lats gene, such that homologous recombination occurs, followed by injecting the ES cells into a blastocyst, and implanting the blastocyst into a foster mother, followed by the birth of the chimeric animal ("knockout animal") in which a lats gene has been inactivated (see Capecchi, 1989, Science 244:1288-1292) . The chimeric animal can be bred to produce additional knockout animals. Such animals can be mice, hamsters, sheep, pigs, cattle, etc., and are preferably non-human mammals. In a specific embodiment, a knockout mouse is produced. Such knockout animals are expected to develop or be predisposed to developing diseases or disorders involving cell overproliferation (e . g . , malignancy) and thus can have use as animal models of such diseases and disorders, e.g., to screen for or test molecules (e.g., potential anti-cancer therapeutics) for the ability to inhibit overproliferation (e.g., tumor formation) and thus treat or prevent such diseases or disorders. In a different embodiment of the invention, transgenic animals that have incorporated and express a functional lats gene have use as animal modelε of diεeases and diεorderε involving deficiencieε in cell proliferation or in which cell proliferation iε deεired. Such animals can be used to screen for or test moleculeε for the ability to promote proliferation and thuε treat or prevent such diseaseε and disorders. 5.16. METHODS OF IDENTIFYING TUMOR SUPPRESSOR GENES AND OTHER GENES WITH IDENTIFIABLE PHENOTYPES . . . The invention also provides methods of identifying a tumor suppressor gene (or potential tumor suppressor gene) comprising identifying an overproliferation phenotype in a genetic mosaic, and isolating a gene that is mutated in cells exhibiting the overproliferation phenotype. The genetic mosaic is achieved by induction of somatic cells in an animal that is heterozygous for an induced mutation to become homozygous for the mutation, at any desired developmental stage. The mutation can be induced by any known method, e.g.. X-ray exposure or chemical mutation exposure or insertion of a transposable element (e . g . , P-element) . A genetic mosaic is produced by induction of homozygosity by mitotic recombination between homologous arms of both parental chromosomes, which is achieved using a site-specific recombination system [a sequence capable of expressing a site-specific recombinase; and its target sites (sequences at which the recombinase promotes recombination) ] , that have been inserted in the homozygous arms of both parental chromosomes. The target sites are preferably inserted close to the centromere on each chromosome arm (the closer to the centromere, the more preferred) , so that mitotic recombination events will result in cells being homozygous for the mutation located on the chromosome arm distal to the insertion of the target site. For example, an FLP recombinase can be used with FRT target siteε; Cre recombinaεe can be uεed with lox target εites. The recombinase coding sequence, used to expreεε recombinase, preferably, but need not be, intrachromosomally situated. For at least one chromosome, the target sites are intrachromosomally inserted on the homologous arms of both parental (maternal and paternal) chromosomes. The genetic mosaic can be an animal, e . g . , mouse, hamster, sheep, pig, cow, Drosophila , etc., and is preferably a non-human mammal. In a specific embodiment relating to the production of a non-human mammal that is a genetic mosaic, a recombinase target site iε introduced onto one arm of a chromosome in an embryo-derived stem cell (ES) . The target site can be introduced into the cell by homologous recombination (by use of flanking sequences from the desired site of intrachromosomal integration) or by random integration resulting from cell transformation (e.g., by transfection, electroporation) , etc. This ES is then injected into a blastocyst, the blastocyst is implanted into a foster mother, followed by birth of the recombinant animal. Thiε mammal is bred to a wild-type female, to produce siblings. Siblings carrying the target site insertion are mated, and offspring carrying the target site on the homologous arms of both parental chromosomes are isolated ("the target strain") . A target strain member is then mutagenized and mated with a non-mutagenized target strain member of the opposite sex (preferably also carrying a recombinant nucleic acid encoding and capable of expressing a recombinase that promotes recombination at the target sites) , to obtain a target strain member that is heterozygous for the mutation. Provision of the recombinase (by expression) in mitotically active cells of a developing animal or an adult animal promotes mitotic recombination between the homologous armε of the parental chromosomes, resulting in a cell that is homozygous for the mutation. Cells that display a mutant phenotype by virtue of their being homozygous for the mutation are then detected, and the mutant gene can be genetically mapped by any known method, and can be isolated. In a Drosophila animal, a site-specific recombination system can be introduced by use of P-element- mediated insertions. In one embodiment, target sites are introduced onto homologous arms of both of a set of parental chromosomes, for one chromosome. In another embodiment, target sites are introduced onto homologous arms of both of a εet of parental chromosomes, for a plurality of chromosomes. The recombinase can be under the control of a constitutive (e.g., phosphorylated kinase promoter) or inducible (e.g., heat shock promoter) or tissue-specific promoter. The recombinase can be expressed episo ally (e . g . , from a plasmid) or chromosomally. Once the recombination system is introduced into the animal, genetic moεaiciε iε produced by the activity of the recombinase (which promotes recombination at the target sites) . In a specific embodiment, an animal is used that contains a recombinant nucleic acid encoding an FLP recombinase (Broach and Hicks, 1980, Cell 21:501-508) such that it is expressible by a cell of the animal, and intrachromosomal insertions of an FRT site on the homologous arms of both parental chromosomes; and genetic mosaicis is produced by inducing mitotic recombination between the FRT sites on the homologous chromosome arms after FLP recombinaεe expression (e.g., by heat shock, when expression of the FLP recombinase is under the control of a heat shock promoter) . In another specific embodiment, an animal is uεed that contains a recombinant nucleic acid encoding a Cre recombinase (Sauer and Henderson, 1988, Proc. Natl. Acad. Sci. USA 85:5166-5170) such that it is expresεible by a cell of the animal, and intrachromosomal insertions of a lox site on homologous arms of both parental chromosomes; and genetic mosaicism is produced by inducing mitotic recombination between the lox sites on the homologous chromosome armε after Cre recombinase expression. The animal may optionally further comprise intrachromosomal insertions of marker genes (comprising a sequence encoding a protein containing a reporter group such as an epitope tag) , to facilitate confirmation and/or monitoring of recombination events. For example, in a non- human mammal, a marker gene (e.g., lacZ) operably linked to a constitutive promoter can be inserted, on the same chromosome arm as that carrying the target site and the induced mutation. In a specific embodiment, the overproliferation phenotype is the formation of overproliferated outgrowth tissue in a non-position-dependent fashion. In another specific embodiment, the overproliferation phenotype is the formation of a normal structure of larger than normal εize. The above-deεcribed genetic oεaicε have uεeε not only in identifying tumor εuppressor genes, but, more generally, in identifying genes with an identifiable phenotype, i.e., those genes which in mutated form cause an observable mutant phenotype to be displayed in the genetic mosaic. In another embodiment, the invention provides a method of identifying genes with an observable mutant phenotype by use of human (or other animal) tissue culture cells that have incorporated a site-specific recombination system such as described above. The site-specific recombination system can be introduced by methods such as described above, so as to introduce a recombinant source of recombinase and effect intrachromosomal inεertionε of the recombinase target sites on the homologous arms of both of a set of parental chromosomes, for one or more chromosomes. In a preferred aspect relating to thiε use of culture cells, the recombinase target sites are ligated to a selectable marker (e.g., an antibiotic resistance gene), and cells are obtained that have the target sites on each of the homologous chromosome arms, by selecting under selection conditions of relatively high stringency (e . g . , by increasing the antibiotic concentration in the cell medium) , As with the use of genetic mosaics as described above, once mitotic recombination is induced between the target sites on the homologous chromosome arms, one then identifies cells displaying a mutant phenotype, and recovers a gene mutated in cells exhibiting the mutant phenotype. For example, a potential tumor suppressor gene can be identified by isolating a gene that is mutated in cultured cells exhibiting a transformed phenotype. 6. IDENTIFYING TUMOR SUPPRESSORS IN GENETIC MOSAICS: THE DROSOPHILA LATS GENE ENCODES A PUTATIVE PROTEIN KINASE We have identified recessive overproliferation mutations by screening and examining clones of mutant cells in genetic mosaics of the fruitfly Drosophila melanogaster (Fig. IA) . Flies that carry small groups of somatic cells mutated for negative regulators of cell proliferation or tumor suppressors are viable, yet the overproliferated mutant tissues can be readily identifiable. One way to generate mosaic animals is to induce mitotic recombination in developing heterozygous individuals (Fig. IB) . Recently, it was found that the site-specific recombination system from yeast, the FLP recombinase and its target site FRT, can be used to induce high frequency of mitotic recombination in Drosophila (Golic and Lindquist, 1989, Cell 59:499-509; Golic, 1991, Science 252:958-961). To produce and analyze genetic mosaics, a series of special Drosophila strains were constructed, containing the FLP/FRT recombination system on genetically marked chromosomes (Xu and Rubin, 1993, Development 117:1223-1237). Using these strains, high frequencies of mosaiciεm can be produced for more than 95% of the Drosophila geneε. We have uεed these strains to identify overproliferation mutations in mosaic animals. Our results show that screening for overproliferation mutationε in mosaic animals is a powerful way to identify negative regulators of cell proliferation and potential tumor suppressor genes. One of the identified genes, large tumor suppressor (lats) , has been cloned, and encodes a predicted novel protein kinase. Mutations in lats cause dramatic overproliferation phenotypes and various developmental defects in both moεaic animalε and homozygouε mutants. 6.1. MATERIALS AND METHODS Genetics Fly stocks and crosses were grown on standard medium at 25°C unless otherwise indicated. The Fl moεaic screens were modified from the one described in Xu and Rubin (1993, Development 117:1223-1237) and in Xu and Harrison (1994, Methods in Cell Biology 44:655-682). Briefly, the Fl mosaic individuals were produced from three crosses: Mutagenized y w hεFLPl ; P[ry + ; hs-neo; FRTJ 40A males were mated to the y w hsFLPl ; P[ry + ; y + ]25F, P[mini-w + ; hs-NM]31E, P[ry + ; hs-neo; FRTJ40A females. Mutagenized y w hsFLPl ; P[ry + ; hs-neo; FRTJ42D males were mated to the y w hsFLPl ; P[ry + ; hs-neo; FRTJ42D, P[ry + ; y + ]44B, P[mini-w + ; hs- NM]46F/CyO females. Finally, mutagenized y w hsFLPl ; P[ry + ; hs-neo; FRTJ82B males were mated to the y w hsFLPl; P[ry + ; hs-neo; FRT]82B f P[mini-w + ; hs-ττM]87E, Sib"*, P[ry + ; y + ]96E females. The male parents were irradiated with X-rays (4000 r) and were removed from the crosses after four days of mating. The eggs from the crosses were collected for every 12 hours and aged for another 30 hours before being incubated in a 38°C water bath for 60 minutes. The F, animals were then returned to normal culture conditions until eclosion. About 25,000 F, adults from these crosses were examined. Each P- induced lethal mutation was recombined onto one of the FRT- carrying arms using the neo R and w double selection as described in Xu and Harrison (1994, Methods in Cell Biology 44:655-682) before examining its clonal phenotype. The lats*' mutation was meiotically mapped to the right of claret . It was further localized to the 100A1-5 region since it complemented Df (3R) til'(100A2-5; 100C2-3) and failed to complement Df (3R) tll PiX (100A1-2; 100B4-5) and Df (3R) til 20 (100A1-3; 100B1-2) . A saturation genetic screen had previously been performed for this interval, and three lethal complementation groups, l(3)100Aa, l(3)100Ab and the zfh-1 , were isolated (Lai et al., 1993, Proc. Natl. Acad. Sci. USA 90:4122-4126). The lats" mutation failed to complement the EMS-induced mutations in l(3)100Aa (lats"'*' 5 ) , but complement mutations in l(3)100Ab and zfh-1 . The clonal phenotypes were examined for ι a tε x ' p ' α, α2 α6 tDά α!n induced either with the FLP/FRT-marker system or X-ray irradiation. The lats pι allele was recovered from a mosaic male produced from the cross of y w hsFLPl ; P[ry + ; hs-neo; FRTJ82B x y w P[lacZ; w + ]5; P[ry + ; hs-neo; FRT] 82B/del ta2-3 , S . The mutant chromosome was cleaned up before performing complementation testε and an excision screen (Robertson et al., 1988, Genetics 118:461-470). Two hundred and fifteen excision lines were established that had lost the w* gene in the P[lacZ; w + ] element (Bier et al., 1989, Genes Dev. 3:1273-1287). In about 50% of these lines, the pupal lethality had been reverted completely to wild type, indicating the mutant phenotype is caused by the P-element insertion. Five lines were found to cause lethality at late embryonic and/or early first instar larval stages. The remaining lines were found to cause lethality at larval and pupal stages or to produce viable mutant animals. All of these mutant excision lines (except one which iε located outside the 100A1-5 region) failed to complement latff"and lats" , but do complement mutations in the zfh-1 and l(3)100Ab loci. The insert in lats cDNA A2 was cloned into the pCaSpeR-hs vector (Thummel and Pirrotta, 1992, Drosophila Inform. Service 71:150) for germ line transformation. Three of the transformed lines were tested and were able to rescue the lethality of the lats"' /lats 1 ' , lats e2( 'animalε after one hour heat shock for every 24 hours during larval and pupal development. Histology Fixation and sectioning (2 mm) of adult Drosophila tissues were performed as described (Tomlinson and Ready, 1987, Dev. Biol. 123:264-275). Scanning electron microεcopy was performed as described (Xu and Artavanis-Tεakonaε, 1990, Genetics 126:665-677). Nucleic Acid Manipulation A PI genomic clone (DS02640) mapped in the 100A1-7 region was obtained from the Berkeley Droεophila Genome Center (personal communication; Hartl et al., 1994, Proc. Natl. Acad. Sci. USA 91:6824-6829). DNA fragments from this PI clone and genomic DNA obtained by plaεmid rescue from the latε pl mutant (Bier et al., 1989, Genes Dev. 3:1273-1287) were used to isolate several overlapping cosmids including CLT-52 from the genomic library prepared by J. Tamkun. Genomic DNA from +7.5 (Bglll) to -4.2 (EcoRI; Fig. 3) waε used to screen a total imaginal disc cDNA library prepared by A. Cowman. Screening approximately 2 million phage yielded three groups of cDNAs (five lats cDNAs; fifteen Tl cDNAs; fourteen T2 cDNAs) . The sizes of the inserts in the lats cDNAs are as follows: 5.6 kb in A2; 5.1 kb in Bl; 1.1 kb in 9 and 4; and 5 0.9 kb in B3. Genomic DNA from lats x '/TM6B , latε α ' l5 /TM6B , lats pι /TM6B, lats e 2 /TM6B, lats e7s /TM6B, lats e '°° /TM6B, lats e " v /TM6B and lats el48 /TM6B flies was digested with a combination of the EcoRI , BamHI , Bglll and Xhol restriction enzymes for Southern 0 analysis. DNA Sequencing DNA sequence was determined by the dideoxy chain termination method (Sanger et al., 1977, Proc. Natl. Acad. 5 Sci. USA 74:5463-5467) using Tag polymerase (Perkin Elmer) and Sequenase (U.S. Biochemical Corp.). The sequenceε of lats cDNAs were determined from both strands using templates generated from plasmids containing EcoRI fragments inεerted into the pBlueScriptll vector. Templateε generated from 0 DNase l deletion subclones were also used. The complete sequences of cDNAs A2 and 9 were determined; partial sequences were determined for cDNAs Bl and 4. Templates of genomic DNA were generated from plasmids containing EcoRI fragments and were sequenced on one strand uεing synthetic 5 oligonucleotide primers. Mutant DNA from the lats"' allele was amplified with PCR reactions uεing εynthetic oligonucleotide primerε and cloned in the pBlueScript II vector for sequencing. 0 6.2. RESULTS Screening for Overproliferation Mutations in Mosaic Animals We have screened individuals carrying clones of cells that were homozygous for either X-ray or P-element _ induced mutations for overproliferation phenotypes. (Fig. IB; Materialε and Methods) . Two types of overproliferation phenotypes were sought: a) Clones of mutant cells formed overproliferated, outgrowth tissues in a non-position- dependent fashion; b) Clones of mutant cells formed normal structures, but proliferated faster than wild-type cells εuch that the sizes of the mutant clones were larger than their wt twin-spot clones. Three independent mutations were identified that caused the first type of phenotype (Fig. 2A- 2E) . A mutation which was allelic to one of the original mutations was later found to cause the second type of phenotype (see below) . All three mutations in the first class caused embryonic and/or early larval lethality and they represented single alleles of different loci since they had different chromosome locationε. One of them waε identified among 215 randomly chosen lethal mutations in which each were caused by a P-element insertion in a different essential gene (Karpen and Spradling, 1992, Genetics 132:737-753; Berkeley Drosophila Genome Center, personal communication) . In addition to theεe overproliferation mutationε, one P-induced mutation was found to cause both unpatterned outgrowth and duplications of patterned structures in mosaic animals, suggesting that this mutation may not directly affect cell proliferation. The lats Locus Iε Defined by a Single Complementation Group of Mutationε That Cause Defects Throughout Development The mutations caused different levels of overproliferation. One mutation (lats x! ) produced much more dramatic overproliferated clones than the ones produced by the other mutations (Fig. 2A, 2B) . The lats mutant clones induced in first instar larvae can be as large as 1/5 of the body size. Tu orous outgrowth caused by lats 1 ' was found in all the tisεues that had been examined including eyes, legs, wingε, headε, notums, antenna, and abdominal cuticles. The lats*' mutation waε genetically mapped in the 100A1-5 region and the locus was further defined by a single complementation group of over fifty alleles including mutations induced by X-ray, EMS, P-element insertion and imprecise excision of the P-element (Table 2; Materials and Methods). TABLE 2 The alleles of the lats locus * Phenotypes Phenotypes of of mutant Representative No. of Alleles homozygous animals clones alleles alleles Strong Late embryonic and Large lats 1 ', lats" 1 , 14 early let inβtar outgrowth lats 04 larval lethal Medium Late larval and pupal Large lats"', lats' 16 lethal, normal size of outgrowth animals Pupal lethal, giant Large lats ,r26-l animals outgrowth Weak Semi-viable and Mutant lats"" lats' 17 viable: rough eye clones outgrowth on head, larger or wing held-out, sterile normal in size The various alleles of the lats gene are classified into three main groups as indicated in the left column. Their phenotypes, displayed in either homozygous mutant animals or clones of mutant cells in mosaic animals, are listed in the next two columns respectively. For a given viable or semi- viable allele, the homozygous mutant animals display one, two, three, or all four of the listed phenotypes. Representative alleles and the numbers of alleles for each group are given in the two right columns. The origins of these alleles are described in the Material and Methods. Removing the P-element insertion reverted the lethal chromosome into wild type, indicating the P-element insertion is responsible for the mutant phenotype. Furthermore, five of the imprecise excision lines caused late embryonic and early larval lethality which were εtronger than the pupal lethality phenotype caused by the lats 1 ' 1 mutation. These five excision lines failed to complement lats'' , but complemented the mutations in two other complementation groups (1 (3) lOOAb and zfh-1 ) in the 100A1-5 region, indicating that these two genes were not affected by the excision alleles. The lats alleles can be classified into three main groups (Table 2) . Strong alleleε caused homozygous animals to die at a late embryonic stage or shortly after hatching with no obvious cuticular defect. Mutationε in the group of medium alleles cause lethality at different times in larval and pupal development. This group was further divided into two subgroups because three of the excision alleles not only caused pupal lethality, but the sizes of the homozygous mutant animals were also significantly larger than wt animals (Fig. 2C) . The weak mutations caused either one or a combination of the following phenotypes: held out wings with broadened blades, rough eye with ventral outgrowth, outgrowth on the dorsal-anterior region of the head and partial to complete sterility (Table 2) . Proliferation defects were observed in both mutant clones in mosaic animals and homozygous mutantε. Cloneε of cells on the head that were homozygous for strong or medium alleles formed unpatterned, overproliferated tisεues with many lobes or folds. The mutant cells seemed to be "budding out" of the surface to form new proliferation centers or lobes (Fig. 2A, 2F, 2H) . The sizes and the shapes of these mutant cells were very irregular. Cells several times larger than their neighbors were often seen in mutant clones, indicating problematic cell division (Fig. 2F, 2G) . Furthermore, lats mutant clones behaved differently from clones mutant for the previously identified Drosophila tumor suppressor genes such as dig, lgl and hyd . The dig, lgl or hyd mutant cells proliferated slower than wt cells and thus, the mutant clones induced in first inεtar larvae were competed away during growth and did not form detectable clones in the adults (Bryant, 1987, Experimental and genetic analyεis of growth and cell proliferation in Drosophila imaginal discs, in "Genetic Regulation of Development," A.R. Liss, New York, pp. 339-372; Woods and Bryant, 1989; Dev. Biol. 134:222-235; Mansfield et al., 1994, Dev. Biol. 165:507-526; Allen Shearn, personal communication) . In contrast, the lats mutant clones induced at similar developmental stages formed dramatic overproliferated tissues, suggesting the mutant cellε proliferated faεter than wt cells. Consistent with this notion, clones of cells mutant for a weak lats allele (lats" 10 ) produced normal looking tissues, but the mutant clones were significantly larger than their wt twin-spot clones. In homozygous animals, the imaginal discs and the central nervous system in many of the pupal lethal mutants were dramatically overproliferated (Fig. 2D, 2E) . The discs lost the single layer of epithelial structure and formed multi-layer, deformed tissues. The lats overproliferation phenotype was not caused by prevention of differentiation. Cells in the overproliferated mutant clones on the body differentiated and produced bristles and hairs, although the morphologieε of theεe εtructures were not wild type (Fig. 2I-2L) . Careful examination of multiple mutant clones confirmed that lats caused mutant cells (wcells in the eye, y"bristles and enlarged-base hairs on the body) to overproliterate and did not affect the surrounding wt tissues. Finally, the frequency of overproliferated clones was similar to wt clonal frequency induced with the same FRT element, indicating that loss of the lats function alone iε sufficient to initiate the overproliferation process. Cloning of the lats Gene Genomic DNA from the 100A1-5 region was isolated using probes mapped to this region (Materials and Methods) . A restriction map of the relevant genomic region is illustrated in Figure 3. Genomic DNA flanking the P-insertion site (+7.5 to -4.2) was used to screen a total imaginal disc cDNA library. A group of cDNAs corresponding to a 5.7 kb transcript (lats) was found to contain sequence from the region where the P-element was inserted (Fig. 3) . Two other groups of cDNAs were also isolated (Tl and T2) . The 5.7 kb tranεcript waε located in an intron of the Tl gene (Fig. 3) . The intron-exon structure of the 5.7 transcription unit was determined by Southern and sequence analysis of the cDNA clones and the corresponding genomic DNA (Materials and Methods) . The zfh-1 gene was found to be located at the left side of the 5.7 kb transcription unit (Fig. 3; Fortini et al., 1991, Mechanisms of Development 34:113-122). In addition to lats PI , genomic DNA from the five strong excision alleles was analyzed. All of them deleted exon sequences from the 5.7 kb transcript and, in addition, three of them also deleted sequences in the next transcript (T2; Fig. 3). Furthermore, DNA from the X-ray and EMS induced mutants was analyzed with cDNA probes made from the 5.7 kb, T2 and Tl transcripts. In two cases alterations were detected in the 5.7 kb tranεcription unit: a 0.4 kb and a 0.3 kb deletions associated with lats"'and lats" 4 , respectively (Fig. 3) . The 446 bp deletion in lats"' was revealed by sequencing. It removed codons 92 to 238 of the open reading frame and caused a frame shift from codon 239 (Fig. 5) . Finally, transformants containing a cDNA corresponding to the 5.7 transcript driving by the hsp70 promoter rescued the lethality of both strong and medium lats alleles. These findings indicate that the 5.7 kb transcription unit which correspond to the lats gene and strong latsalleles including lats β/ were either amorphic or nearly amorphic alleles. The lats Gene Encodes a Putative Protein-Serine/Threonine Kinaεe The 5.7 kb lats transcript was detected throughout development (Fig. 4) and in both adult males and females (data not shown). In addition, probes from the 5.7 kb transcript also detected a second tranεcript, which iε about 1 kb shorter (4.7 kb) , in young embryos (0-4 hrs; Fig. 4) and in adult males and females. Northern analyεis showed there was more maternally deposited 4.7 kb transcripts than 5.7 kb transcripts in young embryos (0-2 hrs; Fig. 4). The 5.7 kb transcript became the dominant meεsage at the embryonic stage (4-6 hrs) , known to have zygotic gene expression (Fig. 4) . No effort was made to iεolate cDNA clones corresponding to the 4.7 kb tranεcript; thus the exact sequence of this εhort tranεcript iε not known. However, a polyadenylation signal consensus sequence was found at nucleotide position 4655 - 4660 in the 5.7 kb transcript and in the corresponding genomic DNA (Fig. 5) and a 0.51 kb probe from the 3' end of the 5.7 kb transcript did not hybridize to the 4.7 kb transcript while a 1 kb probe from the 5' untranslated region of the 5.7 kb transcript hybridized to both the 5.7 kb and 4.7 kb transcripts. This suggests that the 4.7 kb transcript may be a truncated version of the 5.7 kb transcript. The genomic and cDNA sequence corresponding to the 5.7 kb transcript was determined (Materials and Methods) . The entire 5720 bp cDNA sequence, which is interrupted by seven introns, and the putative lats product (lats) , deduced from the long open reading frame, are illustrated in Figure 5. An interesting feature of the 5.7 kb transcript iε the exiεtence of a 141 bp segment located in the 3' untranslated region (Fig. 5), which is identical to the first 141 bp of the 5' untranslated region of the class I transcript from the Drosophila phospholipase C gene, plc-21 (Shortridge et al., 1991, J. Biol. Chem. 266:12474-12480). The functional significance of this sequence motif is unknown. It could be a regulatory target sequence that is shared by both genes. There are 34 differences between the lats cDNA and genomic sequences and 31 of them do not affect the deduced amino acid sequence. In the remaining three differences, one changes the serine 206 in cDNA into a cysteine. The second change in the genomic sequence adds an additional glutamine in the poly-glutamine opa repeat (Fig. 6; Wharton et al., 1985, Cell 40:55-62). The third is the addition of a fifteen bp sequence in the genomic DNA after the nucleotide 2644 of the cDNA. This sequence could be translated into another copy of the Arg-Glu-Arg-Asp-Gln (part of SEQ ID NO:2) peptide. However, this sequence is not present in the two independent cDNA clones that were sequenced. The predicted latε product contains 1099 amino acid residues. The kinase domain of latε iε more similar to protein-serine/threonine kinases than to protein-tyrosine kinases, especially in the sequences of the domains VI and VIII defined by Hanks et al. (1988, Science 241:42-52); protein-serine/threonine kinase consensus in domain VI: Asp- Leu-Lys-Pro-Glu-Asn (SEQ ID NO:9). Lats sequence in domain VI: Arg-Asp-Ile-Lys-Pro-Asp-Asn (836-842) (part of SEQ ID NO:2); protein-serine/threonine kinase consensus in domain VIII: Gly-Thr/Ser-X-X-Tyr/Phe-X-Ala-Pro-Glu (SEQ ID NO: 10). Lats sequence in domain VIII: Gly-Thr-Pro- 5 Asn-Tyr-Ile-Ala-Pro-Glu (917-925) (part of SEQ ID NO:2) . The C-terminal half of lats shares extensive sequence similarity with a group of six proteins including the Dbf20 and Dbf2 cell cycle protein-ser/thr kinases from Saccharomyceε cerevisiae (Johnston et al., 1990, Mol. Cell. Biol. 10:1358- 10 1366; Toyn et al., 1991, Gene 104:63-70; Toyn and Johnston, 1994, EMBO J. 13:1103-1113), and the COT-1 putative protein kinase from Neurospora crassa (Yarden et al., 1992; EMBO J. 11:2159-2166) (Fig. 6A, 6B) . The sequence similarity between the kinase domains of lats and these proteins (39-49% 15 identity) is much higher than the sequence similarity observed between the different subgroups of protein-ser/thr kinases (20-25% identity; Hanks et al., 1988, Science 241:42-52) . However, there is an inεertion of about 40 amino acid residues within the kinase domains of these proteins, 20 sharing little sequence similarity (denoted by a black bar in Fig. 6B) . The human myotonic dystrophy protein kinaseε (MDPK) also have significant similarity with the C-terminal region of lats (Brook et al., 1992, Cell 68:799-808; Fu et al., 1993; Science 260:235-238, Mahadevan et al., 1993, Hum. 25 Mol. Genet. 2:299-304), but their kinase domains do not contain this " 40 amino acid insertion. In addition, lats and these proteins also share significant levels of sequence similarity in the two regions (each contains " 100-150 amino acids) flanking the kinase domain (20-28% identity; Fig. 6A, 30 6B) . In the case of Dbf20, its entire sequence except for the 20 C-terminal most residueε can be aligned with lats, indicating latε iε a close relative of Dbf20. A poly- glutamine opa repeat is located near the middle of the protein (Fig. 5; Wharton et al., 1985, Cell 40:55-62) . The 35 N-terminal half of latε containε many εhort homopolymeric runs including poly-proline which makes up about 15% of the residues. At least one of the proline-rich stretcheε closely matches the consensus of SH3-binding sites (Fig. 3B; Ren et al., 1993, Science 259:1157-1161), raising the possibility that it may interact with SH3-containing proteins. No putative signal sequence appears in the lats protein, indicating that it is an intracellular protein. 6.3. DISCUSSION Screening for Mutations in Mosaic Animals to Identify and Study Potential Tumor Suppressors The comparison between mosaic flies and tumor patientε is simplistic yet useful. Tumor patients contain wt tumor suppressor genes in moεt of their cellε and only εmall groupε of cells sustain mutations in tumor suppresεors. We have searched for recessive overproliferation mutations in mosaic animals. Flies that carry somatic cells mutated for tumor suppressors or negative regulators of cell proliferation are viable, yet the overproliferation mutant phenotype iε readily identifiable. Therefore, mosaic flies, which are in a fashion analogous to tumor patients, provide a mean to screen for potential tumor suppresεorε. Three overproliferation mutations were identified in our screen. They were not identified as "interesting" mutations in screenε for embryonic lethal mutations. Identifying overproliferation mutations in homozygous mutant larvae and pupae is not only biased against embryonic lethals, but also laboriouε, εince it requireε eεtablishment of individual lines before examining the potential phenotypes. Further screenε for overproliferation mutationε in moεaic animals will allow uε to identify other important players in pathways that negatively regulate cell proliferation. The overproliferation phenotypes that we observed were caused by losε of function in a single gene. In humans, it was suggested that most retinoblastomas are caused by defectε in a εingle tumor εuppressor (Knudson, 1971, Proc. Natl. Acad. Sci. USA 68:820-823). On the other hand, evidence indicateε that tumorigeneεis in other human tissues (e.g., colon cancer) is a multistep process which involveε inactivation of more than one gene (Fearon and Vogelstein, 1990, Cell 61:759-767; Vogelstein and Kinzler, 1993, Trends Genet. 9:138-141) . Overproliferation caused by defects in multiple genes is unlikely to be detected in our screens unless these genes are located on the same chromosome arm. To identify this type of gene, one could perform a modified mosaic screen which induces clones of cells to become homozygous for more than one mutagenized chromosome arm. latε Affectε Many Tiεεueε Throughout Development The latε gene is genetically defined by a single complementation group that consists of various alleleε causing a wide range of defects. Different alleles were found to cause lethality at almost every stage during development: embryo, early larvae, late larvae, early pupae, late pupae and pharate-adult. The embryonic lethality occurs in the pharate first instar stage. The early embryonic requirements for lats could well be masked by the wt products that are maternally deposited in the egg. Weak lats alleles produce viable animals with phenotypeε ranging from rough eye to sterility. The lats transcripts were detected throughout development up to adult stage, conεiεtent with the observation that lats mutants affect all these stageε. Although mutations at lats cause many defects, affecting cell proliferation could cause most of the phenotypes including overproliferation in mutant clones, lethality at the various stages, tissue overproliferation on the head, broadened wing blade, and sterility in ho ozygouε mutants. However, phenotypeε such as extra cuticle depositε and malformed bristles and hairs are evidence of defects in differentiation. The different behavior of the latε mutant clones and clones mutant for other previously identified Drosophila tumor suppressors is interesting. Cells mutant for dig , lgl or hyd seem to fail to receive growth regulation signalε. They proliferated slower than wt cells during larval stages when the cells were instructed to proliferate, and they failed to terminate proliferation in late larval and pupal stages when the wt cells have ceased proliferation. On the other hand, the lats mutant clones induced during the larval stages were overproliferated, and later the mutant cells on the body were differentiated to form adult cuticular structures. Thus, lats could be a negative regulator that monitors the rate of proliferation. The lats gene is located in a complex region. The 5' end of the lats 5.7 kb transcript (cDNA) is only about 550 bp away from the T2 transcript and its 3' end iε about 1.5 kb away from the zfh-1 transcript. Furthermore, all three of these closely located transcripts are located in an intron of the Tl transcription unit. Thus, a sizable deletion in the 5.7 kb transcription unit could affect the function of any of the genes in the region, which makes it difficult to determine which transcript is responsible for the lats phenotype. The fact that P-element tranεform lines carrying a cDNA from the 5.7 kb transcript under the hεp70 promoter rescued all types of latε alleles demonstrated that the 5.7 kb transcription unit is the latε gene. The lats Putative Protein-Ser/Thr Kinase Shares Homology With Proteins That Are Involved in Regulation of Cell Cycle and Growth in Budding Yeast and Neuroεpora All 11 subdomains of the kinase domain that are found in previously identified protein kinases (Hanks et al., 1988, Science 241:42-52) are conserved in lats. This predicts that lats is a protein kinase. Furthermore, the sequence comparisons suggest lats to be a ser/thr kinase aε the lats kinase domain is more εimilar to protein-εer/thr kinaεeε than to protein-tyr kinaεeε. The C-terminal half of lats shares extensive sequence similarity with a group of six proteins. Mutations are known for three of these genes and in each case they affect either cell cycle or growth. The cot-1 (colonial temperature senεitive-1) gene of Neuroεpora waε identified by a temperature sensitive mutant that causes compact colony growth (Mitchell and Mitchell, 1954, Proc. Natl. Acad. Sci. USA 40:436-440; Galsworthy, 1966, Diss. Abstr. 26:6348) . Wild-type filamentous ascomycete Neuroεpora grows on solid media by continuous hyphal elongation and branching to form spreading colonies. Strains lacking functional cot-1 gene are viable, but their hyphae branch extensively, resulting in compact colonial growth (Yarden et al., 1992, EMBO J. 11:2159-2166). This extensive branching phenotype is somewhat similar to the growth property of the latε mutant clones: the lats mutant cells continue to "bud" out of the surface to form new proliferation lobes. Another homologous gene, the DBF2 gene of the budding yeast, was identified in a genetic screen for mutations causing defects in DNA synthesis (Johnston and Thomas, 1982, Mol. Gen. Genet. 186:439-444) . The temperature sensitive alleles of DBF2 were found to both delay the initiation of S phase and also to arrest the cell cycle during nuclear division (Johnston et al., 1990, Mol. Cell. Biol. 10:1358-1366). The DBF20 gene waε identified through cross hybridization with DBF2 DNA (Toyn et al., 1991, Gene 104:63-70). Strains carrying deletions for either DBF2 or DBF20 are viable; however, deleting both genes in the same strain causes lethality. The kinaεe activitieε of both proteins have been shown to be specific for serine/threonine residues and are regulated during the cell cycle (Toyn and Johnston, 1994, EMBO J. 13:1103-1113) . In the case of Dbf20, its entire sequence except the 20 most C-terminal residueε can be aligned with latε. The mutant phenotype of lats and its sequence homology with the cell cycle protein kinases is consistent with the notion that lats might be directly involved in regulation of the cell cycle. The N-terminal half of lats contains many proline-rich stretches and at least one of them closely matcheε the consensus sequence of SH3 binding sites (Ren et al., 1993, Science 259:1157-1161) , raising the possibility that thiε region could be a regulatory domain for the latε kinase, which binds to SH3 domain-containing proteins. In recent years, many protein kinases have been identified to be involved in regulation of the cell cycle and cell proliferation. While Weel is an inhibitor of the Cdc2 kinase (Russell and Nurse, 1987, Cell 49:559-567; 5 Featherstone and Russell, 1991, Nature 349:808-811), all other previously identified protein kinases are positive regulators of cell proliferation. They are either required for completion of the cell cycle or for signalling cells to proliferate. Lats is the first predicted protein-ser/thr 0 kinase that has been shown to cause overproliferation when its function is removed. Studies of latε and other overproliferation mutationε in Droεophila will provide a better understanding of how cell proliferation is regulated during development and how mutationε could lead to abnormal 5 growth. 7. ISOLATION AND CHARACTERIZATION OF MAMMALIAN LATS HOMOLOGS As described herein, we have cloned and sequenced _ both mouse and human latε homologs. 7.1. ISOLATION AND CHARACTERIZATION OF MOUSE LATS HOMOLOGS cDNA clones for two different latε homologs in mice were obtained as follows. _ Screening of Mouse Homologs: Probe: A 2.2 kb BamHI fragment containing the kinase domain of the Droεophila latε gene waε labeled with 32 P by random labeling Library: Newborn mouse brain lambda ZAP cDNA library from Stratagene 0 Hybridization Condition: 45°C, overnight in 6x SSC 5x Denhart's 0.5 SDS (εodium dodecyl εulfate) 100 μg/ml εalmon εperra DNA 5 Wash: 50°C, 30 min. x 4, in 2x SSC 0.1% SDS Results: Three positive clones were identified. (M41 clone for the m-latε gene, and M51 and M31 clones for th m-lats2 gene.) Two different mouse lats homologs, termed -latε and m-lats2 , respectively, were isolated and sequenced. Both the m-lats and m-lats2 clones are missing a small amount of the 5' end of their respective genes. The cDNA sequence (SEQ ID NO:5) and deduced protein sequence (SEQ ID NO:6) of -latε are shown in Figure 7. The cDNA sequence (SEQ ID NO:7) and deduced protein sequence (SEQ ID NO:8) of m-latε2 are shown in Figure 8. Portionε of both the m-latε and m-latε2 cDNAε were used as probes to screen a mouse genomic library, under standard hybridization conditions. Genomic clones for both m-latε and m-latε2 have been isolated that contain most of the coding regions of these genes. 7.2. ISOLATION AND CHARACTERIZATION OF HUMAN LATS HOMOLOGS cDNA clones for at least one human latε homolog were obtained as follows. Screening of Human Homologs (moderately εtringent conditions) : Probe: A 2.1 kb PstI fragment containing the kinase domain of the m-latε gene waε labeled with 32 P by random labeling Library: Fetal human brain lambda gtlO cDNA library from Clontech Hybridization Condition: 55°C, overnight in 6x SSC 5x Denhart'ε 0.5% SDS 100 μg/ml salmon sperm DNA Wash: 60°C, 30 min. x 2, in lx SSC 0.1= SDS Results: About 20 positive clones were identified for the h-latε gene. One human latε homolog, termed h-latε , was isolated and sequenced. The cDNA sequence (SEQ ID NO:3) and deduced protein sequence (SEQ ID NO:4) of h-lats are shown in Figure 9. The deduced protein sequence is full-length. The complete coding sequence of the h-latε cDNA was inserted into a bacterial cloning vector (derived from Bluescript (KS)- 5 vector; Stratagene) to form plasmid pBS(KS)-h-lats (Fig. 10). The total size of pBS(KS)-h-lats is 6.96 kb. A h-lats cDNA fragment was used as a probe under conditions of moderate stringency to screen a human genomic cosmid library. Genomic h-latε clones were isolated. Over 10 70 kb of the genomic h-latε sequence has been isolated; the isolated sequences include all of the h-latε coding εequence (but not all the exon sequences) . An m-latε2 cDNA fragment was used as a probe to screen a human genomic phage library under the conditions 15 described above, except that hybridization was carried out at 50°C, and washing was carried out at 55°C with 2X SSC, 0.1% SDS. Two genomic h-lats clones have been isolated that specifically hybridize to m-latε2 cDNA probes and do not hybridize to m-latε and h-latε cDNA probes. 20 8. CONSERVATION OF SEQUENCES AND DOMAIN STRUCTURE AMONG LATS HOMOLOGS OF DIFFERENT SPECIES Comparison of the sequences of Droεophila lats, h-lats, m-lats, and m-latε2 showed a startlingly high degree 25 of sequence conservation, both overall and within domains of the lats protein. An alignment of the h-lats (SEQ ID NO:4) and m-lats (SEQ ID NO:6) protein sequences is shown in Figure 11. The overall amino acid sequence identity between h-lats and m-lats iε 93%. An alignment of the h-latε (SEQ ID NO: 4) 30 and m-lats2 (SEQ ID NO:8) protein sequenceε iε shown in Figure 12. Homologous domainε (i.e., domainε conserved) between the different lats homologs were identified. Figure 13 presents an alignment of the h-latε protein εequence (SEQ 35 ID NO: 4) and the Droεophila lats protein sequence (SEQ ID NO:2), and indicateε the domainε identified aε conserved among the lats homologs from the various species. The identified domains were as follows: (1) Lats C-terminal domain 3 (LCD3) The last three amino acids (VYV) are completely conserved in all four homologs including Drosophila lats, h-lats, m-lats, and m-lats2. (2) Lats C-terminal domain 2 (LCD2) amino acid residues h-lats 1077-1086 Drosophila lats 1075-1084 This domain is completely conserved in all four homologs including Drosophila lats, h-lats, m-lats, and m-lats2 (10/10 identical residues) . (3) Lats C-terminal domain 1 (LCDl) amino acid residueε h-lats 1032-1043 Drosophila lats 1035-1047 This domain is completely conserved among Drosophila lats, h-lats, and m-lats (12/12 identical) , and iε highly conεerved between any of the foregoing and m-lats2 (11/12 identical) . (4) Kinase domain amino acid residues h-lats 703-1014 Drosophila latε 711-1018 This domain is highly conserved among the four homologs (76% identical between Droεophila lats and h-lats; 99% identical between h-lats and m-lats; 83% identical between h-lats and m-lats2) . A potential phosphorylation residue in Droεophila lats and the mammalian homologs that could lead to the activation of the latε kinaεes after phoεphorylation was identified. Activitieε of protein kinaεeε are often regulated by varying the phoεphorylation εtate of specific serine, threonine, and tyrosine residues. Phosphorylation of a serine or threonine within twenty residueε upεtrea of an Ala-Pro-Glu consensus in subdomain eight of the kinase domain, is often required for catalytic activities of many protein-ser/thr kinases (Hanks et al., 1988, Science 241:42-52). For example, Thrl67 and Thrl97 are phosphorylated in Cdc2 of fission yeast and in the cardiac muscle adenosine 3',5'-phosphate dependent protein kinase, respectively (Ducommun et al., 1991, EMBO J. 10:3311-3319; Gould et al., 1991, EMBO J. 10:3297-3309; Shoji et al., 1983, Biochem. 22:3702-3709) . A ser residue in a similar position of the lats kinaεe domain is conserved in Droεophila lats, h-lats, m-lats, and m-lats2 (Ser914 in Drosophila latε; Ser909 in h-lats) . Thus, the activitieε of Drosophila lats and its mammalian homologs may be regulated by phosphorylation of this ser residue. (5) Lats flanking domain (LFD) amino acid residueε h-lats 607-702 Drosophila lats 612-710 LFD is a domain that flanks and is amino-terminal to the kinase domain. This domain is highly conserved between Drosophila lats and h-lats (68% identical) and is also highly conserved between h-lats and m-lats2 (71% identical) . This domain is completely conserved between h-lats and m-lats (100% identical) . (6) Lats split domain 1 (LSDl) amino acid residues LSDl Drosophila-lats 365-392 LSDl anterior (LSDla) h-lats 328-334 LSDl posterior (LSDlp) h-latε 498-518 Certain latε domains have been termed split domains because the amino- (anterior) and carboxy- (posterior) portions of the domain appear separated from each other in at least one of the lats homologs. Split domains may constitute discontinuous binding/functional regions (e.g., brought together by tertiary structure) . The LSDla subdomain is completely conserved among Droεophila lats, h-lats, and m-lats (7/7 identical), and is not conserved in m-lats. The LSDlp subdomain is conserved between the four homologs (14/21 identical among Drosophila lats, h-lats, and m-lats; 13/21 identical between h-lats and m-lats2) . The LSDla and LSDlp subdomains are adjacent to each other in Drosophila lats and are separated in the mammalian homologs. (7) Lats split domain 2 (LSD2) amino acid residueε LSD2 Drosophila lats 536-544 LSD2 anterior (LSD2a) h-lats 28-31 LSD2 posterior (LSD2p) h-lats 555-559 Both the LSD2a and LSD2p subdomains are completely conserved among the four homologs. However, the two subdomains are adjacent to each other in Drosophila lats and are separated in the mammalian homologs. (8) Putative SH3-binding domain (SH3-binding) amino acid residues h-lats 247-268 Droεophila lats 196-217 This domain is highly conserved among Droεophila lats, h-lats, and m-latε (10/22 identical) , and doeε not exist in m-lats2. . The opa domain does not appear in the mammalian lats homologs. 9. FUNCTIONAL INTERCHANGEABILITY OF THE HUMAN AND DROSOPHILA LATS HOMOLOGS 9.1. OVEREXPRESSION OF HUMAN LATS OR OF DROSOPHILA LATS CAUSES A SMALLER, ROUGH EYE IN DROSOPHILA Overexpresεion of latε and h-latε in the developing Droεophila eye waε carried out. The Droεophila latε cDNA and h-latε cDNA were each cloned into the pGMR P-element vector. This vector was constructed by Bruce Hay and Gerald M. Rubin at the University of California at Berkeley, and will direct the expression of a cDNA of interest in the posterior region of the developing third inεtar larval eye imaging diεc of Drosophila . Ten independent transformant lines for each of the pGMR-lats and pGMR-h-lats constructs were generated. The adult eyes of all these lines displayed a small-rough eye phenotype (eyes smaller than normal, with irregular, rough appearance) . This indicates that both lats and h-lats genes have the same biological effect when they are overexpressed in the developing Drosophila eye. 9.2. HUMAN H-LATS GENE CAN REPLACE THE DROSOPHILA HOMOLOG TO PREVENT DEATH IN DROSOPHILA ANIMALS HAVING MUTANT DROSOPHILA LATS The Drosophila latε cDNA was cloned into the pCaSpeR-hs vector (Thummel and Pirrotta, 1992, Drosophila Inform. Service 71:150) for germ line transformation of Drosophila . Three of the transformed lines were tested and were able to rescue the lethality of the lats"' / lats*' , lats pι and lats' 26' ' animals after one hour heat shock for every 24 hours during larval and pupal development. The human h-latε cDNA (in a Xhol (blunted)-Xbal fragment) from pBS(SK)-h-lats (Fig. 10) was cloned into the Hpal-Xbal sites of the pCaSpeR-hs vector, to produce plasmid pCaSpeR-hs-h-latε (Fig. 14) . Plasmid pCaSpeR-hs-h-lats was used for germ line transformant. Three of the pCaSpeR-hs-h-lats transformant lines were tested and were able to rescue the lethality of the lats Pl and lats' 26 "' animals under the same conditions used in rescuing experiments for the Drosophila gene. 10. HUMAN LATS EXPRESSION IS FOUND IN ALL NORMAL TISSUES TESTED AND IS ABSENT IN A LARGE NUMBER OF TUMOR CELL LINES 10.1. HUMAN LATS EXPRESSION IN NORMAL TISSUES The expression of human latε RNA was investigated in various adult tissues. A 1.2 kb BamHI fragment of the h-lats cDNA was used as a 32 P-labeled probe for Northern analysis. Hybridization was to a nylon membrane containing polyA + RNA from various human fetal and adult tissues, obtained from Clontech. The Northern analysis was carried out according to the recommended instructions of the manufacturer (Clontech) . The results are shown in Figure 15. h-lats was expressed in every tissue tested (fetal brain, fetal lung, fetal liver, fetal kidney, adult spleen, adult thymus, adult prostate, adult testis, adult ovary, adult small intestine, adult colon, and adult blood leukocytes) . Expression was higher in fetal tissues than in adult tiεεueε. 10.2. HUMAN LATS EXPRESSION IN VARIOUS TUMOR CELL LINES The 3 P-labeled BamHI fragment of h-latε was used as a probe for Northern analysiε, for hybridization to total RNAs isolated from 42 different human tumor cell lines (obtained from the American Type Culture Collection, Rockville, MD) . No h-lats expression was detected in 20 of the tumor lines (48%) . The name and tissue origin of the tumor cell lines tested, and the results of the Northern analysis are presented in Table 3. SW480 Colon X Caco-2 Colon + HEL 92.1.7 Erythroleukemia X MOLT-4 Leukemia X CEM-CM3 Leukemia X K-562 Leukemia X Jurkat Leukemia HUT 78 Lymphoma SK-LU-1 Lung X A-427 Lung X Calu-1 Lung X NCI-H69 Lung X SK-MEL-3 Melanoma X SK-MEL-28 Melanoma X SK-MEL-31 Melanoma X MIA PaCa-2 Pancreas X BxPC-3 Pancreas X HS 700T Pancreas X HS 766T Pancreas X RD Sarcoma X A-204 Sarcoma X AN3 CA Uterine X SK-UT-1 Uterine X HEC-l-A Uterine + *: weak signal Thus, 48% of the tumor cell lines tested had no detectable h-lats expresεion, whereas 100% of the normal tissues tested had detectable h-lats expression. It should be noted that the 48% figure may be an underestimate of the actual number of tumor cell lineε that had decreaεed lats protein level or activity relative to normal tissue, since while lack of latε RNA (i.e., a transcriptional block) allows the conclusion that no lats protein is made, tumor cells that expressed the latε RNA may still have had no or low lats protein levels and/or activity due to the possible existence of a translational block or the preεence of mutation(ε) in an expressed lats protein. 11. DEPOSIT OF MICROORGANISM Bacteria strain E. coli TG2 containing plasmid pBS(KS)-h-lats was deposited on March 24, 1995 with the American Type Culture Collection, 1201 Parklawn Drive, Rockville, Maryland 20852, under the provisions of the Budapest Treaty on the International Recognition of the Deposit of Microorganisms for the Purposeε of Patent Procedures, and asεigned Accession No. 69769. The present invention is not to be limited in εcope by the microorganiεm depoεited or the specific embodiments described herein. Indeed, various modificationε of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications are intended to fall within the scope of the appended claims. Various references are cited herein, the disclosures of which are incorporated by reference in their entireties. SEQUENCE LISTING (1) GENERAL INFORMATION: (i) APPLICANT: Xu, Tian Tao, Wufan Wang, Weiyi Zhang, Sheng Yu, Wan (ii) TITLE OF INVENTION: NUCLEOTIDE AND PROTEIN SEQUENCES OF LATS GENES AND METHODS BASED THEREON (iii) NUMBER OF SEQUENCES: 16 (iv) CORRESPONDENCE ADDRESS: (A) ADDRESSEE: Pennie & Edmonds (B) STREET: 1155 Avenue of the Americas (C) CITY: New York (D) STATE: New York (E) COUNTRY: USA (F) ZIP: 10036-2711 (v) COMPUTER READABLE FORM: (A) MEDIUM TYPE: Floppy disk (B) COMPUTER: IBM PC compatible (C) OPERATING SYSTEM: PC-DOS/MS-DOS (D) SOFTWARE: Patentin Release #1.0, Version #1.30 (vi) CURRENT APPLICATION DATA: (A) APPLICATION NUMBER: To Be Assigned (B) FILING DATE: On Even Date Herewith (C) CLASSIFICATION: (viii) ATTORNEY/AGENT INFORMATION: (A) NAME: Misrock, S. Leslie (B) REGISTRATION NUMBER: 18,872 (C) REFERENCE/DOCKET NUMBER: 6523-007 (ix) TELECOMMUNICATION INFORMATION: (A) TELEPHONE: (212) 790-9090 (B) TELEFAX: (212) 869-9741/8864 (C) TELEX: 66141 PENNIE (2) INFORMATION FOR SEQ ID NO:l: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 5720 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: cDNA (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 1103..4402 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:l: ATCTAGCACG ACGGCAGCAA CAAAACCACG AATTAATTTT ACTAAATTTA AGCCAAACGC 60 GCATCGGAAA TGCCTGAAAA TGCGATTGAA TGCACGCGAA AAGTGATGGG TTGCGAACGC 120 GAGTGAATCA AGTGAAAATA CGTCGGCAAA TATCAGCGAA TTGTCGTCAA AAGGCAAGGA 180 AAAACGGAGA AAAAGAGGAA AAGCAATAAG TGCCGTGTGT GGGAAACGCG AAAAAGGCGA 240 GAACAAAGAG GCGAAAAGCG AGGAAATTGC GTGGAAAACG TGGAAAACGC GAAGAAGCGA 300 AGCTCCAAGT TGGCCGCCAT CGATTCGTGC GTAGGATCAA TTAAGATTCC GAGTGGTCGA 360 GAATCGGCTC AAATCAAATT AAAATCAACT AATATTTTGG TATTCAGATA TTCAAATGGA 420 ATTCATTCAT CGCCTGCGAC TTTTATTCGG ATCTGCCAAC TATTTTTGAA TTTGAATTGT 480 GTGTCTGCGG CTGGCGCAGA ATCTCTGATA AAGCAGAGGA ATAAAATCGG AAGAACAACA 540 AATACAAATA CAAATGAAAT GCGGGGAGCA GTATTTACAT GCCAAATGAA TGCTGGATAG 600 GCGAAAGGGG GGGTTTCTCT TATAATGCAA ATGTGAATGT GAATGCGAAT GCGAATGCGA 660 GTGGAAGAAT TCCCGGCGCG AGTGATAAAT AATCCGACGA CAAACAAAGC AGAAGCCTAC 720 ACCGCGAGAA AGAGCAGCGC AAACACAATT ATCTTTATTG AGAGCAACAA TATCAAGATC 780 GAGATAATAA AGCATCCTAA AACCCGCGCC TTAGTTCGTT TTAGTCTCGC CACGGATATA 840 GATATTCAAA GGCAAAAAGG TGGTGTCGGC ATCGCCAGAC AAACAAGTAA AGCATCTATT 900 TCATACAAAA CAACCAATTA AATAATAATA AAAATAATAA TAATCGTAGA GAGGCAGAGC 960 CAAATCAAAT TCCCGGCCGC CGATGTGCCC CAGTGTGTGT GCGTGTGTGT GTGTGTGTGC 1020 TGTGCTGTGC TGTGCGAGTG TTAGTGTGCG GAGCATTTCT GTGATATGAG TGCTAAATGC 1080 CACAGGGCGA AGCAGCAGCA TC ATG CAT CCA GCG GGC GAA AAA AGG GGC GGT 1132 Met His Pro Ala Gly Glu Lys Arg Gly Gly 1 5 10 CGC CCC AAT GAT AAA TAC ACG GCG GAA GCC CTC GAG AGC ATC AAG CAG 1180 Arg Pro Asn Asp Lys Tyr Thr Ala Glu Ala Leu Glu Ser lie Lys Gin 15 20 25 GAC CTA ACC CGA TTT GAA GTA CAA AAT AAC CAT AGG AAT AAT CAG AAT 1228 Aβp Leu Thr Arg Phe Glu Val Gin Asn Asn His Arg Asn Asn Gin Asn 30 35 40 TAC ACA CCT CTG CGA TAC ACG GCG ACC AAC GGA CGC AAC GAT GCA CTT 1276 Tyr Thr Pro Leu Arg Tyr Thr Ala Thr Asn Gly Arg Asn Asp Ala Leu 45 50 55 ACT CCT GAC TAT CAC CAC GCC AAG CAG CCG ATG GAG CCG CCA CCC TCC 1324 Thr Pro Asp Tyr His His Ala Lys Gin Pro Met Glu Pro Pro Pro Ser 60 65 70 GCC TCT CCT GCT CCG GAC GTG GTC ATA CCG CCG CCG CCC GCC ATT GTA 1372 Ala Ser Pro Ala Pro Asp Val Val lie Pro Pro Pro Pro Ala He Val 75 80 85 90 GGT CAG CCC GGA GCC GGC TCC ATA TCC GTA TCC GGT GTG GGC GTT GGA 1420 Gly Gin Pro Gly Ala Gly Ser He Ser Val Ser Gly Val Gly Val Gly 95 100 105 GTG GTG GGT GTG GCG AAC GGA CGT GTG CCA AAG ATG ATG ACG GCC CTA 1468 Val Val Gly Val Ala Asn Gly Arg Val Pro Lys Met Met Thr Ala Leu 110 115 120 ATG CCA AAC AAA CTG ATC CGG AAG CCG AGC ATC GAA CGG GAC ACG GCG 1516 Met Pro Asn Lye Leu He Arg Lys Pro Ser He Glu Arg Asp Thr Ala 125 130 135 AGC AGT CAC TAC CTG CGC TGC AGT CCG GCT CTG GAC TCC GGA GCC GGT 1564 Ser Ser His Tyr Leu Arg Cys Ser Pro Ala Leu Aβp Ser Gly Ala Gly 140 145 150 AGC TCC CGA TCG GAC AGC CCC CAT TCG CAC CAC ACC CAC CAG CCG AGC 1612 Ser Ser Arg Ser Asp Ser Pro Hie Ser His His Thr His Gin Pro Ser 155 160 165 170 TCG AGG ACG GTG GGT AAT CCA GGT GGA AAT GGT GGA TTT TCT CCG TCG 1660 Ser Arg Thr Val Gly Asn Pro Gly Gly Asn Gly Gly Phe Ser Pro Ser 175 180 185 CCA AGC GGT TTC AGT GAG GTG GCT CCA CCG GCG CCG CCG CCA CGC AAT 1708 Pro Ser Gly Phe Ser Glu Val Ala Pro Pro Ala Pro Pro Pro Arg Asn 190 195 200 CCC ACC GCC TCC AGC GCG GCC ACG CCC CCA CCG CCA GTG CCG CCC ACC 1756 Pro Thr Ala Ser Ser Ala Ala Thr Pro Pro Pro Pro Val Pro Pro Thr 205 210 215 AGC CAG GCG TAC GTG AAG CGG CGA TCA CCG GCC CTG AAC AAC CGC CCG 1804 Ser Gin Ala Tyr Val Lys Arg Arg Ser Pro Ala Leu Asn Asn Arg Pro 220 225 230 CCG GCG ATA GCG CCA CCC ACT CAG CGA GGC AAC TCA CCT GTA ATA ACC 1852 Pro Ala He Ala Pro Pro Thr Gin Arg Gly Asn Ser Pro Val He Thr 235 240 245 250 CAA AAC GGG CTG AAG AAC CCG CAG CAG CAG TTG ACG CAG CAG CTG AAG 1900 Gin Asn Gly Leu Lys Asn Pro Gin Gin Gin Leu Thr Gin Gin Leu Lys 255 260 265 TCC CTG AAC CTA TAC CCA GGC GGA GGC AGT GGA GCA GTG GTG GAG CCA 1948 Ser Leu Asn Leu Tyr Pro Gly Gly Gly Ser Gly Ala Val Val Glu Pro 270 275 280 CCG CCG CCC TAC CTA ATT CAA GGC GGA GCC GGA GGA GCA GCA CCG CCG 1996 Pro Pro Pro Tyr Leu He Gin Gly Gly Ala Gly Gly Ala Ala Pro Pro 285 290 295 CCG CCA CCA CCC AGT TAC ACG GCC TCC ATG CAG TCG CGG CAG TCG CCC 2044 Pro Pro Pro Pro Ser Tyr Thr Ala Ser Met Gin Ser Arg Gin Ser Pro 300 305 310 ACA CAA TCC CAA CAA TCG GAC TAC AGG AAA TCC CCG AGC AGT GGG ATA 2092 Thr Gin Ser Gin Gin Ser Asp Tyr Arg Lys Ser Pro Ser Ser Gly He 315 320 325 330 TAC TCG GCC ACC TCG GCG GGC TCG CCG AGC CCC ATA ACT GTG TCG CTG 2140 Tyr Ser Ala Thr Ser Ala Gly Ser Pro Ser Pro He Thr Val Ser Leu 335 340 345 CCG CCG GCG CCG CTG GCG AAG CCA CAA CCA CGA GTC TAC CAG GCC AGG 2188 Pro Pro Ala Pro Leu Ala Lys Pro Gin Pro Arg Val Tyr Gin Ala Arg 350 355 360 AGT CAG CAG CCG ATC ATC ATG CAG AGT GTG AAG AGC ACG CAG GTC CAA 2236 Ser Gin Gin Pro He He Met Gin Ser Val Lys Ser Thr Gin Val Gin 365 370 375 AAG CCC GTG CTG CAA ACA GCA GTG GCG CGC CAA TCG CCA TCG AGT GCC 2284 Lys Pro Val Leu Gin Thr Ala Val Ala Arg Gin Ser Pro Ser Ser Ala 380 385 390 TCG GCC AGC AAT TCA CCA GTC CAC GTG CTG GCC GCT CCA CCC TCT TAC 2332 Ser Ala Ser Asn Ser Pro Val His Val Leu Ala Ala Pro Pro Ser Tyr 395 400 405 410 CCT CAG AAG TCC GCG GCA GTG GTG CAG CAG CAG CAA CAG GCA GCA GCG 2380 Pro Gin Lys Ser Ala Ala Val Val Gin Gin Gin Gin Gin Ala Ala Ala 415 420 425 GCG GCC CAC CAG CAG CAG CAT CAG CAC CAG CAA TCC AAA CCA CCA ACG 2428 Ala Ala His Gin Gin Gin His Gin His Gin Gin Ser Lys Pro Pro Thr 430 435 440 CCA ACC ACA CCG CCC TTG GTG GGT CTG AAC AGC AAG CCC AAT TGC CTG 2476 Pro Thr Thr Pro Pro Leu Val Gly Leu Asn Ser Lys Pro Asn Cys Leu 445 450 455 GAG CCA CCG TCC TAT GCC AAG AGC ATG CAG GCC AAG GCG GCC ACG GTG 2524 Glu Pro Pro Ser Tyr Ala Lys Ser Met Gin Ala Lys Ala Ala Thr Val 460 465 470 GTA CAG CAG CAG CAA CAG CAG CAG CAA CAA CAG CAG GTC CAG CAG CAG 2572 Val Gin Gin Gin Gin Gin Gin Gin Gin Gin Gin Gin Val Gin Gin Gin 475 480 485 490 CAG GTG CAA CAG CAG CAG CAA CAG CAG CAA CAG CAA CTG CAG GCC TTG 2620 Gin Val Gin Gin Gin Gin Gin Gin Gin Gin Gin Gin Leu Gin Ala Leu 495 500 505 AGG GTG CTC CAG GCA CAG GCT CAG AGG GAG CGG GAT CAA CGG GAG CGG 2668 Arg Val Leu Gin Ala Gin Ala Gin Arg Glu Arg Asp Gin Arg Glu Arg 510 515 520 GAA CGG GAT CAG CAG AAG CTG GCC AAC GGA AAT CCT GGC CGG CAG ATG 2716 Glu Arg Asp Gin Gin Lys Leu Ala Asn Gly Asn Pro Gly Arg Gin Met 525 530 535 CTT CCG CCG CCG CCC TAT CAG AGC AAC AAC AAC AAC AAC AGC GAG ATC 2764 Leu Pro Pro Pro Pro Tyr Gin Ser Asn Asn Asn Asn Asn Ser Glu He 540 545 550 AAA CCG CCG AGC TGC AAC AAC AAC AAC ATA CAG ATA AGC AAC AGC AAC 2812 Lys Pro Pro Ser Cys Asn Asn Asn Asn He Gin He Ser Asn Ser Asn 555 560 565 570 CTG GCG ACG ACA CCA CCC ATT CCG CCT GCC AAA TAC AAT AAC AAC TCC 2860 Leu Ala Thr Thr Pro Pro He Pro Pro Ala Lys Tyr Asn Asn Asn Ser 575 580 585 TCC AAC ACG GGC GCG AAT AGC TCG GGC GGC AGC AAC GGA TCC ACC GGC 2908 Ser Asn Thr Gly Ala Asn Ser Ser Gly Gly Ser Asn Gly Ser Thr Gly 590 595 600 ACC ACC GCC TCC TCG TCG ACC AGC TGC AAG AAG ATC AAG CAC GCC TCG 2956 Thr Thr Ala Ser Ser Ser Thr Ser Cys Lys Lys He Lys His Ala Ser 605 610 615 CCC ATC CCG GAG CGC AAG AAG ATC TCC AAG GAG AAG GAG GAG GAG CGC 3004 Pro He Pro Glu Arg Lys Lys He Ser Lys Glu Lys Glu Glu Glu Arg 620 625 630 AAG GAG TTC CGC ATC AGG CAG TAC TCG CCG CAA GCC TTC AAG TTC TTC 3052 Lys Glu Phe Arg He Arg Gin Tyr Ser Pro Gin Ala Phe Lys Phe Phe 635 640 645 650 ATG GAG CAG CAC ATA GAG AAC GTG ATC AAG TCG TAT CGC CAG CGC ACG 3100 Met Glu Gin His He Glu Asn Val He Lys Ser Tyr Arg Gin Arg Thr 655 660 665 TAT CGC AAG AAT CAG CTG GAG AAG GAG ATG CAC AAA GTG GGA CTG CCC 3148 Tyr Arg Lys Aβn Gin Leu Glu Lys Glu Met Hie Lys Val Gly Leu Pro 670 675 680 GAT CAG ACC CAA ATC GAG ATG AGG AAA ATG CTG AAC CAA AAG GAG AGC 3196 Aβp Gin Thr Gin He Glu Met Arg Lys Met Leu Aβn Gin Lye Glu Ser 685 690 695 AAC TAC ATT CGA TTG AAG CGC GCC AAG ATG GAC AAG AGC ATG TTC GTC 3244 Aβn Tyr He Arg Leu Lye Arg Ala Lye Met Aβp Lye Ser Met Phe Val 700 705 710 AAA CTG AAG CCC ATT GGA GTG GGT GCA TTT GGC GAG GTA ACG CTG GTG 3292 Lye Leu Lys Pro He Gly Val Gly Ala Phe Gly Glu Val Thr Leu Val 715 720 725 730 AGC AAA ATC GAT ACC TCG AAC CAT TTG TAT GCG ATG AAA ACC CTG CGG 3340 Ser Lys He Aβp Thr Ser Aβn Hie Leu Tyr Ala Met Lys Thr Leu Arg 735 740 745 AAA GCG GAC GTT CTC AAG CGG AAT CAG GTG GCA CAC GTG AAG GCC GAG 3388 Lys Ala Asp Val Leu Lys Arg Asn Gin Val Ala His Val Lys Ala Glu 750 755 760 AGG GAT ATC CTC GCG GAA GCC GAC AAT AAC TGG GTG GTG AAG TTG TAC 3436 Arg Aβp He Leu Ala Glu Ala Aβp Aβn Aβn Trp Val Val Lys Leu Tyr 765 770 775 TAC AGC TTC CAG GAC AAG GAT AAT CTG TAC TTT GTG ATG GAC TAC ATA 3484 Tyr Ser Phe Gin Asp Lye Aβp Aβn Leu Tyr Phe Val Met Aβp Tyr He 780 785 790 CCA GGT GGT GAT CTG ATG TCG CTG CTC ATC AAA CTG GGC ATT TTC GAG 3532 Pro Gly Gly Asp Leu Met Ser Leu Leu He Lys Leu Gly He Phe Glu 795 800 805 810 GAG GAA CTG GCC AGA TTC TAC ATC GCC GAG GTC ACC TGC GCC GTG GAC 3580 Glu Glu Leu Ala Arg Phe Tyr He Ala Glu Val Thr Cys Ala Val Asp 815 820 825 AGC GTT CAC AAA ATG GGC TTC ATT CAC AGA GAC ATC AAG CCT GAC AAC 3628 Ser Val His Lys Met Gly Phe He His Arg Asp He Lys Pro Asp Asn 830 835 840 ATA CTC ATC GAT AGG GAC GGA CAC ATA AAG CTC ACC GAC TTT GGC CTG 3676 He Leu He Aβp Arg Aβp Gly His He Lys Leu Thr Asp Phe Gly Leu 845 850 855 TGC ACG GGA TTC CGA TGG ACG CAC AAC TCG AAG TAC TAC CAG GAG AAC 3724 Cys Thr Gly Phe Arg Trp Thr His Asn Ser Lys Tyr Tyr Gin Glu Aβn 860 865 870 GGC AAT CAC TCG CGC CAG GAC TCG ATG GAG CCC TGG GAG GAA TAC TCC 3772 Gly Asn His Ser Arg Gin Asp Ser Met Glu Pro Trp Glu Glu Tyr Ser 875 880 885 890 GAG AAC GGA CCG AAG CCC ACC GTG CTG GAG AGG CGA CGG ATG CGC GAT 3820 Glu Asn Gly Pro Lys Pro Thr Val Leu Glu Arg Arg Arg Met Arg Asp 895 900 905 CAC CAA AGA GTC CTG GCC CAC TCG CTG GTG GGC ACC CCG AAC TAC ATA 3868 His Gin Arg Val Leu Ala His Ser Leu Val Gly Thr Pro Asn Tyr He 910 915 920 GCT CCC GAG GTG CTG GAG AGG AGT GGG TAC ACG CAG CTG TGC GAC TAC 3916 Ala Pro Glu Val Leu Glu Arg Ser Gly Tyr Thr Gin Leu Cys Asp Tyr 925 930 935 TGG AGC GTG GGC GTC ATC CTT TAC GAG ATG CTG GTG GGT CAG CCG CCC 3964 Trp Ser Val Gly Val He Leu Tyr Glu Met Leu Val Gly Gin Pro Pro 940 945 950 TTT CTG GCC AAC AGT CCG CTG GAA ACG CAA CAA AAG GTC ATC AAC TGG 4012 Phe Leu Ala Aβn Ser Pro Leu Glu Thr Gin Gin Lys Val He Aβn Trp 955 960 965 970 GAG AAA ACG CTG CAT ATT CCG CCG CAG GCC GAG TTA TCC CGC GAG GCT 4060 Glu Lye Thr Leu Hie He Pro Pro Gin Ala Glu Leu Ser Arg Glu Ala 975 980 985 ACG GAC TTG ATA AGG AGG CTC TGT GCG TCG GCT GAC AAG CGG CTG GGC 4108 Thr Aβp Leu He Arg Arg Leu Cys Ala Ser Ala Aβp Lys Arg Leu Gly 990 995 1000 AAG AGC GTG GAC GAG GTC AAG AGC CAC GAC TTC TTC AAG GGC ATC GAC 4156 Lye Ser Val Aβp Glu Val Lye Ser His Asp Phe Phe Lye Gly He Aβp 1005 1010 1015 TTT GCG GAC ATG CGG AAG CAG AAA GCG CCC TAC ATA CCG GAA ATC AAG 4204 Phe Ala Aβp Met Arg Lye Gin Lye Ala Pro Tyr He Pro Glu He Lys 1020 1025 1030 CAC CCA ACG GAC ACA TCC AAC TTT GAT CCC GTG GAT CCG GAG AAG CTG 4252 Hie Pro Thr Aβp Thr Ser Aβn Phe Aβp Pro Val Asp Pro Glu Lys Leu 1035 1040 1045 1050 CGC TCG AAT GAC TCC ACC ATG AGC AGC GGC GAT GAT GTC GAC CAG AAT 4300 Arg Ser Aβn Aβp Ser Thr Met Ser Ser Gly Aβp Asp Val Asp Gin Aβn 1055 1060 1065 GAC CGC ACT TTC CAC GGC TTT TTC GAA TTT ACC TTC CGT CGC TTC TTC 4348 Aβp Arg Thr Phe Hie Gly Phe Phe Glu Phe Thr Phe Arg Arg Phe Phe 1070 1075 1080 GAC GAC AAG CAG CCG CCG GAT ATG ACG GAC GAT CAG GCG CCG GTT TAC 4396 Aβp Aβp Lys Gin Pro Pro Asp Met Thr Asp Aβp Gin Ala Pro Val Tyr 1085 1090 1095 GTC TGA AATGGATGCT CTCCATGTGC CCAACACCAA CACCCCGCCC CCGAATCATT 4452 Val * 1100 GTTAGTCAAA TAGTCACAAA AAGGGGATAG AAACCATTGA GTGGGCTTGC ATTGTAAAGG 4512 AAGCGTGGCT ATAGAATGAA ACTATCTATA TACATTATAT AAATTATAGG AGACAGTAGA 4572 GGCGGGAGCT ACGTATATAC ATACAAATAA TATACATATA TTTGATATAT ATATATATAT 4632 ATATGCCGTA GGGCATGAAC TGAATAAATA TAAAACGGAG CCGAGTAGAG ATGAAACGAG 4692 AGGAGCGAGT CAGGACCTTC GACCTTTAAC TGAACATAGT ATATCCTTGT GCACTACTAC 4752 TCCACAACAA ATATATATTT TTAAATTGTT AGAATTCAAA AGGGACCAAC TGGAAATCGA 4812 ACCTTTCTGG TGCTCAAAGC AAAGCAAAGC AAAGCAAAAC AAAACGCCTT AAACTAAATG 4872 AGACGCGAAT TTACCCAACC ACTTCACTCC TCTCCTTTCT CCACCTCCGA TCGGTGGCCG 4932 GATTCGAACT CAGCAGGCTG GTTGCATCCG GCCATCCCAT TGACTTCCCA TTCAGAATTG 4992 AGATTGCGAG GTGTGCGATG GAGAACGAAC GGAGACCAAA AGTCGCACGG CAGCGATATA 5052 AGCGGGTCTT ATAAGCCTAA TCTAAATCTA AACTGGGAGA ACAGGACCTA TGTATGTCCT 5112 GCTATCCAAT TCGTCTATCA CTGCTCTTCA TCTGTGTACG ACCCCCACCC CCCCCCTCCC 5172 CATCCAAAAG AACAAACTTA GACGTAGCCT ATGTGAAAAG CTAGCAATGT TAGACCAACT 5232 TGTTGAATGC CAAATGAAAT TGTTTAGCCC CACGAGGAAA ACGCGGGGGA AATTCAACAC 5292 TTATTCTCTG ATAGCAAACG GAAAAGAAAG AAAGAAAAAA AAAAACAGAA ACAGTACGAG 5352 AAAATTGTAA TCTTCTTAAT GTAATATTGT AAAGAACACG TTAATTGTAA TCTATGCTAG 5412 AGTTGTGTAG CGCCCTAAGA TGTTTTTTAG TTTATAGACC GCTAACCGTA ATCTAGTTTA 5472 ATTCCTAACA CTAAGCGAGA GTACAGTACA TTGGTTTTTT TGTTTGTCGT AGGTTCGTTG 5532 GAAAATGCTT AACGGGAAAC GATTTGTTTT TCTCTTTAAT TAGCTTCAGT TTGTATGTGC 5592 GTGTGTTTTT ATTATGACTT ATATATAGTC CATCTGAATA TTCGTGGATG GAGCCTATTT 5652 TAAATGTGAG ATCGAGCTAA TTGAAGGAAA TACAAACAAA CTCTGTGTGC CTTGGCCAAT 5712 TAGTTTAC 5720 (2) INFORMATION FOR SEQ ID NO:2: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1100 amino acids (B) TYPE: amino acid (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2: Met His Pro Ala Gly Glu Lys Arg Gly Gly Arg Pro Aβn Asp Lye Tyr 1 5 10 15 Thr Ala Glu Ala Leu Glu Ser He Lye Gin Aβp Leu Thr Arg Phe Glu 20 25 30 Val Gin Aβn Aβn His Arg Asn Asn Gin Aβn Tyr Thr Pro Leu Arg Tyr 35 40 45 Thr Ala Thr Asn Gly Arg Asn Asp Ala Leu Thr Pro Aβp Tyr His Hie 50 55 60 Ala Lye Gin Pro Met Glu Pro Pro Pro Ser Ala Ser Pro Ala Pro Aβp 65 70 75 80 Val Val He Pro Pro Pro Pro Ala He Val Gly Gin Pro Gly Ala Gly 85 90 95 Ser He Ser Val Ser Gly Val Gly Val Gly Val Val Gly Val Ala Aβn 100 105 110 Gly Arg Val Pro Lys Met Met Thr Ala Leu Met Pro Asn Lys Leu He 115 120 125 Arg Lys Pro Ser He Glu Arg Asp Thr Ala Ser Ser His Tyr Leu Arg 130 135 140 Cys Ser Pro Ala Leu Asp Ser Gly Ala Gly Ser Ser Arg Ser Asp Ser 145 150 155 160 Pro His Ser His His Thr His Gin Pro Ser Ser Arg Thr Val Gly Asn 165 170 175 Pro Gly Gly Aβn Gly Gly Phe Ser Pro Ser Pro Ser Gly Phe Ser Glu 180 185 190 Val Ala Pro Pro Ala Pro Pro Pro Arg Aβn Pro Thr Ala Ser Ser Ala 195 200 205 Ala Thr Pro Pro Pro Pro Val Pro Pro Thr Ser Gin Ala Tyr Val Lye 210 215 220 Arg Arg Ser Pro Ala Leu Aβn Aβn Arg Pro Pro Ala He Ala Pro Pro 225 230 235 240 Thr Gin Arg Gly Aβn Ser Pro Val He Thr Gin Aβn Gly Leu Lye Aβn 245 250 255 Pro Gin Gin Gin Leu Thr Gin Gin Leu Lye Ser Leu Asn Leu Tyr Pro 260 265 270 Gly Gly Gly Ser Gly Ala Val Val Glu Pro Pro Pro Pro Tyr Leu He 275 280 285 Gin Gly Gly Ala Gly Gly Ala Ala Pro Pro Pro Pro Pro Pro Ser Tyr 290 295 300 Thr Ala Ser Met Gin Ser Arg Gin Ser Pro Thr Gin Ser Gin Gin Ser 305 310 315 320 Asp Tyr Arg Lye Ser Pro Ser Ser Gly He Tyr Ser Ala Thr Ser Ala 325 330 335 Gly Ser Pro Ser Pro He Thr Val Ser Leu Pro Pro Ala Pro Leu Ala 340 345 350 Lys Pro Gin Pro Arg Val Tyr Gin Ala Arg Ser Gin Gin Pro He He 355 360 365 Met Gin Ser Val Lys Ser Thr Gin Val Gin Lys Pro Val Leu Gin Thr 370 375 380 Ala Val Ala Arg Gin Ser Pro Ser Ser Ala Ser Ala Ser Aβn Ser Pro 385 390 395 400 Val His Val Leu Ala Ala Pro Pro Ser Tyr Pro Gin Lys Ser Ala Ala 405 410 415 Val Val Gin Gin Gin Gin Gin Ala Ala Ala Ala Ala His Gin Gin Gin 420 425 430 Hie Gin His Gin Gin Ser Lys Pro Pro Thr Pro Thr Thr Pro Pro Leu 435 440 445 Val Gly Leu Asn Ser Lys Pro Asn Cys Leu Glu Pro Pro Ser Tyr Ala 450 455 460 Lys Ser Met Gin Ala Lys Ala Ala Thr Val Val Gin Gin Gin Gin Gin 465 470 475 480 Gin Gin Gin Gin Gin Gin Val Gin Gin Gin Gin Val Gin Gin Gin Gin 485 490 495 Gin Gin Gin Gin Gin Gin Leu Gin Ala Leu Arg Val Leu Gin Ala Gin 500 505 510 Ala Gin Arg Glu Arg Asp Gin Arg Glu Arg Glu Arg Asp Gin Gin Lys 515 520 525 Leu Ala Asn Gly Asn Pro Gly Arg Gin Met Leu Pro Pro Pro Pro Tyr 530 535 540 Gin Ser Asn Asn Asn Asn Asn Ser Glu He Lys Pro Pro Ser Cys Asn 545 550 555 560 Aβn Aβn Aβn He Gin He Ser Aβn Ser Aβn Leu Ala Thr Thr Pro Pro 565 570 575 He Pro Pro Ala Lye Tyr Aβn Aβn Aβn Ser Ser Aβn Thr Gly Ala Aβn 580 585 590 Ser Ser Gly Gly Ser Asn Gly Ser Thr Gly Thr Thr Ala Ser Ser Ser 595 600 605 Thr Ser Cys Lye Lye He Lye Hie Ala Ser Pro He Pro Glu Arg Lye 610 615 620 Lye He Ser Lye Glu Lye Glu Glu Glu Arg Lye Glu Phe Arg He Arg 625 630 635 640 Gin Tyr Ser Pro Gin Ala Phe Lye Phe Phe Met Glu Gin Hie He Glu 645 650 655 Aβn Val He Lye Ser Tyr Arg Gin Arg Thr Tyr Arg Lye Aβn Gin Leu 660 665 670 Glu Lye Glu Met Hie Lys Val Gly Leu Pro Aβp Gin Thr Gin He Glu 675 680 685 Met Arg Lys Met Leu Asn Gin Lys Glu Ser Aβn Tyr He Arg Leu Lys 690 695 700 Arg Ala Lys Met Asp Lys Ser Met Phe Val Lye Leu Lys Pro He Gly 705 710 715 720 Val Gly Ala Phe Gly Glu Val Thr Leu Val Ser Lys He Aβp Thr Ser 725 730 735 Aβn Hie Leu Tyr Ala Met Lye Thr Leu Arg Lye Ala Asp Val Leu Lye 740 745 750 Arg Aβn Gin Val Ala His Val Lys Ala Glu Arg Asp He Leu Ala Glu 755 760 765 Ala Asp Asn Asn Trp Val Val Lys Leu Tyr Tyr Ser Phe Gin Asp Lys 770 775 780 Asp Aβn Leu Tyr Phe Val Met Aβp Tyr He Pro Gly Gly Aβp Leu Met 785 790 795 800 Ser Leu Leu He Lys Leu Gly He Phe Glu Glu Glu Leu Ala Arg Phe 805 810 815 Tyr He Ala Glu Val Thr Cys Ala Val Asp Ser Val His Lys Met Gly 820 825 830 Phe He His Arg Asp He Lys Pro Asp Asn He Leu He Asp Arg Asp 835 840 845 Gly His He Lys Leu Thr Asp Phe Gly Leu Cys Thr Gly Phe Arg Trp 850 855 860 Thr His Asn Ser Lys Tyr Tyr Gin Glu Asn Gly Asn His Ser Arg Gin 865 870 875 880 Asp Ser Met Glu Pro Trp Glu Glu Tyr Ser Glu Asn Gly Pro Lys Pro 885 890 895 Thr Val Leu Glu Arg Arg Arg Met Arg Asp His Gin Arg Val Leu Ala 900 905 910 His Ser Leu Val Gly Thr Pro λβn Tyr He Ala Pro Glu Val Leu Glu 915 920 925 Arg Ser Gly Tyr Thr Gin Leu Cyβ Aβp Tyr Trp Ser Val Gly Val He 930 935 940 Leu Tyr Glu Met Leu Val Gly Gin Pro Pro Phe Leu Ala Aβn Ser Pro 945 950 955 960 Leu Glu Thr Gin Gin Lye Val He Aβn Trp Glu Lye Thr Leu Hie He 965 970 975 Pro Pro Gin Ala Glu Leu Ser Arg Glu Ala Thr Aβp Leu He Arg Arg 980 985 990 Leu Cyβ Ala Ser Ala Asp Lys Arg Leu Gly Lys Ser Val Asp Glu Val 995 1000 1005 Lys Ser Hie Aβp Phe Phe Lye Gly He Aβp Phe Ala Asp Met Arg Lys 1010 1015 1020 Gin Lys Ala Pro Tyr He Pro Glu He Lys His Pro Thr Aβp Thr Ser 1025 1030 1035 1040 Aβn Phe Asp Pro Val Asp Pro Glu Lys Leu Arg Ser Asn Asp Ser Thr 1045 1050 1055 Met Ser Ser Gly Aβp Aβp Val Aβp Gin Aβn Aβp Arg Thr Phe Hie Gly 1060 1065 1070 Phe Phe Glu Phe Thr Phe Arg Arg Phe Phe Asp Asp Lys Gin Pro Pro 1075 1080 1085 Asp Met Thr Aβp Asp Gin Ala Pro Val Tyr Val * 1090 1095 1100 (2) INFORMATION FOR SEQ ID NO:3: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 3984 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: cDNA (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 231..3623 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3: ACCTTTGGGT TGCTGGGACG GACTCTGGCC GCCTCAGCGT CCGCCCTCAG GCCCGTGGCC 60 GCTGTCCAGG AGCTCTGCTC TCCCCTCCAG AGTTAATTAT TTATATTGTA AAGAATTTTA 120 ACAGTCCTGG GGACTTCCTT GAAGGATCAT TTTCACTTTT GCTCAGAAGA AAGCTCTGGA 180 TCTATCAAAT AAAGAAGTCC TTCGTGTGGG CTACATATAT AGATGTTTTC ATG AAG 236 Met Lys 1 AGG AGT GAA AAG CCA GAA GGA TAT AGA CAA ATG AGG CCT AAG ACC TTT 284 Arg Ser Glu Lys Pro Glu Gly Tyr Arg Gin Met Arg Pro Lys Thr Phe 5 10 15 CCT GCC AGT AAC TAT ACT GTC AGT AGC CGG CAA ATG TTA CAA GAA ATT 332 Pro Ala Ser Asn Tyr Thr Val Ser Ser Arg Gin Met Leu Gin Glu He 20 25 30 CGG GAA TCC CTT AGG AAT TTA TCT AAA CCA TCT GAT GCT GCT AAG GCT 380 Arg Glu Ser Leu Arg Aβn Leu Ser Lys Pro Ser Aβp Ala Ala Lye Ala 35 40 45 50 GAG CAT AAC ATG AGT AAA ATG TCA ACC GAA GAT CCT CGA CAA GTC AGA 428 Glu Hie Aβn Met Ser Lye Met Ser Thr Glu Aβp Pro Arg Gin Val Arg 55 60 65 AAT CCA CCC AAA TTT GGG ACG CAT CAT AAA GCC TTG CAG GAA ATT CGA 476 Aβn Pro Pro Lye Phe Gly Thr Hie Hie Lye Ala Leu Gin Glu He Arg 70 75 80 AAC TCT CTG CTT CCA TTT GCA AAT GAA ACA AAT TCT TCT CGG AGT ACT 524 Aβn Ser Leu Leu Pro Phe Ala Aβn Glu Thr Aβn Ser Ser Arg Ser Thr 85 90 95 TCA GAA GTT AAT CCA CAA ATG CTT CAA GAC TTG CAA GCT GCT GGA TTT 572 Ser Glu Val Asn Pro Gin Met Leu Gin Aβp Leu Gin Ala Ala Gly Phe 100 105 110 GAT GAG GAT ATG GTT ATA CAA GCT CTT CAG AAA ACT AAC AAC AGA AGT 620 Asp Glu Aβp Met Val He Gin Ala Leu Gin Lye Thr Aβn Aβn Arg Ser 115 120 125 130 ATA GAA GCA GCA ATT GAA TTC ATT AGT AAA ATG AGT TAC CAA GAT CCT 668 He Glu Ala Ala He Glu Phe He Ser Lys Met Ser Tyr Gin Asp Pro 135 140 145 CGA CGA GAG CAG ATG GCT GCA GCA GCT GCC AGA CCT ATT AAT GCC AGC 716 Arg Arg Glu Gin Met Ala Ala Ala Ala Ala Arg Pro He Asn Ala Ser 150 155 160 ATG AAA CCA GGG AAT GTG CAG CAA TCA GTT AAC CGC AAA CAG AGC TGG 764 Met Lys Pro Gly Aβn Val Gin Gin Ser Val Asn Arg Lye Gin Ser Trp 165 170 175 AAA GGT TCT AAA GAA TCC TTA GTT CCT CAG AGG CAT GGC CCG CCA CTA 812 Lye Gly Ser Lys Glu Ser Leu Val Pro Gin Arg His Gly Pro Pro Leu 180 185 190 GGA GAA AGT GTG GCC TAT CAT TCT GAG AGT CCC AAC TCA CAG ACA GAT 860 Gly Glu Ser Val Ala Tyr His Ser Glu Ser Pro Aβn Ser Gin Thr Aβp 195 200 205 210 GTA GGA AGA CCT TTG TCT GGA TCT GGT ATA TCA GCA TTT GTT CAA GCT 908 Val Gly Arg Pro Leu Ser Gly Ser Gly He Ser Ala Phe Val Gin Ala 215 220 225 CAC CCT AGC AAC GGA CAG AGA GTG AAC CCC CCA CCA CCA CCT CAA GTA 956 His Pro Ser Asn Gly Gin Arg Val Asn Pro Pro Pro Pro Pro Gin Val 230 235 240 AGG AGT GTT ACT CCT CCA CCA CCT CCA AGA GGC CAG ACT CCC CCT CCA 1004 Arg Ser Val Thr Pro Pro Pro Pro Pro Arg Gly Gin Thr Pro Pro Pro 245 250 255 AGA GGT ACA ACT CCA CCT CCC CCT TCA TGG GAA CCA AAC TCT CAA ACA 1052 Arg Gly Thr Thr Pro Pro Pro Pro Ser Trp Glu Pro Asn Ser Gin Thr 260 265 270 AAG CGC TAT TCT GGA AAC ATG GAA TAC GTA ATC TCC CGA ATC TCT CCT 1100 Lys Arg Tyr Ser Gly Aβn Met Glu Tyr Val He Ser Arg He Ser Pro 275 280 285 290 GTC CCA CCT GGG GCA TGG CAA GAG GGC TAT CCT CCA CCA CCT CTC AAC 1148 Val Pro Pro Gly Ala Trp Gin Glu Gly Tyr Pro Pro Pro Pro Leu Aβn 295 300 305 ACT TCC CCC ATG AAT CCT CCT AAT CAA GGA CAG AGA GGC ATT AGT TCT 1196 Thr Ser Pro Met Aβn Pro Pro Aβn Gin Gly Gin Arg Gly He Ser Ser 310 315 320 GTT CCT GTT GGC AGA CAA CCA ATC ATC ATG CAG AGT TCT AGC AAA TTT 1244 Val Pro Val Gly Arg Gin Pro He He Met Gin Ser Ser Ser Lys Phe 325 330 335 AAC TTT CCA TCA GGG AGA CCT GGA ATG CAG AAT GGT ACT GGA CAA ACT 1292 Aβn Phe Pro Ser Gly Arg Pro Gly Met Gin Aβn Gly Thr Gly Gin Thr 340 345 350 GAT TTC ATG ATA CAC CAA AAT GTT GTC CCT GCT GGC ACT GTG AAT CGG 1340 Aβp Phe Met He Hie Gin Aβn Val Val Pro Ala Gly Thr Val Aβn Arg 355 360 365 370 CAG CCA CCA CCT CCA TAT CCT CTG ACA GCA GCT AAT GGA CAA AGC CCT 1388 Gin Pro Pro Pro Pro Tyr Pro Leu Thr Ala Ala Aβn Gly Gin Ser Pro 375 380 385 TCT GCT TTA CAA ACA GGG GGA TCT GCT GCT CCT TCG TCA TAT ACA AAT 1436 Ser Ala Leu Gin Thr Gly Gly Ser Ala Ala Pro Ser Ser Tyr Thr Aβn 390 395 400 GGA AGT ATT CCT CAG TCT ATG ATG GTG CCA AAC AGA AAT AGT CAT AAC 1484 Gly Ser He Pro Gin Ser Met Met Val Pro Aβn Arg Asn Ser His Asn 405 410 415 ATG GAA CTA TAT AAC ATT AGT GTA CCT GGA CTG CAA ACA AAT TGG CCT 1532 Met Glu Leu Tyr Aβn He Ser Val Pro Gly Leu Gin Thr Asn Trp Pro 420 425 430 CAG TCA TCT TCT GCT CCA GCC CAG TCA TCC CCG AGC AGT GGG CAT GAA 1580 Gin Ser Ser Ser Ala Pro Ala Gin Ser Ser Pro Ser Ser Gly His Glu 435 440 445 450 ATC CCT ACA TGG CAA CCT AAC ATA CCA GTG AGG TCA AAT TCT TTT AAT 1628 He Pro Thr Trp Gin Pro Asn He Pro Val Arg Ser Asn Ser Phe Aβn 455 460 465 AAC CCA TTA GGA AAT AGA GCA AGT CAC TCT GCT AAT TCT CAG CCT TCT 1676 Asn Pro Leu Gly Asn Arg Ala Ser Hie Ser Ala Aβn Ser Gin Pro Ser 470 475 480 GCT ACA ACA GTC ACT GCA ATT ACA CCA GCT CCT ATT CAA CAG CCT GTG 1724 Ala Thr Thr Val Thr Ala He Thr Pro Ala Pro He Gin Gin Pro Val 485 490 495 AAA AGT ATG CGT GTA TTA AAA CCA GAG CTA CAG ACT GCT TTA GCA CCT 1772 Lys Ser Met Arg Val Leu Lys Pro Glu Leu Gin Thr Ala Leu Ala Pro 500 505 510 ACA CAC CCT TCT TGG ATA CCA CAG CCA ATT CAA ACT GTT CAA CCC AGT 1820 Thr His Pro Ser Trp He Pro Gin Pro He Gin Thr Val Gin Pro Ser 515 520 525 530 CCT TTT CCT GAG GGA ACC GCT TCA AAT GTG ACT GTG ATG CCA CCT GTT 1868 Pro Phe Pro Glu Gly Thr Ala Ser Asn Val Thr Val Met Pro Pro Val 535 540 545 GCT GAA GCT CCA AAC TAT CAA GGA CCA CCA CCA CCC TAC CCA AAA CAT 1916 Ala Glu Ala Pro Asn Tyr Gin Gly Pro Pro Pro Pro Tyr Pro Lys His 550 555 560 CTG CTG CAC CAA AAC CCA TCT GTT CCT CCA TAC GAG TCA ATC AGT AAG 1964 Leu Leu Hie Gin Aβn Pro Ser Val Pro Pro Tyr Glu Ser He Ser Lye 565 570 575 CCT AGC AAA GAG GAT CAG CCA AGC TTG CCC AAG GAA GAT GAG AGT GAA 2012 Pro Ser Lye Glu Aβp Gin Pro Ser Leu Pro Lye Glu Aβp Glu Ser Glu 580 585 590 AAG AGT TAT GAA AAT GTT GAT AGT GGG GAT AAA GAA AAG AAA CAG ATT 2060 Lye Ser Tyr Glu Asn Val Aβp Ser Gly Asp Lye Glu Lye Lye Gin He 595 600 605 610 ACA ACT TCA CCT ATT ACT GTT AGG AAA AAC AAG AAA GAT GAA GAG CGA 2108 Thr Thr Ser Pro He Thr Val Arg Lye Aβn Lye Lye Asp Glu Glu Arg 615 620 625 AGG GAA TCT CGT ATT CAA AGT TAT TCT CCT CAA GCA TTT AAA TTC TTT 2156 Arg Glu Ser Arg He Gin Ser Tyr Ser Pro Gin Ala Phe Lye Phe Phe 630 635 640 ATG GAG CAA CAT GTA GAA AAT GTA CTC AAA TCT CAT CAG CAG CGT CTA 2204 Met Glu Gin His Val Glu Asn Val Leu Lys Ser His Gin Gin Arg Leu 645 650 655 CAT CGT AAA AAA CAA TTA GAG AAT GAA ATG ATG CGG GTT GGA TTA TCT 2252 Hie Arg Lye Lye Gin Leu Glu Asn Glu Met Met Arg Val Gly Leu Ser 660 665 670 CAA GAT GCC CAG GAT CAA ATG AGA AAG ATG CTT TGC CAA AAA GAA TCT 2300 Gin Aβp Ala Gin Aβp Gin Met Arg Lye Met Leu Cyβ Gin Lye Glu Ser 675 680 685 690 AAT TAC ATC CGT CTT AAA AGG GCT AAA ATG GAC AAG TCT ATG TTT GTG 2348 Aβn Tyr He Arg Leu Lys Arg Ala Lys Met Aβp Lye Ser Met Phe Val 695 700 705 AAG ATA AAG ACA CTA GGA ATA GGA GCA TTT GGT GAA GTC TGT CTA GCA 2396 Lys He Lys Thr Leu Gly He Gly Ala Phe Gly Glu Val Cys Leu Ala 710 715 720 AGA AAA GTA GAT ACT AAG GCT TTG TAT GCA ACA AAA ACT CTT CGA AAG 2444 Arg Lye Val Aep Thr Lys Ala Leu Tyr Ala Thr Lys Thr Leu Arg Lys 725 730 735 AAA GAT GTT CTT CTT CGA AAT CAA GTC GCT CAT GTT AAG GCT GAG AGA 2492 Lys Asp Val Leu Leu Arg Aβn Gin Val Ala Hie Val Lye Ala Glu Arg 740 745 750 GAT ATC CTG GCT GAA GCT GAC AAT GAA TGG GTA GTT CGT CTA TAT TAT 2540 Aβp He Leu Ala Glu Ala Aβp Aβn Glu Trp Val Val Arg Leu Tyr Tyr 755 760 765 770 TCA TTC CAA GAT AAG GAC AAT TTA TAC TTT GTA ATG GAC TAC ATT CCT 2588 Ser Phe Gin Asp Lys Asp Asn Leu Tyr Phe Val Met Asp Tyr He Pro 775 780 785 GGG GGT GAT ATG ATG AGC CTA TTA ATT AGA ATG GGC ATC TTT CCA GAA 2636 Gly Gly Asp Met Met Ser Leu Leu He Arg Met Gly He Phe Pro Glu 790 795 800 AGT CTG GCA CGA TTC TAC ATA GCA GAA CTT ACC TGT GCA GTT GAA AGT 2684 Ser Leu Ala Arg Phe Tyr He Ala Glu Leu Thr Cys Ala Val Glu Ser 805 810 815 GTT CAT AAA ATG GGT TTT ATT CAT AGA GAT ATT AAA CCT GAT AAT ATT 2732 Val His Lys Met Gly Phe He His Arg Asp He Lye Pro Aβp Asn He 820 825 830 TTG ATT GAT CGT GAT GGT CAT ATT AAA TTG ACT GAC TTT GGC CTC TGC 2780 Leu He Aβp Arg Aβp Gly Hie He Lye Leu Thr Aβp Phe Gly Leu Cyβ 835 840 845 850 ACT GGC TTC AGA TGG ACA CAC GAT TCT AAG TAC TAT CAG AGT GGT GAC 2828 Thr Gly Phe Arg Trp Thr Hie Aβp Ser Lye Tyr Tyr Gin Ser Gly Aep 855 860 865 CAT CCA CGG CAA GAT AGC ATG GAT TTC AGT AAT GAA TGG GGG GAT CCC 2876 Hie Pro Arg Gin Aep Ser Met Aep Phe Ser Aβn Glu Trp Gly Aβp Pro 870 875 880 TCA AGC TGT CGA TGT GGA GAC AGA CTG AAG CCA TTA GAG CGG AGA GCT 2924 Ser Ser Cyβ Arg Cyβ Gly Aβp Arg Leu Lye Pro Leu Glu Arg Arg Ala 885 890 895 GCA CGC CAG CAC CAG CGA TGT CTA GCA CAT TCT TTG GTT GGG ACT CCC 2972 Ala Arg Gin His Gin Arg Cyβ Leu Ala Hie Ser Leu Val Gly Thr Pro 900 905 910 AAT TAT ATT GCA CCT GAA GTG TTG CTA CGA ACA GGA TAC ACA CAG TTG 3020 Aβn Tyr He Ala Pro Glu Val Leu Leu Arg Thr Gly Tyr Thr Gin Leu 915 920 925 930 TGT GAT TGG TGG AGT GTT GGT GTT ATT CTT TTT GAA ATG TTG GTG GGA 3068 Cyβ Aβp Trp Trp Ser Val Gly Val He Leu Phe Glu Met Leu Val Gly 935 940 945 CAA CCT CCT TTC TTG GCA CAA ACA CCA TTA GAA ACA CAA ATG AAG GTT 3116 Gin Pro Pro Phe Leu Ala Gin Thr Pro Leu Glu Thr Gin Met Lys Val 950 955 960 ATC AAC TGG CAA ACA TCT CTT CAC ATT CCA CCA CAA GCT AAA CTC AGT 3164 He Asn Trp Gin Thr Ser Leu His He Pro Pro Gin Ala Lys Leu Ser 965 970 975 CCT GAA GCT TCT GAT CTT ATT ATT AAA CTT TGC CGA GGA CCC GAA GAT 3212 Pro Glu Ala Ser Asp Leu He He Lys Leu Cyβ Arg Gly Pro Glu Asp 980 985 990 CGC TTA GGC AAG AAT GGT GCT GAT GAA ATA AAA GCT CAT CCA TTT TTT 3260 Arg Leu Gly Lys Asn Gly Ala Aβp Glu He Lye Ala His Pro Phe Phe 995 1000 1005 1010 AAA ACA ATT GAC TTC TCC AGT GAC CTG AGA CAG CAG TCT GCT TCA TAC 3308 Lys Thr He Asp Phe Ser Ser Asp Leu Arg Gin Gin Ser Ala Ser Tyr 1015 1020 1025 ATT CCT AAA ATC ACA CAC CCA ACA GAT ACA TCA AAT TTT GAT CCT GTT 3356 He Pro Lys He Thr His Pro Thr Aβp Thr Ser Aβn Phe Aβp Pro Val 1030 1035 1040 GAT CCT GAT AAA TTA TGG AGT GAT GAT AAC GAG GAA GAA AAT GTA AAT 3404 Aβp Pro Asp Lys Leu Trp Ser Aep Asp Asn Glu Glu Glu Aβn Val Aβn 1045 1050 1055 GAC ACT CTC AAT GGA TGG TAT AAA AAT GGA AAG CAT CCT GAA CAT GCA 3452 Asp Thr Leu Asn Gly Trp Tyr Lys Asn Gly Lys His Pro Glu His Ala 1060 1065 1070 TTC TAT GAA TTT ACC TTC CGA AGG TTT TTT GAT GAC AAT GGC TAC CCA 3500 Phe Tyr Glu Phe Thr Phe Arg Arg Phe Phe Asp Asp Asn Gly Tyr Pro 1075 1080 1085 1090 TAT AAT TAT CCG AAG CCT ATT GAA TAT GAA TAC ATT AAT TCA CAA GGC 3548 Tyr Asn Tyr Pro Lys Pro He Glu Tyr Glu Tyr He Asn Ser Gin Gly 1095 1100 1105 TCA GAG CAG CAG TCG GAT GAA GAT GAT CAA AAC ACA GGC TCA GAG ATT 3596 Ser Glu Gin Gin Ser Aβp Glu Aβp Aβp Gin Aβn Thr Gly Ser Glu He 1110 1115 1120 AAA AAT CGC GAT CTA GTA TAT GTT TAA CACACTAGTA AATAAATGTA 3643 Lye Aβn Arg Aβp Leu Val Tyr Val * 1125 1130 ATGAGGATTT GTAAAAGGGC CTGAAATGCG AGGTGTTTTG AGGTTCTGAG AGTAAAATTA 3703 TGCAAATATG ACAGAGCTAT ATATGTGTGC TCTGTGTACA ATATTTTATT TTCCTAAATT 3763 ATGGGAAATC CTTTTAAAAT GTTAATTTAT TCCAGCCGTT TAAATCAGTA TTTAGAAAAA 3823 AATTGTTATA AGGAAAGTAA ATTATGAACT GAATATTATA GTCAGTTCTT GGTACTTAAA 3883 GTACTTAAAA TAAGTAGTGC TTTGTTTAAA AGGAGAAACC TGGTATCTAT TTGTATATAT 3943 GCTAAATAAT TTTAAAATAC AAGAGTTTTT GAAATTTTTT T 3984 (2) INFORMATION FOR SEQ ID NO: : (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1131 amino acids (B) TYPE: amino acid (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4: Met Lys Arg Ser Glu Lys Pro Glu Gly Tyr Arg Gin Met Arg Pro Lys 1 5 10 15 Thr Phe Pro Ala Ser Asn Tyr Thr Val Ser Ser Arg Gin Met Leu Gin 20 25 30 Glu He Arg Glu Ser Leu Arg Asn Leu Ser Lys Pro Ser Asp Ala Ala 35 40 45 Lys Ala Glu His Aβn Met Ser Lys Met Ser Thr Glu Aβp Pro Arg Gin 50 55 60 Val Arg Aβn Pro Pro Lys Phe Gly Thr Hie Hie Lye Ala Leu Gin Glu 65 70 75 80 He Arg Asn Ser Leu Leu Pro Phe Ala Asn Glu Thr Asn Ser Ser Arg 85 90 95 Ser Thr Ser Glu Val Asn Pro Gin Met Leu Gin Asp Leu Gin Ala Ala 100 105 110 Gly Phe Asp Glu Asp Met Val He Gin Ala Leu Gin Lys Thr Asn Asn 115 120 125 Arg Ser He Glu Ala Ala He Glu Phe He Ser Lys Met Ser Tyr Gin 130 135 140 Aep Pro Arg Arg Glu Gin Met Ala Ala Ala Ala Ala Arg Pro He Asn 145 150 155 160 Ala Ser Met Lys Pro Gly Asn Val Gin Gin Ser Val Asn Arg Lys Gin 165 170 175 Ser Trp Lys Gly Ser Lys Glu Ser Leu Val Pro Gin Arg His Gly Pro 180 185 190 Pro Leu Gly Glu Ser Val Ala Tyr Hie Ser Glu Ser Pro Aβn Ser Gin 195 200 205 Thr Aβp Val Gly Arg Pro Leu Ser Gly Ser Gly He Ser Ala Phe Val 210 215 220 Gin Ala Hie Pro Ser Aβn Gly Gin Arg Val Aβn Pro Pro Pro Pro Pro 225 230 235 240 Gin Val Arg Ser Val Thr Pro Pro Pro Pro Pro Arg Gly Gin Thr Pro 245 250 255 Pro Pro Arg Gly Thr Thr Pro Pro Pro Pro Ser Trp Glu Pro Aβn Ser 260 265 270 Gin Thr Lye Arg Tyr Ser Gly Aβn Met Glu Tyr Val He Ser Arg He 275 280 285 Ser Pro Val Pro Pro Gly Ala Trp Gin Glu Gly Tyr Pro Pro Pro Pro 290 295 300 Leu Aβn Thr Ser Pro Met Aβn Pro Pro Aβn Gin Gly Gin Arg Gly He 305 310 315 320 Ser Ser Val Pro Val Gly Arg Gin Pro He He Met Gin Ser Ser Ser 325 330 335 Lye Phe Aβn Phe Pro Ser Gly Arg Pro Gly Met Gin Aβn Gly Thr Gly 340 345 350 Gin Thr Aβp Phe Met He His Gin Asn Val Val Pro Ala Gly Thr Val 355 360 365 Aβn Arg Gin Pro Pro Pro Pro Tyr Pro Leu Thr Ala Ala Asn Gly Gin 370 375 380 Ser Pro Ser Ala Leu Gin Thr Gly Gly Ser Ala Ala Pro Ser Ser Tyr 385 390 395 400 Thr Aβn Gly Ser He Pro Gin Ser Met Met Val Pro Aβn Arg Asn Ser 405 410 415 Hie Aβn Met Glu Leu Tyr Asn He Ser Val Pro Gly Leu Gin Thr Aβn 420 425 430 Trp Pro Gin Ser Ser Ser Ala Pro Ala Gin Ser Ser Pro Ser Ser Gly 435 440 445 Hie Glu He Pro Thr Trp Gin Pro Aβn He Pro Val Arg Ser Aβn Ser 450 455 460 Phe Asn Asn Pro Leu Gly Asn Arg Ala Ser His Ser Ala Asn Ser Gin 465 470 475 480 Pro Ser Ala Thr Thr Val Thr Ala He Thr Pro Ala Pro He Gin Gin 485 490 495 Pro Val Lys Ser Met Arg Val Leu Lys Pro Glu Leu Gin Thr Ala Leu 500 505 510 Ala Pro Thr His Pro Ser Trp He Pro Gin Pro He Gin Thr Val Gin 515 520 525 Pro Ser Pro Phe Pro Glu Gly Thr Ala Ser Asn Val Thr Val Met Pro 530 535 540 Pro Val Ala Glu Ala Pro Asn Tyr Gin Gly Pro Pro Pro Pro Tyr Pro 545 550 555 560 Lys Hie Leu Leu His Gin Asn Pro Ser Val Pro Pro Tyr Glu Ser He 565 570 575 Ser Lye Pro Ser Lys Glu Asp Gin Pro Ser Leu Pro Lye Glu Aβp Glu 580 585 590 Ser Glu Lye Ser Tyr Glu Asn Val Aβp Ser Gly Asp Lye Glu Lye Lye 595 600 605 Gin He Thr Thr Ser Pro He Thr Val Arg Lys Asn Lys Lye Aβp Glu 610 615 620 Glu Arg Arg Glu Ser Arg He Gin Ser Tyr Ser Pro Gin Ala Phe Lye 625 630 635 640 Phe Phe Met Glu Gin His Val Glu Aβn Val Leu Lye Ser Hie Gin Gin 645 650 655 Arg Leu His Arg Lys Lys Gin Leu Glu Asn Glu Met Met Arg Val Gly 660 665 670 Leu Ser Gin Asp Ala Gin Asp Gin Met Arg Lys Met Leu Cys Gin Lye 675 680 685 Glu Ser Aβn Tyr He Arg Leu Lys Arg Ala Lys Met Aβp Lys Ser Met 690 695 700 Phe Val Lys He Lys Thr Leu Gly He Gly Ala Phe Gly Glu Val Cye 705 710 715 720 Leu Ala Arg Lys Val Asp Thr Lys Ala Leu Tyr Ala Thr Lys Thr Leu 725 730 735 Arg Lys Lys Asp Val Leu Leu Arg Asn Gin Val Ala His Val Lys Ala 740 745 750 Glu Arg Asp He Leu Ala Glu Ala Asp Asn Glu Trp Val Val Arg Leu 755 760 765 Tyr Tyr Ser Phe Gin Asp Lys Asp Aβn Leu Tyr Phe Val Met Aβp Tyr 770 775 780 He Pro Gly Gly Aβp Met Met Ser Leu Leu He Arg Met Gly He Phe 785 790 795 800 Pro Glu Ser Leu Ala Arg Phe Tyr He Ala Glu Leu Thr Cyβ Ala Val 805 810 815 Glu Ser Val His Lys Met Gly Phe He His Arg Asp He Lys Pro Asp 820 825 830 Asn He Leu He Asp Arg Asp Gly His He Lys Leu Thr Asp Phe Gly 835 840 845 Leu Cys Thr Gly Phe Arg Trp Thr His Asp Ser Lys Tyr Tyr Gin Ser 850 855 860 Gly Asp His Pro Arg Gin Asp Ser Met Asp Phe Ser Asn Glu Trp Gly 865 870 875 880 Asp Pro Ser Ser Cys Arg Cys Gly Asp Arg Leu Lys Pro Leu Glu Arg 885 890 895 Arg Ala Ala Arg Gin His Gin Arg Cys Leu Ala His Ser Leu Val Gly 900 905 910 Thr Pro Aβn Tyr He Ala Pro Glu Val Leu Leu Arg Thr Gly Tyr Thr 915 920 925 Gin Leu Cyβ Aβp Trp Trp Ser Val Gly Val He Leu Phe Glu Met Leu 930 935 940 Val Gly Gin Pro Pro Phe Leu Ala Gin Thr Pro Leu Glu Thr Gin Met 945 950 955 960 Lye Val He Aβn Trp Gin Thr Ser Leu Hie He Pro Pro Gin Ala Lye 965 970 975 Leu Ser Pro Glu Ala Ser Asp Leu He He Lys Leu Cyβ Arg Gly Pro 980 985 990 Glu Asp Arg Leu Gly Lye Aβn Gly Ala Aβp Glu He Lys Ala His Pro 995 1000 1005 Phe Phe Lys Thr He Asp Phe Ser Ser Asp Leu Arg Gin Gin Ser Ala 1010 1015 1020 Ser Tyr He Pro Lys He Thr His Pro Thr Aβp Thr Ser Asn Phe Aβp 1025 1030 1035 1040 Pro Val Aβp Pro Asp Lys Leu Trp Ser Aβp Asp Aβn Glu Glu Glu Aβn 1045 1050 1055 Val Aβn Asp Thr Leu Asn Gly Trp Tyr Lys Aβn Gly Lys His Pro Glu 1060 1065 1070 His Ala Phe Tyr Glu Phe Thr Phe Arg Arg Phe Phe Asp Asp Asn Gly 1075 1080 1085 Tyr Pro Tyr Asn Tyr Pro Lys Pro He Glu Tyr Glu Tyr He Asn Ser 1090 1095 1100 Gin Gly Ser Glu Gin Gin Ser Aep Glu Asp Asp Gin Asn Thr Gly Ser 1105 1110 1115 1120 Glu He Lys Asn Arg Asp Leu Val Tyr Val * 1125 1130 (2) INFORMATION FOR SEQ ID NO:5: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 3213 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: cDNA (i ) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 1..2889 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5: GTG CAA CAT TCA ATT AAC CGA AAA CAA AGC TGG AAA GGT TCT AAA GAG 48 Val Gin His Ser He Asn Arg Lys Gin Ser Trp Lys Gly Ser Lys Glu 1 5 10 15 TCT CTA GTT CCT CAG AGA CAC GGC CCA TCT CTA GGA GAA AAT GTG GTT 96 Ser Leu Val Pro Gin Arg His Gly Pro Ser Leu Gly Glu Asn Val Val 20 25 30 TAT CGT TCT GAA AGC CCC AAC TCA CAG GCG GAT GTA GGA AGA CCT CTG 144 Tyr Arg Ser Glu Ser Pro Asn Ser Gin Ala Aβp Val Gly Arg Pro Leu 35 40 45 TCT GGA TCC GGC ATT GCA GCA TTT GCT CAA GCT CAC CCA AGC AAT GGA 192 Ser Gly Ser Gly He Ala Ala Phe Ala Gin Ala Hie Pro Ser Aβn Gly 50 55 60 CAG AGA GTG AAC CCC CCA CCA CCA CCT CAA GTT AGG AGT GTT ACT CCT 240 Gin Arg Val Aβn Pro Pro Pro Pro Pro Gin Val Arg Ser Val Thr Pro 65 70 75 80 CCA CCA CCT CCG AGA GGC CAG ACC CCA CCT CCC CGA GGC ACC ACT CCC 288 Pro Pro Pro Pro Arg Gly Gin Thr Pro Pro Pro Arg Gly Thr Thr Pro 85 90 95 CCT CCC CCC TCA TGG GAA CCA AGC TCT CAG ACA AAG CGC TAC TCT GGG 336 Pro Pro Pro Ser Trp Glu Pro Ser Ser Gin Thr Lye Arg Tyr Ser Gly 100 105 110 AAC ATG GAG TAC GTA ATC TCC CGA ATC TCC CCT GTT CCA CCT GGG GCG 384 Aβn Met Glu Tyr Val He Ser Arg He Ser Pro Val Pro Pro Gly Ala 115 120 125 TGG CAG GAG GGG TAC CCT CCA CCA CCT CTT ACC ACT TCT CCC ATG AAT 432 Trp Gin Glu Gly Tyr Pro Pro Pro Pro Leu Thr Thr Ser Pro Met Aβn 130 135 140 CCC CCT AGC CAG GCT CAG AGG GCC ATT AGT TCT GTT CCA GTT GGT AGA 480 Pro Pro Ser Gin Ala Gin Arg Ala He Ser Ser Val Pro Val Gly Arg 145 150 155 160 CAA CCC ATC ATC ATG CAG AGT ACT AGC AAA TTT AAC TTT ACA CCA GGG 528 Gin Pro He He Met Gin Ser Thr Ser Lye Phe Aβn Phe Thr Pro Gly 165 170 175 CGA CCT GGA GTT CAG AAT GGT GGT GGT CAG TCT GAT TTT ATC GTG CAC 576 Arg Pro Gly Val Gin Aβn Gly Gly Gly Gin Ser Asp Phe He Val His 180 185 190 CAA AAT GTC CCC ACT GGT TCT GTG ACT CGG CAG CCA CCA CCT CCA TAT 624 Gin Aβn Val Pro Thr Gly Ser Val Thr Arg Gin Pro Pro Pro Pro Tyr 195 200 205 CCT CTG ACC CCA GCT AAT GGA CAA AGC CCC TCT GCT TTA CAA ACA GGG 672 Pro Leu Thr Pro Ala Aβn Gly Gin Ser Pro Ser Ala Leu Gin Thr Gly 210 215 220 GCT TCT GCT GCT CCA CCA TCA TTC GCC AAT GGA AAC GTT CCT CAG TCG 720 Ala Ser Ala Ala Pro Pro Ser Phe Ala Aβn Gly Aβn Val Pro Gin Ser 225 230 235 240 ATG ATG GTG CCC AAC AGG AAC AGT CAT AAC ATG GAG CTT TAT AAT ATT 768 Met Met Val Pro Asn Arg Asn Ser Hie Aβn Met Glu Leu Tyr Aβn He 245 250 255 AAT GTC CCT GGA CTG CAA ACA GCC TGG CCC CAG TCG TCT TCT GCT CCT 816 Aβn Val Pro Gly Leu Gin Thr Ala Trp Pro Gin Ser Ser Ser Ala Pro 260 265 270 GCG CAG TCA TCC CCA AGC GGT GGG CAT GAA ATT CCT ACA TGG CAA CCT 864 Ala Gin Ser Ser Pro Ser Gly Gly Hie Glu He Pro Thr Trp Gin Pro 275 280 285 AAC ATA CCA GTG AGG TCA AAT TCT TTT AAT AAC CCA TTA GGA AGT AGA 912 Asn He Pro Val Arg Ser Aβn Ser Phe Aβn Aβn Pro Leu Gly Ser Arg 290 295 300 GCA AGT CAC TCT GCT AAT TCT CAG CCT TCT GCC ACT ACA GTC ACT GCC 960 Ala Ser Hie Ser Ala Aβn Ser Gin Pro Ser Ala Thr Thr Val Thr Ala 305 310 315 320 ATC ACA CCC GCT CCT ATT CAA CAG CCC GTG AAA AGC ATG CGC GTC CTG 1008 He Thr Pro Ala Pro He Gin Gin Pro Val Lye Ser Met Arg Val Leu 325 330 335 AAA CCA GAG CTG CAG ACT GCT TTA GCC CCA ACC CAT CCT TCT TGG ATG 1056 Lye Pro Glu Leu Gin Thr Ala Leu Ala Pro Thr Hie Pro Ser Trp Met 340 345 350 CCA CAG CCA GTT CAG ACT GTT CAG CCT ACC CCT TTT TCT GAG GGT ACA 1104 Pro Gin Pro Val Gin Thr Val Gin Pro Thr Pro Phe Ser Glu Gly Thr 355 360 365 GCT TCA AGT GTG CCT GTC ATC CCA CCT GTT GCT GAA GCT CCA AGC TAT 1152 Ala Ser Ser Val Pro Val He Pro Pro Val Ala Glu Ala Pro Ser Tyr 370 375 380 CAA GGT CCA CCA CCG CCT TAT CCA AAA CAT CTG CTA CAC CAA AAC CCA 1200 Gin Gly Pro Pro Pro Pro Tyr Pro Lye Hie Leu Leu His Gin Asn Pro 385 390 395 400 TCT GTC CCT CCA TAT GAG TCA GTA AGT AAG CCC TGC AAA GAT GAA CAG 1248 Ser Val Pro Pro Tyr Glu Ser Val Ser Lys Pro Cys Lys Asp Glu Gin 405 410 415 CCT AGC TTA CCC AAG GAA GAT GAT AGT GAG AAG AGT GCG GAC AGT GGT 1296 Pro Ser Leu Pro Lys Glu Asp Aβp Ser Glu Lys Ser Ala Asp Ser Gly 420 425 430 GAC TCT GGG GAT AAA GAA AAG AAA CAG ATT ACA ACT TCA CCT ATC ACT 1344 Aβp Ser Gly Aβp Lye Glu Lys Lye Gin He Thr Thr Ser Pro He Thr 435 440 445 GTT CGG AAA AAC AAG AAA GAT GAA GAA CGA AGA GAG TCT CGG ATT CAG 1392 Val Arg Lys Asn Lys Lyε Asp Glu Glu Arg Arg Glu Ser Arg He Gin 450 455 460 AGT TAC TCC CCA CAG GCC TTT AAG TTC TTC ATG GAG CAG CAC GTA GAG 1440 Ser Tyr Ser Pro Gin Ala Phe Lys Phe Phe Met Glu Gin His Val Glu 465 470 475 480 AAC GTC CTG AAG TCT CAT CAG CAG CGT CTG CAT CGG AAG AAG CAG CTA 1488 Aβn Val Leu Lys Ser His Gin Gin Arg Leu His Arg Lys Lys Gin Leu 485 490 495 GAA AAT GAA ATG ATG CGG GTT GGA TTA TCT CAA GAT GCC CAG GAT CAA 1536 Glu Asn Glu Met Met Arg Val Gly Leu Ser Gin Asp Ala Gin Asp Gin 500 505 510 ATG AGA AAG ATG CTT TGC CAG AAA GAG TCT AAC TAT ATT CGT CTT AAA 1584 Met Arg Lys Met Leu Cys Gin Lys Glu Ser Asn Tyr He Arg Leu Lys 515 520 525 AGG GCT AAA ATG GAC AAG TCT ATG TTT GTA AAG ATA AAG ACA TTA GGA 1632 Arg Ala Lys Met Asp Lys Ser Met Phe Val Lys He Lys Thr Leu Gly 530 535 540 ATA GGA GCG TTT GGT GAA GTC TGT CTA GCA AGA AAA GTC GAT ACT AAA 1680 He Gly Ala Phe Gly Glu Val Cys Leu Ala Arg Lys Val Asp Thr Lys 545 550 555 560 GCT TTG TAT GCA ACA AAG ACT CTT CGA AAG AAA GAC GTT CTG CTC CGA 1728 Ala Leu Tyr Ala Thr Lys Thr Leu Arg Lys Lys Aβp Val Leu Leu Arg 565 570 575 AAT CAG GTG GCT CAT GTG AAA GCG GAG AGG GAT ATC CTA GCA GAA GCC 1776 Aβn Gin Val Ala Hiβ Val Lye Ala Glu Arg Aβp He Leu Ala Glu Ala 580 585 590 GAC AAT GAG TGG GTG GTC CGC CTG TAC TAC TCT TTC CAG GAC AAG GAC 1824 λβp Aβn Glu Trp Val Val Arg Leu Tyr Tyr Ser Phe Gin Aβp Lye Aβp 595 600 605 AAC TTG TAC TTT GTG ATG GAC TAC ATT CCT GGG GGG GAT ATG ATG AGC 1872 Aβn Leu Tyr Phe Val Met Aβp Tyr He Pro Gly Gly λβp Met Met Ser 610 615 620 CTA TTA ATT AGλ λTG GGC λTC TTT CCT Gλλ λλT CTG GCλ CGλ TTC TλC 1920 Leu Leu He λrg Met Gly He Phe Pro Glu Asn Leu Ala Arg Phe Tyr 625 630 635 640 ATλ GCA GAA CTT ACC TGT GCA GTT GAA AGT GTT CAT AAA ATG GGT TTT 1968 He Ala Glu Leu Thr Cys Ala Val Glu Ser Val Hiβ Lye Met Gly Phe 645 650 655 ATT CAT AGA GAT ATT AAA CCT GAT AAC ATT TTG ATT GAC CGT GAT GGC 2016 He Hie Arg Aβp He Lye Pro Aβp Aβn He Leu He Aβp Arg Aβp Gly 660 665 670 CAT ATT AAA TTG ACT GAC TTT GGC TTG TGC ACT GGC TTC AGA TGG ACA 2064 Hiβ He Lye Leu Thr Aβp Phe Gly Leu Cyβ Thr Gly Phe Arg Trp Thr 675 680 685 CAT GAC TCC AAG TAC TAC CAG AGT GGG GAT CAC CCA CGG CAA GAT AGC 2112 Hiβ Asp Ser Lys Tyr Tyr Gin Ser Gly Aβp Hiβ Pro Arg Gin Aβp Ser 690 695 700 ATG GAT TTC AGT AAC GAA TGG GGA GAT CCT TCC AAT TGT CGG TGT GGG 2160 Met Aβp Phe Ser Asn Glu Trp Gly Asp Pro Ser Asn Cys Arg Cys Gly 705 710 715 720 GAC AGA CTG AAG CCA CTG GAG CGG AGA GCT GCT CGC CAG CAC CAG CGA 2208 Asp Arg Leu Lys Pro Leu Glu Arg Arg Ala Ala Arg Gin His Gin Arg 725 730 735 TGT CTA GCC CAT TCT CTG GTT GGG ACT CCC AAT TAT ATT GCA CCT GAA 2256 Cyβ Leu Ala Hiβ Ser Leu Val Gly Thr Pro Aβn Tyr He Ala Pro Glu 740 745 750 GTG CTA CTG CGA ACA GGA TAT ACA CAG CTG TGT GAC TGG TGG AGT GTT 2304 Val Leu Leu Arg Thr Gly Tyr Thr Gin Leu Cyβ Aβp Trp Trp Ser Val 755 760 765 GGT GTT ATT CTT TGT GAA ATG TTG GTG GGA CAA CCT CCT TTC TTG GCA 2352 Gly Val He Leu Cys Glu Met Leu Val Gly Gin Pro Pro Phe Leu Ala 770 775 780 CAA ACC CCA TTA GAA ACA CAA ATG AAG GTT ATC ATC TGG CAA ACT TCT 2400 Gin Thr Pro Leu Glu Thr Gin Met Lys Val He He Trp Gin Thr Ser 785 790 795 800 CTA CAC ATC CCT CCT CAA GCT AAG CTG AGT CCT GAA GCC TCT GAC CTC 2448 Leu His He Pro Pro Gin Ala Lys Leu Ser Pro Glu Ala Ser Asp Leu 805 810 815 ATT ATC AAA CTG TGT CGA GGA CCA GAA GAC CGC CTC GGC AAG AAC GGT 2496 He He Lys Leu Cys Arg Gly Pro Glu Asp Arg Leu Gly Lys Asn Gly 820 825 830 GCT GAT GAG ATA AAG GCT CAT CCA TTT TTT AAG ACC ATC GAT TTC TCT 2544 Ala Aβp Glu He Lys Ala His Pro Phe Phe Lys Thr He Asp Phe Ser 835 840 845 AGT GAT CTG AGA CAG CAG TCT GCT TCA TAC ATC CCT AAA ATC ACG CAT 2592 Ser Aβp Leu Arg Gin Gin Ser Ala Ser Tyr He Pro Lys He Thr Hie 850 855 860 CCA ACA GAT ACA TCC AAT TTC GAC CCT GTT GAT CCT GAT AAA TTG TGG 2640 Pro Thr Aβp Thr Ser Asn Phe Aβp Pro Val Aβp Pro Aβp Lye Leu Trp 865 870 875 880 AGC GAT GGC AGC GAG GAG GAA AAT ATC AGT GAC ACT CTG AGC GGA TGG 2688 Ser Aβp Gly Ser Glu Glu Glu Aβn He Ser Aβp Thr Leu Ser Gly Trp 885 890 895 TAT AAA AAT GGG AAG CAC CCC GAG CAC GCT TTC TAT GAG TTC ACC TTT 2736 Tyr Lys Asn Gly Lys His Pro Glu Hiβ Ala Phe Tyr Glu Phe Thr Phe 900 905 910 CGG AGG TTT TTT GAT GAC AAT GGC TAC CCA TAT AAT TAT CCA AAG CCT 2784 Arg Arg Phe Phe Aep Aβp Aβn Gly Tyr Pro Tyr Aβn Tyr Pro Lye Pro 915 920 925 ATT GAG TAT GAA TAC ATT CAT TCA CAG GGC TCA GAA CAA CAG TCT GAT 2832 He Glu Tyr Glu Tyr He Hiβ Ser Gin Gly Ser Glu Gin Gin Ser Aβp 930 935 940 GAA GAT GAT CAA CAC ACA AGC TCC GAT GGA AAC AAC CGA GAT CTA GTG 2880 Glu Aβp λβp Gin His Thr Ser Ser Asp Gly Aβn Aβn Arg Aβp Leu Val 945 950 955 960 TλT GTT TAA TAAACTAGGA GATCATTGTλ λGAATTTGCA AGAGGCCTGA 2929 Tyr Val * AGTGCAGGGG TTTTTGAλGT TTTGλGAAλA TTλTGCλλλT GTGACAGAGT TTGTGTGCTC 2989 TGTGTACAAT ATTTTATTTT CCTAAGTTAT GGGAλλTTGT TTTAAAATGT TAATTTATTC 3049 CACCCTTTTA ATTCAGTAAT TTAGAAAAAA TTGTTATAAG GAAAGTAAAT TATGAACTGA 3109 GTATTATAGT CAATTCTTGG TACTTAAAGT ACTTλλAAAG AGAAGCCTGG TATCTTTTGT 3169 λTATATAATA AATAATTTTA AAATCCCAAA AAAAAAAAAA AAAA 3213 (2) INFORMATION FOR SEQ ID NO:6: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 963 amino acids (B) TYPE: amino acid (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6: Val Gin His Ser He Asn Arg Lys Gin Ser Trp Lys Gly Ser Lys Glu 1 5 10 15 Ser Leu Val Pro Gin Arg His Gly Pro Ser Leu Gly Glu Asn Val Val 20 25 30 Tyr Arg Ser Glu Ser Pro Asn Ser Gin Ala Asp Val Gly Arg Pro Leu 35 40 45 Ser Gly Ser Gly He Ala Ala Phe Ala Gin Ala Hie Pro Ser Asn Gly 50 55 60 Gin Arg Val λsn Pro Pro Pro Pro Pro Gin Val λrg Ser Val Thr Pro 65 70 75 80 Pro Pro Pro Pro Arg Gly Gin Thr Pro Pro Pro Arg Gly Thr Thr Pro 85 90 95 Pro Pro Pro Ser Trp Glu Pro Ser Ser Gin Thr Lye Arg Tyr Ser Gly 100 105 110 λβn Met Glu Tyr Val He Ser λrg He Ser Pro Val Pro Pro Gly λla 115 120 125 Trp Gin Glu Gly Tyr Pro Pro Pro Pro Leu Thr Thr Ser Pro Met λβn 130 135 140 Pro Pro Ser Gin λla Gin λrg λla He Ser Ser Val Pro Val Gly λrg 145 150 155 160 Gin Pro He He Met Gin Ser Thr Ser Lye Phe λβn Phe Thr Pro Gly 165 170 175 λrg Pro Gly Val Gin λsn Gly Gly Gly Gin Ser λsp Phe He Val His 180 185 190 Gin λβn Val Pro Thr Gly Ser Val Thr λrg Gin Pro Pro Pro Pro Tyr 195 200 205 Pro Leu Thr Pro λla λβn Gly Gin Ser Pro Ser λla Leu Gin Thr Gly 210 215 220 λla Ser λla Ala Pro Pro Ser Phe Ala Aβn Gly λβn Val Pro Gin Ser 225 230 235 240 Met Met Val Pro λsn λrg Asn Ser His Aβn Met Glu Leu Tyr Aβn He 245 250 255 λβn Val Pro Gly Leu Gin Thr λla Trp Pro Gin Ser Ser Ser λla Pro 260 265 270 λla Gin Ser Ser Pro Ser Gly Gly Hiβ Glu He Pro Thr Trp Gin Pro 275 280 285 Asn He Pro Val Arg Ser Aβn Ser Phe Aβn Asn Pro Leu Gly Ser Arg 290 295 300 λla Ser His Ser λla λsn Ser Gin Pro Ser λla Thr Thr Val Thr λla 305 310 315 320 He Thr Pro λla Pro He Gin Gin Pro Val Lys Ser Met λrg Val Leu 325 330 335 Lys Pro Glu Leu Gin Thr Ala Leu Ala Pro Thr His Pro Ser Trp Met 340 345 350 Pro Gin Pro Val Gin Thr Val Gin Pro Thr Pro Phe Ser Glu Gly Thr 355 360 365 Ala Ser Ser Val Pro Val He Pro Pro Val Ala Glu Ala Pro Ser Tyr 370 375 380 Gin Gly Pro Pro Pro Pro Tyr Pro Lys His Leu Leu His Gin Asn Pro 385 390 395 400 Ser Val Pro Pro Tyr Glu Ser Val Ser Lys Pro Cys Lys Asp Glu Gin 405 410 415 Pro Ser Leu Pro Lys Glu Asp Asp Ser Glu Lys Ser Ala Asp Ser Gly 420 425 430 λβp Ser Gly λβp Lye Glu Lye Lye Gin He Thr Thr Ser Pro He Thr 435 440 445 Val λrg Lye λβn Lye Lys λsp Glu Glu λrg λrg Glu Ser λrg He Gin 450 455 460 Ser Tyr Ser Pro Gin λla Phe Lys Phe Phe Met Glu Gin Hiβ Val Glu 465 470 475 480 Asn Val Leu Lye Ser Hiβ Gin Gin Arg Leu Hie λrg Lye Lye Gin Leu 485 490 495 Glu λβn Glu Met Met λrg Val Gly Leu Ser Gin λβp λla Gin λβp Gin 500 505 510 Met λrg Lye Met Leu Cys Gin Lys Glu Ser λβn Tyr He λrg Leu Lys 515 520 525 λrg λla Lys Met λβp Lye Ser Met Phe Val Lye He Lys Thr Leu Gly 530 535 540 He Gly λla Phe Gly Glu Val Cys Leu λla λrg Lys Val λsp Thr Lys 545 550 555 560 λla Leu Tyr λla Thr Lys Thr Leu λrg Lys Lys λβp Val Leu Leu λrg 565 570 575 λβn Gin Val λla Hiβ Val Lys λla Glu λrg λsp He Leu λla Glu λla 580 585 590 λβp λβn Glu Trp Val Val λrg Leu Tyr Tyr Ser Phe Gin Aβp Lys Asp 595 600 605 λsn Leu Tyr Phe Val Met λsp Tyr He Pro Gly Gly λsp Met Met Ser 610 615 620 Leu Leu He λrg Met Gly He Phe Pro Glu λsn Leu λla Arg Phe Tyr 625 630 635 640 He Ala Glu Leu Thr Cys Ala Val Glu Ser Val His Lys Met Gly Phe 645 650 655 He His Arg Asp He Lys Pro Asp Asn He Leu He Asp λrg λsp Gly 660 665 670 His He Lys Leu Thr λβp Phe Gly Leu Cyβ Thr Gly Phe λrg Trp Thr 675 680 685 His λβp Ser Lys Tyr Tyr Gin Ser Gly λsp His Pro λrg Gin λsp Ser 690 695 700 Met λsp Phe Ser Asn Glu Trp Gly Asp Pro Ser Asn Cys Arg Cys Gly 705 710 715 720 Asp Arg Leu Lys Pro Leu Glu Arg Arg Ala Ala λrg Gin His Gin λrg 725 730 735 Cys Leu λla His Ser Leu Val Gly Thr Pro Asn Tyr He Ala Pro Glu 740 745 750 Val Leu Leu Arg Thr Gly Tyr Thr Gin Leu Cys Asp Trp Trp Ser Val 755 760 765 Gly Val He Leu Cys Glu Met Leu Val Gly Gin Pro Pro Phe Leu Ala 770 775 780 Gin Thr Pro Leu Glu Thr Gin Met Lys Val He He Trp Gin Thr Ser 785 790 795 800 Leu Hiβ He Pro Pro Gin Ala Lye Leu Ser Pro Glu Ala Ser Aep Leu 805 810 815 He He Lye Leu Cyβ Arg Gly Pro Glu Aβp λrg Leu Gly Lye λβn Gly 820 825 830 λla λβp Glu He Lye Ala Hiβ Pro Phe Phe Lye Thr He Aep Phe Ser 835 840 845 Ser Aβp Leu Arg Gin Gin Ser Ala Ser Tyr He Pro Lye He Thr Hie 850 855 860 Pro Thr Aβp Thr Ser Aβn Phe λβp Pro Val λβp Pro λβp Lye Leu Trp 865 870 875 880 Ser λβp Gly Ser Glu Glu Glu λβn He Ser λβp Thr Leu Ser Gly Trp 885 890 895 Tyr Lys λsn Gly Lys His Pro Glu His λla Phe Tyr Glu Phe Thr Phe 900 905 910 λrg λrg Phe Phe λsp λsp λsn Gly Tyr Pro Tyr λsn Tyr Pro Lys Pro 915 920 925 He Glu Tyr Glu Tyr He His Ser Gin Gly Ser Glu Gin Gin Ser λβp 930 935 940 Glu λsp λsp Gin His Thr Ser Ser λβp Gly λsn λsn λrg λβp Leu Val 945 950 955 960 Tyr Val * (2) INFORMATION FOR SEQ ID NO:7: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 3155 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: cDNA (ix) FEλTURE: (λ) NλME/KEY: CDS (B) LOCλTION: 1..2943 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:7: λTG λGA GCC ACC CCG AAG TTT GGA CCT TAT CAA AAA GCT CTC AGG GAA 48 Met Arg Ala Thr Pro Lys Phe Gly Pro Tyr Gin Lys Ala Leu Arg Glu 1 5 10 15 ATC CGA TAT TCC CTC CTG CCT TTT GCC AλC GAG TCA GGC ACT TCG GCA 96 He Arg Tyr Ser Leu Leu Pro Phe λla λsn Glu Ser Gly Thr Ser λla 20 25 30 GCT GCA GAG GTG AAC CGG CAG ATG CTT CAG GAG TTG GTG AAT GCG GCA 144 Ala Ala Glu Val Asn λrg Gin Met Leu Gin Glu Leu Val λsn Ala Ala 35 40 45 TGT GAC CAG GAG ATG GCT GGC λGA GCG CTC ACG CAG λCG GGC λGT λGG 192 Cys λsp Gin Glu Met λla Gly λrg λla Leu Thr Gin Thr Gly Ser λrg 50 55 60 λGT λTC Gλλ GCT GCC TTG GλG TλC λTC λGT λλG λTG GGC TλC CTG GλC 240 Ser He Glu λla λla Leu Glu Tyr He Ser Lye Met Gly Tyr Leu λβp 65 70 75 80 CCC AGG AAT GAG CλG ATT GTG CGA GTC λTC AAG CAG ACC TCC CCA GGA 288 Pro Arg Aβn Glu Gin He Val λrg Val He Lye Gin Thr Ser Pro Gly 85 90 95 λλG GGC CTG GCG TCC λCC CCG GTG λCT CGG CGG CCC λGT TTC GλG GGC 336 Lye Gly Leu λla Ser Thr Pro Val Thr λrg λrg Pro Ser Phe Glu Gly 100 105 110 λCλ GGG GλA GCλ CTC CCλ TCC TλC CλC CλG CTG GGT GGT GCλ AAC TAC 384 Thr Gly Glu Ala Leu Pro Ser Tyr Hiβ Gin Leu Gly Gly Ala λβn Tyr 115 120 125 GλG GGC CCC GCC GCλ CTG GλG GλG λTG CCG CGG Cλλ TλT TTλ GλC TTT 432 Glu Gly Pro λla λla Leu Glu Glu Met Pro λrg Gin Tyr Leu λβp Phe 130 135 140 CTC TTC CCT GGλ GCC GGλ GCC GGC λCC CλC GGT GCC CAG GCT CAC CλG 480 Leu Phe Pro Gly Ala Gly Ala Gly Thr His Gly λla Gin λla His Gin 145 150 155 160 CλT CCT CCC AλA GGG TAC AGC λCA GCA GTA GλG CCλ λGT GCG CλC TTT 528 Hiβ Pro Pro Lye Gly Tyr Ser Thr λla Val Glu Pro Ser λla Hiβ Phe 165 170 175 CCG GGC λCA CAC TAT GGT CGT GGT CAT CTA CTλ TCG GAG CAG TCT GGG 576 Pro Gly Thr His Tyr Gly Arg Gly Hiβ Leu Leu Ser Glu Gin Ser Gly 180 185 190 TAT GGG GTG CAG CGC AGT TCC TCC TTC CAG λλC λλG λCG CCA CCA GAT 624 Tyr Gly Val Gin Arg Ser Ser Ser Phe Gin Aβn Lye Thr Pro Pro λβp 195 200 205 GCC TλT TCC λGC ATG GCC AAG GCC CAG GGT GGC CCT CCC GCC λGC CTC 672 λla Tyr Ser Ser Met Ala Lys Ala Gin Gly Gly Pro Pro Ala Ser Leu 210 215 220 λCC TTT CCT GCC CAT GCT GGG CTG TAC ACT GCC TCG CAC CAC AλG CCG 720 Thr Phe Pro λla His λla Gly Leu Tyr Thr λla Ser His His Lys Pro 225 230 235 240 GCG GCT λCC CCA CCT GGG GCC CAC CCA TTA CAT GTG TTG GGC ACC CGG 768 Ala λla Thr Pro Pro Gly λla His Pro Leu Hiβ Val Leu Gly Thr λrg 245 250 255 GGT CCC ACG TTT ACT GGC GAA AGC TCT GCA CAG GCT GTG CTG GCA CCG 816 Gly Pro Thr Phe Thr Gly Glu Ser Ser Ala Gin Ala Val Leu Ala Pro 260 265 270 TCC AGG AAC AGC CTC AAT GCT GAC TTG TAC GAG CTG GGC TCC ACG GTG 864 Ser Arg Asn Ser Leu Asn Ala Asp Leu Tyr Glu Leu Gly Ser Thr Val 275 280 285 CCC TGG TCT GCA GCT CCA CTG GCA CGC CGC GAC TCG CTG CAG AAG CAG 912 Pro Trp Ser Ala Ala Pro Leu Ala Arg Arg Asp Ser Leu Gin Lys Gin 290 295 300 GGT CTA GAA GCC TCG CGG CCG CAT GTG GCT TTT CGG GCT GGC CCC AGC 960 Gly Leu Glu Ala Ser Arg Pro His Val Ala Phe Arg Ala Gly Pro Ser 305 310 315 320 AGG λCC AAC TCC TTC AAC AAC CCA CAA CCT GAG CCC TCA CTG CCC GCC 1008 λrg Thr λβn Ser Phe λen λβn Pro Gin Pro Glu Pro Ser Leu Pro λla 325 330 335 CCC λλC λCG GTC λCC GCC GTG λCG GCC GCλ CλC λTC CTT CλC CCT GTG 1056 Pro λβn Thr Val Thr λla Val Thr λla Ala Hiβ He Leu Hiβ Pro Val 340 345 350 AλG AGC GTG CGT GTG CTG CGG CCC GAG CCC CAG ACλ GCC GTG GGG CCC 1104 Lye Ser Val λrg Val Leu λrg Pro Glu Pro Gin Thr λla Val Gly Pro 355 360 365 TCG CλC CCC GCC TGG GTG GCT GCG CCC λCλ GCλ CCT GCC λCT GλG AGC 1152 Ser Hiβ Pro Ala Trp Val Ala λla Pro Thr λla Pro λla Thr Glu Ser 370 375 380 CTG GλG λCG λλG GλG GGC λGC GCA GGC CCA CλC CCG CTG GAT GTG GAC 1200 Leu Glu Thr Lye Glu Gly Ser Ala Gly Pro Hiβ Pro Leu Aep Val Aβp 385 390 395 400 TAT GGC GGC TCC GλG CGC AGG TGC CCA CCG CCT CCG TAT CCA AλG CAC 1248 Tyr Gly Gly Ser Glu Arg λrg Cys Pro Pro Pro Pro Tyr Pro Lys Hiβ 405 410 415 TTG CTG CTG CCC AGT AλG TCT GλG CλG TλC λGC GTG GλC CTG GλC AGC 1296 Leu Leu Leu Pro Ser Lye Ser Glu Gin Tyr Ser Val Aβp Leu Aβp Ser 420 425 430 CTG TGC ACC λGT GTG CλG CλG λGT CTG CGλ GGG GGC λCT GλT CTλ GλC 1344 Leu Cyβ Thr Ser Val Gin Gin Ser Leu λrg Gly Gly Thr λβp Leu λβp 435 440 445 GGG λGT GλC λλG λGC CλC AAA GGT GCG λλG GGA GAC AAA GCT GGC AGA 1392 Gly Ser Aβp Lye Ser Hiβ Lye Gly λla Lye Gly λβp Lye λla Gly λrg 450 455 460 GλC AAA AλG CλG λTT CλG λCC TCC CCG GTG CCT GTC CGC AλG λλT λGC 1440 λep Lys Lys Gin He Gin Thr Ser Pro Val Pro Val λrg Lys λsn Ser 465 470 475 480 λGλ GAT Gλλ GAG AλG λGA GAG TCT CGC ATC AAG AGT TAC TCC CCT TλT 1488 λrg λsp Glu Glu Lys λrg Glu Ser λrg He Lys Ser Tyr Ser Pro Tyr 485 490 495 GCC TTC λλλ TTC TTC λTG GAG Cλλ CλC GTG GλG λλT GTC λTC λλλ ACC 1536 Ala Phe Lys Phe Phe Met Glu Gin Hiβ Val Glu Aβn Val He Lye Thr 500 505 510 TAC CAG CAG AAG GTC AGC CGG AGG CTA CAG CTG GAG CAG GλA ATG GCC 1584 Tyr Gin Gin Lys Val Ser Arg Arg Leu Gin Leu Glu Gin Glu Met Ala 515 520 525 AλA GCT GGG CTC TGT GAG GCC GAG CAG GAG CAG ATG AGG AλG λTC CTC 1632 Lys λla Gly Leu Cys Glu Ala Glu Gin Glu Gin Met Arg Lys He Leu 530 535 540 TAC CAG AAG GAG TCT AAC TAC AAC CGG CTG AAG AGG GCC AλG λTG GλC 1680 Tyr Gin Lys Glu Ser λsn Tyr λsn λrg Leu Lys Arg Ala Lys Met Asp 545 550 555 560 AλG TCC ATG TTT GTG AAA ATC AλG ACT CTA GGC ATC GGT GCC TTT GGG 1728 Lys Ser Met Phe Val Lys He Lys Thr Leu Gly He Gly Ala Phe Gly 565 570 575 GλA GTG TGC CTC GCT TGT AAG CTG GAC ACT CAC GCT CTG TAC GCC ATG 1776 Glu Val Cys Leu Ala Cys Lys Leu Asp Thr His Ala Leu Tyr Ala Met 580 585 590 AAG ACT CTC AGG AλG λλG GλT GTC CTG AAC CGG AAT CAA GTG GCC CAT 1824 Lye Thr Leu Arg Lye Lye Aβp Val Leu Asn Arg Aβn Gin Val Ala Hiβ 595 600 605 GTC AλG GCT GλG λGG GλC λTC CTG GCT Gλλ GCλ GλC λAT GAG TGG GTG 1872 Val Lys Ala Glu Arg λβp He Leu λla Glu λla λβp λβn Glu Trp Val 610 615 620 GTC λλλ CTC TλC TλC TCC TTC CλG GλC λλG GλC λGC CTG TλC TTT GTG 1920 Val Lye Leu Tyr Tyr Ser Phe Gin Aβp Lye Aβp Ser Leu Tyr Phe Val 625 630 635 640 ATG GAC TAC λTA CCA GGC GGG GλT λTG λTG λGC CTG CTG λTC λGG λTG 1968 Met λβp Tyr He Pro Gly Gly λβp Met Met Ser Leu Leu He λrg Met 645 650 655 GλG GTC TTC CCT GλG CλC CTG GCC CGC TTC TλC λTT GCλ GλG TTG λCC 2016 Glu Val Phe Pro Glu Hiβ Leu λla λrg Phe Tyr He λla Glu Leu Thr 660 665 670 CTG GCC λTT GλA λGT GTC CλC λλG λTG GGC TTT λTC CλC CGG GAC ATC 2064 Leu Ala He Glu Ser Val His Lys Met Gly Phe He His Arg Aβp He 675 680 685 AλG CCT GAC AλC λTλ CTC λTC GλC CTG GλT GGT CAT ATT AAG CTG ACA 2112 Lye Pro Aβp λβn He Leu He λsp Leu λβp Gly His He Lys Leu Thr 690 695 700 GλT TTT GGC CTC TGC λCT GGA TTC AGG TGG λCT CλC AAT TCC AAG TAC 2160 Aβp Phe Gly Leu Cys Thr Gly Phe Arg Trp Thr His λsn Ser Lys Tyr 705 710 715 720 TλC CλG AλA GGG λλC CλC λTG λGλ CλG GλC λGC λTG GλG CCC GGT GλC 2208 Tyr Gin Lys Gly λsn His Met λrg Gin λβp Ser Met Glu Pro Gly λβp 725 730 735 CTC TGG GλC GλT GTT TCC AAC TGT CGC TGT GGA GAC λGG TTA AλG λCC 2256 Leu Trp Aβp Aβp Val Ser λβn Cys λrg Cys Gly Asp Arg Leu Lys Thr 740 745 750 CTG GAG CAG AGG GCG CAG AλG CλG CλC CλG λGG TGC CTG GCA CAT TCT 2304 Leu Glu Gin λrg λla Gin Lys Gin His Gin λrg Cys Leu λla His Ser 755 760 765 CTT GTC GGG ACA CCA AAT TAC ATC GCT CCG GAG GTG CTT CTC CGC AAλ 2352 Leu Val Gly Thr Pro λsn Tyr He λla Pro Glu Val Leu Leu λrg Lys 770 775 780 GGG TAC ACG CAG CTC TGT GλC TGG TGG AGC GTC GGT GTG ATT CTC TTT 2400 Gly Tyr Thr Gin Leu Cys Asp Trp Trp Ser Val Gly Val He Leu Phe 785 790 795 800 GAG ATG CTG GTT GGG CAG CCG CCT TTC TTG GCC CCC ACC CCC ACA GAG 2448 Glu Met Leu Val Gly Gin Pro Pro Phe Leu Ala Pro Thr Pro Thr Glu 805 810 815 ACG CAG CTG AAG GTG ATC AAC TGG GAG AGC ACG CTG CAT ATC CCT ACG 2496 Thr Gin Leu Lys Val He Asn Trp Glu Ser Thr Leu His He Pro Thr 820 825 830 CAG GTG AGG CTC AGC GCT GAG GCC CGA GAC CTC ATC ACG AAG CTG TGC 2544 Gin Val Arg Leu Ser Ala Glu Ala Arg λsp Leu He Thr Lys Leu Cys 835 840 845 TGC GCG GCT GλC TGC CGC CTG GGC λGG GAT GGG GCA GAT GAC CTC AAG 2592 Cys Ala Ala Aβp Cys Arg Leu Gly Arg Asp Gly Ala Asp Asp Leu Lys 850 855 860 GCλ CλC CCG TTC TTC λλC λCC λTC GλC TTT TCC CGT GλC λTC CGλ λλG 2640 λla His Pro Phe Phe Asn Thr He Aβp Phe Ser Arg Aβp He λrg Lye 865 870 875 880 CλG GCT GCλ CCC TλC GTC CCC λCC λTC λGC CλC CCC λTG GλC λCC TCC 2688 Gin λla λla Pro Tyr Val Pro Thr He Ser Hiβ Pro Met λβp Thr Ser 885 890 895 λλT TTT GλC CCG GTG GλT Gλλ Gλλ λGC CCC TGG CλC GλG GCC λGC GGλ 2736 λβn Phe λβp Pro Val λβp Glu Glu Ser Pro Trp Hiβ Glu λla Ser Gly 900 905 910 GλG λGC GCC λλG GCC TGG GλC λCG CTG GCC TCC CCC λGC λGC λλG CλT 2784 Glu Ser λla Lye λla Trp λβp Thr Leu λla Ser Pro Ser Ser Lye Hiβ 915 920 925 CCλ GλG CλC GCC TTC TλT GλG TTC λCC TTC CGC λGG TTC TTC GλT GAC 2832 Pro Glu Hiβ Ala Phe Tyr Glu Phe Thr Phe Arg Arg Phe Phe Aβp Aβp 930 935 940 AλC GGC TλT CCC TTC CGG TGC CCG λλG CCC TCA GAG CCC GCA GAG AGT 2880 Aβn Gly Tyr Pro Phe Arg Cys Pro Lys Pro Ser Glu Pro Ala Glu Ser 945 950 955 960 GCA GAC CCA GGG GAT GCG GλC TTG Gλλ GGT GCG GCC GλG GGC TGC CλG 2928 λla λβp Pro Gly λβp λla Asp Leu Glu Gly λla λla Glu Gly Cys Gin 965 970 975 CCG GTG TλC GTG TAA GCCTCλGTTA ACCACAλCTC GλGGλAACCC λλλλTGλGλT 2983 Pro Val Tyr Val * 980 TTCTTTTCλG AAGλCλλλCT CAAGCTTAGG λλTCCTTCλT TTTTλGTTCT GGTλλλTGGG 3043 CλλCλGGAAG AGTCAACλTG ATTTCAAATT AGCCCTCTGA GGACCTTCAC TGCATTAAλλ 3103 CλGTλTTTTT TλλAAAλTTλ GTACλGTλTG GAAAGλGCλC TTλTTTTGGG GG 3155 (2) INFORMATION FOR SEQ ID NO:8: (i) SEQUENCE CHARλCTERISTICS: (λ) LENGTH: 981 amino acids (B) TYPE: amino acid (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8: Met Arg Ala Thr Pro Lys Phe Gly Pro Tyr Gin Lys Ala Leu Arg Glu 1 5 10 15 He Arg Tyr Ser Leu Leu Pro Phe Ala Asn Glu Ser Gly Thr Ser λla 20 25 30 λla λla Glu Val λsn λrg Gin Met Leu Gin Glu Leu Val λsn λla λla 35 40 45 Cys λsp Gin Glu Met λla Gly Arg Ala Leu Thr Gin Thr Gly Ser Arg 50 55 60 Ser He Glu λla λla Leu Glu Tyr He Ser Lye Met Gly Tyr Leu λβp 65 70 75 80 Pro λrg λβn Glu Gin He Val λrg Val He Lys Gin Thr Ser Pro Gly 85 90 95 Lye Gly Leu λla Ser Thr Pro Val Thr λrg λrg Pro Ser Phe Glu Gly 100 105 110 Thr Gly Glu λla Leu Pro Ser Tyr Hiβ Gin Leu Gly Gly λla λβn Tyr 115 120 125 Glu Gly Pro λla λla Leu Glu Glu Met Pro λrg Gin Tyr Leu λβp Phe 130 135 140 Leu Phe Pro Gly λla Gly λla Gly Thr Hiβ Gly λla Gin λla Hiβ Gin 145 150 155 160 Hiβ Pro Pro Lye Gly Tyr Ser Thr λla Val Glu Pro Ser λla Hiβ Phe 165 170 175 Pro Gly Thr Hiβ Tyr Gly λrg Gly Hiβ Leu Leu Ser Glu Gin Ser Gly 180 185 190 Tyr Gly Val Gin λrg Ser Ser Ser Phe Gin λβn Lys Thr Pro Pro λβp 195 200 205 λla Tyr Ser Ser Met λla Lye λla Gin Gly Gly Pro Pro λla Ser Leu 210 215 220 Thr Phe Pro λla His λla Gly Leu Tyr Thr λla Ser Hie His Lys Pro 225 230 235 240 λla λla Thr Pro Pro Gly λla His Pro Leu Hie Val Leu Gly Thr λrg 245 250 255 Gly Pro Thr Phe Thr Gly Glu Ser Ser λla Gin λla Val Leu λla Pro 260 265 270 Ser λrg λsn Ser Leu λsn λla λsp Leu Tyr Glu Leu Gly Ser Thr Val 275 280 285 Pro Trp Ser Ala Ala Pro Leu Ala λrg λrg Aβp Ser Leu Gin Lys Gin 290 295 300 Gly Leu Glu Ala Ser Arg Pro His Val λla Phe λrg λla Gly Pro Ser 305 310 315 320 λrg Thr λsn Ser Phe λsn λβn Pro Gin Pro Glu Pro Ser Leu Pro λla 325 330 335 Pro λen Thr Val Thr λla Val Thr λla λla Hie He Leu Hiβ Pro Val 340 345 350 Lys Ser Val Arg Val Leu Arg Pro Glu Pro Gin Thr Ala Val Gly Pro 355 360 365 Ser His Pro Ala Trp Val Ala Ala Pro Thr Ala Pro Ala Thr Glu Ser 370 375 380 Leu Glu Thr Lys Glu Gly Ser Ala Gly Pro His Pro Leu Asp Val Asp 385 390 395 400 Tyr Gly Gly Ser Glu Arg Arg Cys Pro Pro Pro Pro Tyr Pro Lys His 405 410 415 Leu Leu Leu Pro Ser Lys Ser Glu Gin Tyr Ser Val Asp Leu Asp Ser 420 425 430 Leu Cys Thr Ser Val Gin Gin Ser Leu Arg Gly Gly Thr Asp Leu Aβp 435 440 445 Gly Ser Asp Lys Ser Hiβ Lye Gly Ala Lye Gly Aβp Lye Ala Gly Arg 450 455 460 Aβp Lye Lye Gin He Gin Thr Ser Pro Val Pro Val Arg Lye Aβn Ser 465 470 475 480 Arg λβp Glu Glu Lye λrg Glu Ser λrg He Lye Ser Tyr Ser Pro Tyr 485 490 495 λla Phe Lye Phe Phe Met Glu Gin Hiβ Val Glu λβn Val He Lye Thr 500 505 510 Tyr Gin Gin Lye Val Ser λrg Arg Leu Gin Leu Glu Gin Glu Met Ala 515 520 525 Lye Ala Gly Leu Cyβ Glu Ala Glu Gin Glu Gin Met Arg Lye He Leu 530 535 540 Tyr Gin Lye Glu Ser λβn Tyr λβn Arg Leu Lye Arg Ala Lye Met λβp 545 550 555 560 Lye Ser Met Phe Val Lye He Lye Thr Leu Gly He Gly λla Phe Gly 565 570 575 Glu Val Cys Leu λla Cys Lys Leu λβp Thr His λla Leu Tyr Ala Met 580 585 590 Lys Thr Leu Arg Lye Lye λsp Val Leu λβn λrg λβn Gin Val λla Hiβ 595 600 605 Val Lye λla Glu λrg λsp He Leu Ala Glu Ala Asp Asn Glu Trp Val 610 615 620 Val Lys Leu Tyr Tyr Ser Phe Gin Aβp Lys Aβp Ser Leu Tyr Phe Val 625 630 635 640 Met Asp Tyr He Pro Gly Gly Asp Met Met Ser Leu Leu He Arg Met 645 650 655 Glu Val Phe Pro Glu His Leu Ala Arg Phe Tyr He λla Glu Leu Thr 660 665 670 Leu λla He Glu Ser Val His Lys Met Gly Phe He His Arg Aβp He 675 680 685 Lye Pro Asp Asn He Leu He Asp Leu Aep Gly Hiβ He Lye Leu Thr 690 695 700 λβp Phe Gly Leu Cys Thr Gly Phe λrg Trp Thr His λsn Ser Lys Tyr 705 710 715 720 Tyr Gin Lys Gly Asn His Met Arg Gin Aβp Ser Met Glu Pro Gly Aβp 725 730 735 Leu Trp λsp Asp Val Ser Asn Cys Arg Cys Gly Asp λrg Leu Lys Thr 740 745 750 Leu Glu Gin Arg Ala Gin Lys Gin His Gin Arg Cys Leu λla Hiβ Ser 755 760 765 Leu Val Gly Thr Pro Asn Tyr He Ala Pro Glu Val Leu Leu Arg Lys 770 775 780 Gly Tyr Thr Gin Leu Cys Asp Trp Trp Ser Val Gly Val He Leu Phe 785 790 795 800 Glu Met Leu Val Gly Gin Pro Pro Phe Leu Ala Pro Thr Pro Thr Glu 805 810 815 Thr Gin Leu Lys Val He Aβn Trp Glu Ser Thr Leu His He Pro Thr 820 825 830 Gin Val Arg Leu Ser Ala Glu Ala Arg Aβp Leu He Thr Lye Leu Cys 835 840 845 Cyβ Ala Ala Aβp Cyβ Arg Leu Gly Arg Aβp Gly Ala λβp λβp Leu Lye 850 855 860 λla Hiβ Pro Phe Phe λβn Thr He λβp Phe Ser λrg λsp He λrg Lye 865 870 875 880 Gin λla λla Pro Tyr Val Pro Thr He Ser Hiβ Pro Met λβp Thr Ser 885 890 895 λβn Phe λβp Pro Val λβp Glu Glu Ser Pro Trp His Glu λla Ser Gly 900 905 910 Glu Ser λla Lys λla Trp λsp Thr Leu λla Ser Pro Ser Ser Lys His 915 920 925 Pro Glu His Ala Phe Tyr Glu Phe Thr Phe Arg Arg Phe Phe Asp λβp 930 935 940 λβn Gly Tyr Pro Phe λrg Cys Pro Lys Pro Ser Glu Pro Ala Glu Ser 945 950 955 960 Ala λβp Pro Gly λsp λla Asp Leu Glu Gly Ala Ala Glu Gly Cys Gin 965 970 975 Pro Val Tyr Val * 980 (2) INFORMATION FOR SEQ ID NO:9: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 amino acidβ (B) TYPE: amino acid (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9: Asp Leu Lys Pro Glu Asn 1 5 (2) INFORMATION FOR SEQ ID NO:10: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 9 amino acids (B) TYPE: amino acid (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: Peptide (B) LOCATION: 2 (D) OTHER INFORMATION: /label= A /note= "X at the second poβition can be either Threonine or Serine. " (ix) FEATURE: (A) NAME/KEY: Peptide (B) LOCATION: 5 (D) OTHER INFORMλTION: /label= B /note= "X at the fifth position can either be Tyrosine or Phenylalanine. " (xi) SEQUENCE DESCRIPTION: SEQ ID NO:10: Gly Xaa Xaa Xaa Xaa Xaa λla Pro Glu 1 5 (2) INFORMλTION FOR SEQ ID NO:11: (i) SEQUENCE CHλRλCTERISTICS: (λ) LENGTH: 620 amino acidβ (B) TYPE: amino acid (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:11: Met λβp λβn Thr λβn λrg Pro Hiβ Leu λβn Leu Gly Thr λβn λβp Thr 1 5 10 15 λrg Met λla Pro Asn Asp Arg Thr Tyr Pro Thr Thr Pro Ser Thr Phe 20 25 30 Pro Gin Pro Val Phe Pro Glv Gin Gin λla Gly Gly Ser Gin Gin Tyr 35 " 40 45 λβn Gin λla Tyr λla Gin Ser Gly λβn Tyr Tyr Gin Gin λβn Hiβ Aβn 50 55 60 Aep Pro Asn Thr Gly Leu Ala His Gin Phe Ala His Gin λsn He Gly 65 70 75 80 Ser λla Gly λrg λla Ser Pro Tyr Gly Ser λrg Gly Pro Ser Pro λla 85 90 95 Gin λrg Pro λrg Thr Ser Gly λβn Ser Gly Gin Gin Gin Thr Tyr Gly 100 105 110 λsn Tyr Leu Ser Ala Pro Met Pro Ser Asn Thr Gin Thr Glu Phe Ala 115 120 125 Pro Leu Pro Ser Gly Thr Pro Thr Asn Met Ala Pro Met Pro Thr Thr 130 135 140 Thr Arg Arg Ser Ala His Ser Trp Pro Leu Thr Ser Leu Arg Thr λla 145 150 155 160 Ser Ser Ala Pro Gly Ser Ala Thr Arg Gly Glu Cys Cys Ser λsp λla 165 170 175 Leu Leu Pro Leu His Pro Ala Val He Gly Ala Asp Thr Leu Phe λrg 180 185 190 Gin Ser Glu Met Glu Gin Lys Leu Gly Glu Thr λsn λsp λla λrg Arg 195 200 205 λrg Glu Ser He Trp Ser Thr λla Gly λrg Lye Glu Gly Gin Tyr Leu 210 215 220 λrg Phe Leu λrg Thr Lye λβp Lye Pro Glu λβn Tyr Gin Thr He Lye 225 230 235 240 He He Gly Lye Gly λla Phe Gly Glu Val Lye Leu Val Gin Lye Lye 245 250 255 λla λβp Gly Lye Val Tyr λla Met Lye Ser Leu He Lye Thr Glu Met 260 265 270 Phe Lye Lye Aβp Gin Leu Ala Hiβ Val λrg λla Glu λrg Asp He Leu 275 280 285 Ala Glu Ser λβp Ser Pro Trp Val Val Lye Leu Tyr Thr Thr Phe Gin 290 295 300 λβp λla λβn Phe Leu Tyr Met Leu Met Glu Phe Leu Pro Gly Gly λβp 305 310 315 320 Leu Met Thr Met Leu He Lye Tyr Glu He Phe Ser Glu λβp He Thr 325 330 335 λrg Phe Tyr He λla Glu He Val Leu λla He λsp λla Val His Lys 340 345 350 Leu Gly Phe He Hiβ λrg λβp He Lye Pro λβp λβn He Leu Leu λβp 355 360 365 λrg Gly Gly His Val Lys Leu Thr λsp Phe Gly Leu Ser Thr Gly Phe 370 375 380 His Lys Leu His Asp Asn Asn Tyr Tyr Thr Gin Leu Leu Gin Gly Lys 385 390 395 400 Ser Asn Lys Pro Arg λsp λsn λrg λsn Ser Val λla He λβp Gin He 405 410 415 λβn Leu Thr Val Ser Asn Arg Ala Gin He Asn Asp Trp Arg Arg Ser 420 425 430 Arg Arg Leu Met Ala Tyr Ser Thr Val Gly Thr Pro Asp Tyr He λla 435 440 445 Pro Glu He Phe Thr Gly Hie Gly Tyr Ser Phe λβp Cyβ λβp Trp Trp 450 455 460 Ser Leu Gly Thr He Met Phe Glu Cys Leu Val Gly Trp Pro Pro Phe 465 470 475 480 Cys λla Glu Asp Ser His Asp Thr Tyr Arg Lys He Val λsn Trp Arg 485 490 495 His Ser Leu Tyr Phe Pro Asp Asp He Thr Leu Gly Val Asp Ala Glu 500 505 510 Asn Leu He Arg Ser Leu He Cys Asn Thr Glu Asn λrg Leu Gly Arg 515 520 525 Gly Gly Ala His Glu He Lys Ser His Ala Phe Phe Arg Gly Val Glu 530 535 540 Phe Asp Ser Leu Arg Arg He Arg Ala Pro Phe Glu Pro Arg Leu Thr 545 550 555 560 Ser Ala He Asp Thr Thr Tyr Phe Pro Thr Aβp Glu He Aβp Gin Thr 565 570 575 Asp Aβn Ala Thr Leu Leu Lye Ala Gin Gin Ala Ala Arg Gly Ala Ala 580 585 590 λla Pro λla Gin Gin Glu Glu Ser Pro Glu Leu Ser Leu Pro Phe He 595 600 605 Gly Tyr Thr Phe Lye λrg Phe λβp λβn λβn Phe λrg 610 615 620 (2) INFORMλTION FOR SEQ ID NO:12: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 526 amino acids (B) TYPE: amino acid (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:12: Met Aβp Ser Ala Arg Gly Trp Phe Gin Lye Leu Ser Ser Thr Lys Lys 1 5 10 15 Asp Pro Met Ala Ser Gly Arg Glu λβp Gly Lys Pro Val Ser λla Glu 20 25 30 Glu λla Ser λsn He Thr Lys Gin λrg Val λla λla λla Lys Gin Tyr 35 40 45 He Glu Lye Hiβ Tyr λrg Glu Gin Met Lye Asn Leu Gin Glu λrg λrg 50 55 60 Glu λrg λrg He Leu Leu Glu Lys Lys Leu λla λsp λla λsp Val Ser 65 70 75 80 Glu Glu λsp Gin λsn λsn Leu Leu Lys Phe Leu Glu Lys Lys Glu Thr 85 90 95 Glu Tyr Met λrg Leu Gin λrg His Lys Met Gly λla λsp λsp Phe Glu 100 105 110 Leu Leu Thr Met He Gly Lye Gly λla Phe Gly Glu Pro He Cyβ Met 115 120 125 He Gly Phe Ser Val He Thr Gly Gin λsn Cys λrg Glu Lys Thr Thr 130 135 140 Gly Gin Val Tyr Ala Met Lys Lys Leu Lys Lys Ser Glu Met Leu Arg 145 150 155 160 Arg Gly Gin Val Glu His Val Lys Ala Glu Arg Asn Leu Leu Ala Glu 165 170 175 Val Asp Ser Asp Cys He Val Lys Leu Tyr Tyr Ser Phe Gin Asp Asp 180 185 190 Asp Tyr Leu Tyr Leu Val Met Glu Tyr Leu Pro Gly Gly Asp Met Met 195 200 205 Thr Leu Leu Met Arg Lys Asp He Leu Thr Glu Asp Glu Ala λrg Phe 210 215 220 Tyr Val λla Glu Thr Val Leu λla He Glu Ser He Hiβ Lye Hiβ λβn 225 230 235 240 Tyr He Hie λrg λβp He Lye Pro λβp λβn Leu Leu Leu λβp λrg Tyr 245 250 255 Gly Hiβ Leu Lye Leu Ser Asp Phe Gly Leu Cys Lys Pro Leu Aep Cyβ 260 265 270 Ser Thr Leu Glu Glu Lye Aβp Phe Ser Val Gly Aβp λβn λla λβn Gly 275 280 285 Gly Ser λrg Ser λβp Ser Pro Pro λla Pro Lye λrg Thr Gin Gin Glu 290 295 300 Gin Leu Glu Hiβ Trp Gin Lye λβn λrg λrg Met Leu λla Tyr Ser Thr 305 310 315 320 Val Gly Thr Pro λβp Tyr He λla Pro Glu Val Leu Leu Lye Lye Gly 325 330 335 Tyr Gly Met Glu Cys Aβp Trp Trp Ser Leu Gly Ala He Met Tyr Glu 340 345 350 Met Leu Val Gly Tyr Pro Pro Phe Tyr Ser Asp Asp Pro Met Ser Thr 355 360 365 Cyβ λrg Lye He Val λsn Trp Lys λsn His Leu Lys Phe Pro Glu Glu 370 375 380 λla Lys Leu Ser Pro Glu λla Lys λβp He He Ser λrg Leu Leu Cys 385 390 395 400 λsn Val Thr Glu λrg Leu Gly Ser λsn Gly Ala Asp Glu He Lys Val 405 410 415 His Ser Trp Phe Lys Gly He Aβp Trp λβp Arg He Tyr Gin Met Glu 420 425 430 Ala Ala Phe He Pro Glu Val Asn Asp Glu Leu Asp Thr Gin Asn Phe 435 440 445 Glu Lys Phe Glu Glu Ser Glu Ser Hiβ Ser Gin Ser Gly Ser λrg Ser 450 455 460 Gly Pro Trp Arg Lys Met Leu Ser Ser Lye Asp He λβn Phe Val Gly 465 470 475 480 Tyr Thr Tyr Lys λsn Phe Lys Val Val λsn λsp Tyr Gin Val Pro Gly 485 490 495 Met Val Glu Leu Lys Lys Thr λsn Thr Lys Pro Lys Lys Pro Thr He 500 505 510 Lys Ser Leu Phe Gly Asp Glu Ser Glu Ala Ser Glu Asp Asn 515 520 525 (2) INFORMATION FOR SEQ ID NO: 13: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 479 amino acids (B) TYPE: amino acid (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:13: λrg Lye Leu Hiβ λβp λla λβp Val Ser Glu Glu Aβp Gin Aβn Aβn Leu 1 5 10 15 Leu Lye Phe Leu Glu Lye Lye Glu Thr Glu Tyr Met Arg Leu Gin Arg 20 25 30 Hiβ Lye Met Gly Ala λβp Asp Phe Glu Leu Leu Thr Met He Gly Lye 35 40 45 Gly Ala Phe Gly Glu Val Arg Val Cyβ Arg Glu Lye Thr Thr Gly Hiβ 50 55 60 Val Tyr Ala Met Lye Lys Leu Lye Lye Ser Glu Met Leu Arg λrg Gly 65 70 75 80 Gin Val Glu Hiβ Val Lys λla Glu λrg λsn Leu Leu λla Glu Val λβp 85 90 95 Ser λsn Cys He Val Lys Leu Tyr Cys Ser Phe Gin Asp Glu Glu Tyr 100 105 110 Leu Tyr Leu He Met Glu Tyr Leu Pro Gly Gly Aβp Met Met Thr Leu 115 120 125 Leu Met λrg Lys λβp Thr Leu Thr Glu λβp Glu Ala Arg Phe Tyr Val 130 135 140 Ala Glu Thr He Leu Ala He Glu Ser He Hiβ Lye His Asn Tyr He 145 150 155 160 His Arg Asp He Lys Pro Asp λsn Leu Leu Leu λsp Lys Phe Gly His 165 170 175 Leu λrg Leu Ser λsp Phe Gly Leu Cys Lys Pro Leu λβp Cyβ Ser Thr 180 185 190 Leu Glu Glu Lys λsp Phe Glu Val λβn Asn Gly Asn Gly Gly Ser Pro 195 200 205 Ser Asn Glu Gly Ser Thr Lys Pro Arg Arg Thr Gin Gin Glu Gin Leu 210 215 220 Gin His Trp Gin Lys λsn λrg λrg Met Leu λla Tyr Ser Thr Val Gly 225 230 235 240 Thr Pro λsp Tyr He Ala Pro Glu Val Leu Leu Lys Lys Gly Tyr Gly 245 250 255 Met Glu Cys Asp Trp Trp Ser Leu Gly Ala He Met Tyr Glu Met Leu 260 265 270 Val Gly Tyr Pro Pro Phe Tyr Ser Asp Asp Pro Met Ser Thr Cys λrg 275 280 285 Lys He Val Asn Trp Arg Thr His Leu Lys Phe Pro Glu Glu Ala Lys 290 295 300 Leu Ser Pro Glu Ala Lys Asp Leu He Ser Lys Leu Leu Cys Asn Val 305 310 315 320 Thr Gin Arg Leu Gly Ser Asn Gly Ala His Glu He Lys Leu His Pro 325 330 335 Trp Phe λsn Gly He λsp Trp Glu λrg He Tyr Gin Met Glu λla λla 340 345 350 Phe He Pro Glu Val λβn Aβp Glu Leu Aβp Thr Gin λβn Phe Glu Lye 355 360 365 Phe Glu Glu λla λβp λβn Ser Ser Gin Ser Thr Ser Lye λla Gly Pro 370 375 380 Trp λrg Lye Met Leu Ser Ser Lye λβp Leu λβn Phe Val Gly Tyr Thr 385 390 395 400 Tyr Lye λsn Phe Glu He Val λβn λβp Tyr Gin Val Pro Gly He λla 405 410 415 Glu Leu Lye Lys Lys λβp Thr Lye Pro Lys λrg Pro Ser He Lys Ser 420 425 430 Leu Phe Glu λβp Glu Ser Ser λβp Ser Ser Glu λla λla Thr Ser Gly 435 440 445 λβp Gin Ser Val Gin Gly Ser Phe Leu λβn Leu Leu Pro Pro Gin Leu 450 455 460 Glu Val Ser Gin Thr Gin Thr Glu Val Pro Pro Pro Lys Phe Thr 465 470 475 (2) INFORMATION FOR SEQ ID NO:14: (i) SEQUENCE CHARλCTERISTICS: (λ) LENGTH: 500 amino acids (B) TYPE: amino acid (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:14: Met Glu Lys Val Lys Ala Ala Lys Lys Phe He Glu λsn His Tyr λrg 1 5 10 15 Ser Gin Met Lys λsn He Gin Glu λrg Lys Glu λrg λrg Trp Val Leu 20 25 30 Glu Lys Gin Leu λla Ser Ser λβp Val Pro Glu Glu Glu Gin Met Ser 35 40 45 Leu He Lys Asp Leu Glu Arg Lys Glu Thr Glu Phe Met Arg Leu Lys 50 55 60 λrg λsn Arg He Cys Val Asn Asp Phe Glu Leu Leu Thr He He Gly 65 70 75 80 λrg Gly Ala Tyr Gly Glu Val Gin Leu Cys Arg Glu Lys Lys Ser Glu 85 90 95 Asn He Tyr Ala Met Lys Lys Leu Lys Lys Ser Glu Met Leu Ser Arg 100 105 110 Gly Gin Val Glu His Val Arg λla Glu Arg Asn Leu Leu Ala Glu Val 115 120 125 Asp Ser His Cys He Val Lys Leu Phe Tyr Ser Phe Gin Asp Ala Glu 130 135 140 Tyr Leu Tyr Leu He Met Glu Tyr Leu Pro Gly Gly λβp Met Met Thr 145 150 155 160 Leu Leu Met λrg Glu λβp He Leu Thr Glu Lye Val Ala Lye Phe Tyr 165 170 175 He Ala Gin Ser Val Leu Ala He Glu Ser He Hiβ Lye Hiβ Aβn Tyr 180 185 190 He Hie Arg λβp He Lye Pro λβp λβn Leu Leu Leu λβp Lye λβn Gly 195 200 205 Hiβ Met Lye Leu Ser λβp Phe Gly Leu Cyβ Lye Pro Leu λβp Cyβ λla 210 215 220 Thr Leu Ser Thr He Lys Glu λβn Glu Ser Met Aβp Asp Val Ser Lye 225 230 235 240 λβn Ser Met Asp He Asp λla Ser Leu Pro λβp λla Gly λβn Gly Hiβ 245 250 255 Ser Trp λrg Ser λla λrg Glu Gin Leu Gin His Trp Gin λrg λβn λrg 260 265 270 λrg Lys Leu λla Phe Ser Thr Val Gly Thr Pro λβp Tyr He λla Pro 275 280 285 Glu Val Leu Leu Lys Lys Gly Tyr Gly Met Glu Cys λsp Trp Trp Ser 290 295 300 Leu Gly Ala He Met Tyr Glu Met Leu Val Gly Tyr Pro Pro Phe Tyr 305 310 315 320 Ser Aβp Aβp Pro He Thr Thr Cyβ Arg Lye He Val His Trp Arg His 325 330 335 Tyr Leu Lys Phe Pro Asp Aβp Ala Lye Leu Thr Phe Glu Ala Arg λβp 340 345 350 Leu He Cys λrg Leu Leu Cys λβp Val Glu His λrg Leu Gly Thr Gly 355 360 365 Gly λla Glu Gin He Lys Val His λla Trp Phe Lye λβp Val Glu Trp 370 375 380 λsp λrg Leu Tyr Glu Thr λβp λla λla Tyr Lye Pro Gin Val λβn Gly 385 390 395 400 Glu Leu Aβp Thr Gin Aβn Phe Met Lye Phe λsp Glu Ala Asn Pro Pro 405 410 415 Thr Pro Ser Arg Ser Gly Ser Gly Pro Ser Arg Lys Met Leu Thr Ser 420 425 430 Lys Asp Leu Ser Phe Val Gly Tyr Thr Tyr Lys Asn Phe Asp λla Val 435 440 445 Lys Gly Leu Lys His Ser Phe Asp Arg Lys Gly Ser Thr Ser Pro Lys 450 455 460 Arg Pro Ser Leu Asp Ser Met Phe Asn Glu Asn Gly Met Asp Tyr Thr 465 470 475 480 λla Lys His λla Glu Glu Met Asp Val Gin Met Leu Thr Ala Aep Aβp 485 490 495 Cys Met Ser Pro 500 (2) INFORMλTION FOR SEQ ID NO:15: (i) SEQUENCE CHλRλCTERISTICS: (λ) LENGTH: 564 amino acids (B) TYPE: amino acid (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:15: Met Phe Ser λrg Ser λβp λrg Glu Val λβp λβp Leu λla Gly Asn Met 1 5 10 15 Ser Hie Leu Gly Phe Tyr Aβp Leu λβn He Pro Lys Pro Thr Ser Pro 20 25 30 Gin λla Gin Tyr λrg Pro λla λrg Lye Ser Glu λsn Gly λrg Leu Thr 35 40 45 Pro Gly Leu Pro λrg Ser Tyr Lys Pro Cyβ λsp Ser λsp λsp Gin λβp 50 55 60 Thr Phe Lys λsn λrg He Ser Leu λβn Hiβ Ser Pro Lys Lys Leu Pro 65 70 75 80 Lys Asp Phe His Glu Arg Ala Ser Gin Ser Lys Thr Gin Arg Val Val 85 90 95 Aβn Val Cys Gin Leu Tyr Phe Leu λsp Tyr Tyr Cys Asp Met Phe Aβp 100 105 110 Tyr Val He Ser Arg Arg Gin Arg Thr Lys Gin Val Leu λrg Tyr Leu 115 120 125 Glu Gin Gin λrg Ser Val Lys λsn Val Ser Asn Lys Val Leu Aβn Glu 130 135 140 Glu Trp Ala Leu Tyr Leu Gin Arg Glu Hiβ Glu Val Leu λrg Lye λrg 145 150 155 160 Arg Leu Lys Pro Lys His Lys Asp Phe Gin He Leu Thr Gin Val Gly 165 170 175 Gin Gly Gly Tyr Gly Gin Val Tyr Leu λla Lys Lys Lys λsp Ser λβp 180 185 190 Glu He Cys Ala Leu Lys He Leu Asn Lys Lys Leu Leu Phe Lys Leu 195 200 205 Asn Glu Thr Asn His Val Leu Thr Glu Arg Asp He Leu Thr Thr Thr 210 215 220 Arg Ser Asp Trp Leu Val Lys Leu Leu Tyr Ala Phe Gin Asp Pro Glu 225 230 235 240 Ser Leu Tyr Leu Ala Met Glu Phe Val Pro Gly Gly Asp Phe Arg Thr 245 250 255 Leu Leu He Asn Thr Arg He Leu Lys Ser Gly His Ala Arg Phe Tyr 260 265 270 He Ser Glu Met Phe Cyβ λla Val λβn λla Leu Hiβ Glu Leu Gly Tyr 275 280 285 Thr Hiβ λrg λsp Leu Lye Pro Glu λβn Phe Leu He λβp Ala Thr Gly 290 295 300 Hiβ He Lye Leu Thr Aβp Phe Gly Leu λla λla Gly Thr Val Ser λβn 305 310 315 320 Glu λrg He Glu Ser Met Lye He λrg Leu Glu Glu Val Lye λβn Leu 325 330 335 Gin Phe Pro λla Phe Thr Glu λrg Ser He Glu λβp λrg Ser Lye He 340 345 350 Tyr Hiβ λβn Met λrg Lye Thr Glu He Aβn Tyr Ala Asn Ser Met Val 355 360 365 Gly Ser Pro Aβp Tyr Met λla Leu Glu Val Leu Glu Gly Lye Lye Tyr 370 375 380 λβp Phe Thr Val λsp Tyr Trp Ser Leu Gly Cys Met Leu Phe Glu Ser 385 390 395 400 Leu Val Gly Tyr Thr Pro Phe Ser Gly Ser Ser Thr Asn Glu Thr Tyr 405 410 415 Glu Aβn Leu Arg Tyr Trp Lye Lye Thr Leu Arg λrg Pro λrg Thr Glu 420 425 430 λβp Arg Arg Ala Ala Phe Ser Aβp λrg Thr Trp λβp Leu He Thr λrg 435 440 445 Leu He λla λβp Pro He λβn λrg Val λrg Ser Phe Glu Gin Val λrg 450 455 460 Lye Met Ser Tyr Phe λla Glu He λβn Phe Glu Thr Leu λrg Thr Ser 465 470 475 480 Ser Pro Pro Phe He Pro Gin Leu λβp λβp Glu Thr λβp λla Gly Tyr 485 490 495 Phe λap λsp Phe Thr Asn Glu Glu Asp Met Ala Lys Tyr Ala Asp Val 500 505 510 Phe Lye Arg Gin λβn Lye Leu Ser λla Met Val λβp λβp Ser λla Val 515 520 525 Asp Ser Lys Leu Val Gly Phe Thr Phe Arg Hiβ Arg Aβp Gly Lys Gin 530 535 540 Gly Ser Ser Gly He Leu Tyr Asn Gly Ser Glu His Ser Asp Pro Phe 545 550 555 560 Ser Thr Phe Tyr (2) INFORMATION FOR SEQ ID NO: 16: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 561 amino acids (B) TYPE: amino acid (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:16: Met λla Gly λβn Met Ser Asn Leu Ser Phe Asp Gly Hiβ Gly Thr Pro 1 5 10 15 Gly Gly Thr Gly Leu Phe Pro Aβn Gin λβn He Thr Lye λrg λrg Thr 20 25 30 λrg Pro λla Gly He λβn λβp Ser Pro Ser Pro Val Lye Pro Ser Phe 35 40 45 Phe Pro Tyr Glu Asp Thr Ser Aβn Met Aβp He Aep Glu Val Ser Gin 50 55 60 Pro Aβp Met Aβp Val Ser Aβn Ser Pro Lye Lye Leu Pro Pro Lys Phe 65 70 75 80 Tyr Glu Arg Ala Thr Ser Aβn Lye Thr Gin Arg Val Val Ser Val Cyβ 85 90 95 Lye Met Tyr Phe Leu Glu Tyr Tyr Cyβ Aβp Met Phe λβp Tyr Val He 100 105 110 Ser λrg λrg Gin λrg Thr Lye Gin Val Leu Glu Tyr Leu Gin Gin Gin 115 120 125 Ser Gin Leu Pro λβn Ser λβp Gin He Lye Leu λβn Glu Glu Trp Ser 130 135 140 Ser Tyr Leu Gin λrg Glu Hiβ Gin Val Leu Arg Lys Arg Arg Leu Lys 145 150 155 160 Pro Lys Asn Arg Asp Phe Glu Met He Thr Gin Val Gly Gin Gly Gly 165 170 175 Tyr Gly Gin Val Tyr Leu Ala Arg Lys Lys Aβp Thr Lye Glu Val Cys 180 185 190 λla Leu Lys He Leu λsn Lye Lye Leu Leu Phe Lys Leu λsn Glu Thr 195 200 205 Lys His Val Leu Thr Glu Arg Asp He Leu Thr Thr Thr Arg Ser Glu 210 215 220 Trp Leu Val Lye Leu Leu Tyr Ala Phe Gin Glu Leu Gin Ser Leu Tyr 225 230 235 240 Leu λla Met Glu Phe Val Pro Gly Gly λβp Phe λrg Thr Leu Leu He 245 250 255 Asn Thr Arg Cys Leu Lys Ser Gly His Ala Arg Phe Tyr He Ser Glu 260 265 270 Met Phe Cys Ala Val Asn Ala Leu His λsp Leu Gly Tyr Thr His λrg 275 280 285 Asp Leu Lys Pro Glu Asn Phe Leu He Asp Ala Lys Gly His He Lys 290 295 300 Leu Thr Asp Phe Gly Leu Ala Ala Gly Thr He Ser Asn Glu Arg He 305 310 315 320 Glu Ser Met Lys He λrg Leu Glu Lys He Lys λsp Leu Glu Phe Pro 325 330 335 λla Phe Thr Glu Lys Ser He Glu λβp λrg λrg Lye Met Tyr λβn Gin 340 345 350 Leu λrg Glu Lys Glu He λsn Tyr λla λβn Ser Met Val Gly Ser Pro 355 360 365 λβp Tyr Met λla Leu Glu Val Leu Glu Gly Lye Lye Tyr λβp Phe Thr 370 375 380 Val λβp Tyr Trp Ser Leu Gly Cyβ Met Leu Phe Glu Ser Leu Val Gly 385 390 395 400 Tyr Thr Pro Phe Ser Gly Ser Ser Thr λβn Glu Thr Tyr λβp λβn Leu 405 410 415 λrg λrg Trp Lye Gin Thr Leu λrg λrg Pro λrg Gin Ser Aβp Gly Arg 420 425 430 Ala Ala Phe Ser Aβp λrg Thr Trp λβp Leu He Thr λrg Leu He λla 435 440 445 λβp Pro He Asn Arg Leu Arg Ser Phe Glu His Val Lys Arg Met Ser 450 455 460 Tyr Phe λla λsp He λsn Phe Ser Thr Leu λrg Ser Met He Pro Pro 465 470 475 480 Phe Thr Pro Gin Leu λsp Ser Glu Thr λsp λla Gly Tyr Phe λsp λsp 485 490 495 Phe Thr Ser Glu λla Asp Met Ala Lys Tyr Ala λsp Val Phe Lys λrg 500 505 510 Gin λsp Lys Leu Thr λla Met Val λβp λβp Ser λla Val Ser Ser Lye 515 520 525 Leu Val Gly Phe Thr Phe λrg Hiβ λrg λβn Gly Lye Gin Gly Ser Ser 530 535 540 Gly He Leu Phe λsn Gly Leu Glu His Ser λsp Pro Phe Ser Thr Phe 545 550 555 560 Tyr International Application No: PCT/ / MICROORGANISMS Optional Sheet in connection with the microorganism referred to on page 108. lines 1-20 of the description ' A. IDENTIFICATION OF DEPOSIT ' Further deposits are identified on an additional sheet Name of depositary institution ' American Type Culture Collection Address of depositary institution (including postal code and country) 12301 Par lawn Drive Rockville. MD 20852 US Date of deposit ' March 24, 1995 Accession Number " 69769 B. ADDITIONAL INDICATIONS ' (leave Mink if not applicable). This infoππaiion a continued on i separuc -inched sheet C. DESIGNATED STATES FOR WHICH INDICATIONS ARE MADE ' αi*. D. SEPARATE FURNISHING OF INDICATIONS * Oetv blank if not applicable) The indications listed below will be submitted to the International Bureau later ' (Specify the general nature of the indications e.g., "Accession Number of Deposit") E. E This sheet was received with che International application when filed (to be checked by the receiving Office) / " / , - Us " ; :./ : : .- ( I . ' 'I< t ( ' tιτ* * e (Authorized Officer) D The date of receipt (from the applicant) by the Intemauonal Bureau (Authorized Officer) Form PCT/RO/134 (January 1981 ) 151/1

Claims: WHAT IS CLAIMED IS; 1. A purified lats protein. 2. The protein of claim 1 which is a human protein. 3. The protein of claim 1 which is a D . melanogaεter protein. 4. The protein of claim 1 which is a mouse protein. 5. The protein of claim 1 which is a mammalian protein. 6. The protein of claim 2 which comprises the amino acid sequence substantially as set forth in SEQ ID NO:4. 7. A purified protein encoded by a nucleic acid hybridizable to the lats DNA sequence in plasmid PBS(KS) -h-lats as deposited with the ATCC and assigned accession number 69769. 8. A purified protein encoded by a nucleic acid hybridizable to a DNA having a sequence consisting of the coding region of SEQ ID NO:7. 9. The protein of claim 2 which is encoded by plasmid pBS(KS) -h-lats as deposited with the ATCC and assigned accession number 69769. 10. A purified derivative or analog of the protein of claim 1, which displays one or more functional activities of a lats protein. - 152 - 11. The derivative or analog of claim 10 which is able to be bound by an antibody directed against a lats protein. 12. A purified fragment of a lats protein comprising a domain of the lats protein selected from the group consisting of a lats C-terminal domain 3 (LCD3) , lats C-terminal domain 2 (LCD2) , lats C-terminal domain 1 (LCDl) , kinase domain, a kinase subdomain, lats flanking domain (LFD) , lats split domain 1 (LSDl) , lats split domain 2 (LSD2) , SH3-binding domain, and opa repeat domain. 13. A molecule comprising the fragment of claim 12. 14. A protein comprising an amino acid sequence that has at least 60% identity to a domain of a lats protein, in which the percentage identity is determined over an amino acid sequence of identical size to the domain. 15. A protein comprising an amino acid sequence that has at least 90% identity to a domain of a lats protein, in which the percentage identity is determined over an amino acid sequence of identical size to the domain. 16. The derivative or analog of claim 10, which inhibits proliferation of a cell. 17. A chimeric protein comprising a fragment of a lats protein consisting of at least 6 amino acids fused via a covalent bond to an amino acid sequence of a second protein, in which the second protein is not a lats protein. 18. The chimeric protein of claim 17 in which the fragment of a lats protein is a fragment capable of being bound by an anti-lats antibody. - 153 - 19. The fragment of claim 12 which additionally lacks one or more domains of the lats protein. 20. An antibody which is capable of binding a lats protein. 21. The antibody of claim 20 which is monoclonal. 22. A molecule comprising a fragment of the antibody of claim 21, which fragment is capable of binding a lats protein. 23. An isolated nucleic acid comprising a nucleotide sequence encoding a lats protein. 24. The nucleic acid of claim 23 which is a DNA. 25. An isolated nucleic acid comprising a nucleotide sequence complementary to the nucleotide sequence of claim 23. 26. The nucleic acid of claim 23 in which the lats protein is a human lats protein. 27. An isolated nucleic acid comprising the latε coding sequence contained in plasmid pBS(KS)-h-lats as deposited with the ATCC and assigned accession number 69769. 28. An isolated nucleic acid hybridizable to the lats DNA sequence in plasmid pBS(KS) -h-lats as deposited with the ATCC and assigned accession number 69769. 29. An isolated nucleic acid hybridizable to a DNA having a sequence consisting of the coding region of SEQ ID NO:7. - 154 - 30. An isolated nucleic acid comprising a fragment of a lats gene consisting of at least 8 nucleotides. 31. An isolated nucleic acid comprising a nucleotide sequence encoding a fragment of a lats protein that displays one or more functional activities of the lats protein. 32. An isolated nucleic acid comprising a nucleotide sequence encoding the chimeric protein of claim 17. 33. An isolated nucleic acid comprising a nucleotide sequence encoding a protein, said protein comprising the amino acid sequence of SEQ ID NO:4. 34. An isolated nucleic acid comprising a nucleotide sequence encoding the fragment of claim 12. 35. An isolated nucleic acid comprising a nucleotide sequence encoding the protein of claim 14. 36. A recombinant cell containing the nucleic acid of claim 23, in which the nucleotide sequence encoding the lats protein is under the control of a promoter that is not a native latε gene promoter. 37. A recombinant cell containing a nucleic acid vector comprising the nucleic acid of claim 26. 38. A recombinant cell containing the nucleic acid of claim 34. 39. A recombinant cell containing the nucleic acid of claim 35. - 155 - 40. A method of producing a lats protein comprising growing a recombinant cell containing the nucleic acid of claim 23, in which the nucleotide sequence encoding the lats protein is under the control of a promoter that is not a native lats gene promoter, such that the encoded lats protein is expressed by the cell, and recovering the expressed lats protein. 41. A method of producing a lats protein comprising growing a recombinant cell containing a nucleic acid vector comprising the nucleic acid of claim 26 such that the encoded lats protein is expressed by the cell, and recovering the expressed lats protein. 42. A method of producing a lats fragment comprising growing a recombinant cell containing the nucleic acid of claim 34 such that the encoded lats fragment is expressed by the cell, and recovering the expressed lats fragment. 43. A method of producing a protein comprising a fragment of a lats protein, which method comprises growing a recombinant cell containing the nucleic acid of claim 35 such that the encoded protein is expressed by the cell, and recovering the expressed protein. 44. The product of the process of claim 40. 45. The product of the process of claim 41. 46. The product of the process of claim 42. 47. The product of the process of claim 43. 48. A pharmaceutical composition comprising a therapeutically effective amount of a lats protein; and a pharmaceutically acceptable carrier. - 156 - 49. The composition of claim 48 in which the lats protein is a human lats protein. 50. A pharmaceutical composition comprising a therapeutically effective amount of the fragment of claim 12; and a pharmaceutically acceptable carrier. 51. A pharmaceutical composition comprising a therapeutically effective amount of the protein of claim 14; and a pharmaceutically acceptable carrier. 52. A pharmaceutical composition comprising a therapeutically effective amount of the chimeric protein of claim 17; and a pharmaceutically acceptable carrier. 53. A pharmaceutical composition comprising a therapeutically effective amount of the nucleic acid of claim 23; and a pharmaceutically acceptable carrier. 54. A pharmaceutical composition comprising a therapeutically effective amount of the nucleic acid of claim 35; and a pharmaceutically acceptable carrier. 55. A pharmaceutical composition comprising a therapeutically effective amount of the recombinant cell of claim 36; and a pharmaceutically acceptable carrier. 56. A pharmaceutical composition comprising a therapeutically effective amount of an antibody that immunospecifically binds to a lats protein; and a pharmaceutically acceptable carrier. 57. A pharmaceutical composition comprising a therapeutically effective amount of a fragment or derivative of an antibody that immunospecifically binds to a lats protein, said fragment or derivative containing the binding - 157 - domain of the antibody; and a pharmaceutically acceptable carrier. 58. A method of treating or preventing a disease or disorder involving cell overproliferation in a subject comprising administering to a subject in which such treatment or prevention is desired a therapeutically effective amount of a molecule that promotes lats function. 59. The method according to claim 58 in which the disease or disorder is a malignancy. 60. The method according to claim 59 in which the disease or disorder is selected from the group consisting of bladder cancer, breast cancer, colon cancer, leukemia, lung cancer, melanoma, pancreatic cancer, sarcoma, and uterine cancer. 61. The method according to claim 58 in which the subject is a human. 62. The method according to claim 58 in which the disease or disorder is selected from the group consisting of premalignant conditions, benign tumors, hyperproliferative disorders, and benign dysproliferative disorders. 63. The method according to claim 58 in which the molecule that promotes lats function is selected from the group consisting of a lats protein, a lats derivative or analog that is active in inhibiting cell proliferation, a nucleic acid encoding a lats protein, and a nucleic acid encoding a lats derivative or analog that is active in inhibiting cell proliferation. 64. The method according to claim 58 in which the molecule that promotes lats function is a lats derivative or 158 - analog that comprises a kinase domain of a lats protein that has been mutated so as to be dominantly active. 65. The method according to claim 58 in which the molecule that promotes lats function is the protein of claim 14. 66. A method of treating or preventing a disease or disorder involving a deficiency in cell proliferation or in which cell proliferation is desirable for treatment or prevention in a subject comprising administering to a subject in which such treatment or prevention is desired a therapeutically effective amount of a molecule that inhibits lats function. 67. The method according to claim 66 in which the molecule that inhibits lats function is selected from the group consisting of an anti-lats antibody or a fragment or derivative thereof containing the binding region thereof, a lats derivative or analog that is capable of being bound by an anti-lats antibody and that is a dominant-negative protein kinase, a lats antisense nucleic acid, and a nucleic acid comprising at least a portion of a lats gene into which a heterologous nucleotide sequence has been inserted such that said heterologous sequence inactivates the biological activity of the at least a portion of the lats gene, in which the lats gene portion flanks the heterologous sequence so as to promote homologous recombination with a genomic lats gene. 68. The method according to claim 66 in which the molecule that inhibits lats function is an oligonucleotide which (a) consists of at least six nucleotides; (b) comprises a sequence complementary to at least a portion of an RNA transcript of a lats gene; and (c) is hybridizable to the RNA transcript under moderately stringent conditions. - 159 - 69. The method according to claim 66 in which the disease or disorder is selected from the group consisting of degenerative disorders, growth deficiencies, hypoproliferative disorders, physical trauma, lesions, and wounds. 70. An isolated oligonucleotide consisting of at least six nucleotides, and comprising a sequence complementary to at least a portion of an RNA transcript of a lats gene, which oligonucleotide is hybridizable to the RNA transcript under moderately stringent conditions. 71. A pharmaceutical composition comprising the oligonucleotide of claim 70; and a pharmaceutically acceptable carrier. 72. A method of inhibiting the expression of a nucleic acid sequence encoding a lats protein in a cell comprising providing the cell with an effective amount of the oligonucleotide of claim 70. 73. A method of diagnosing a disease or disorder characterized by an aberrant level of lats RNA or protein in a subject, comprising measuring the level of lats RNA or protein in a sample derived from the subject, in which an increase or decrease in the level of lats RNA or protein, relative to the level of lats RNA or protein found in an analogous sample not having the disease or disorder indicates the presence of the disease or disorder in the subject. 74. A method of diagnosing or screening for the presence of or a predisposition for developing a disease or disorder involving cell overproliferation in a subject comprising measuring the level of lats protein, lats RNA or lats functional activity in a sample derived from the subject, in which a decrease in the level of lats protein, - 160 - lats RNA, or lats functional activity in the sample, relative to the level of lats protein, lats RNA, or lats functional activity found in an analogous sample not having the disease or disorder or a predisposition for developing the disease or disorder, indicates the presence of the disease or disorder or a predisposition for developing the disease or disorder. 75. A method of diagnosing or screening for the presence of or a predisposition for developing a disease or disorder involving cell overproliferation in a subject comprising detecting one or more mutations in lats DNA, RNA or protein derived from the subject in which the presence of said one or more mutations indicates the presence of the disease or disorder or a predisposition for developing the disease or disorder. 76. A method of diagnosing or screening for the presence of or a predisposition for developing a disease or disorder involving a deficiency in cell proliferation or in which cell proliferation is desirable for treatment or prevention in a subject comprising measuring the level of lats protein, lats RNA or lats functional activity in a sample derived from the subject, in which an increase in the level of lats protein, lats RNA, or lats functional activity in the sample, relative to the level of lats protein, lats RNA, or lats functional activity found in an analogous sample not having the disease or disorder or a predisposition for developing the disease or disorder, indicates the presence of the disease or disorder or a predisposition for developing the disease or disorder. 77. A kit comprising in one or more containers a molecule selected from the group consisting of an anti-lats antibody, a nucleic acid probe capable of hybridizing to a latε RNA, or a pair of nucleic acid primers capable of priming amplification of at least a portion of a latε nucleic acid. - 161 - 78. A kit comprising in a container a therapeutically effective amount of a lats protein. 79. A method of increasing cell growth in animals or plants comprising inhibiting lats expression or activity in said animals or plants. 80. The method of claim 79 in which cell growth is increased in an edible plant. 81. The method of claim 79 in which cell growth is increased in a farm animal. 82. A method of identifying a molecule that specifically binds to a ligand selected from the group consisting of a lats protein, a fragment of a lats protein comprising a domain of the protein, and a nucleic acid encoding the protein or fragment, comprising (a) contacting said ligand with a plurality of molecules under conditions conducive to binding between said ligand and the molecules; and (b) identifying a molecule within said plurality that specifically binds to said ligand. 83. A recombinant non-human animal or plant that is the product of a process comprising introducing a nucleic acid encoding at least a domain of a lats protein into the plant or animal. 84. A recombinant plant containing and capable of expressing a latε antisense nucleic acid. 85. A recombinant non-human animal or plant in which a latε gene has been inactivated by a method comprising introducing a nucleic acid into the plant or animal or an ancestor thereof, which nucleic acid comprises a non-lats - 162 - sequence flanked by latε genomic sequences that promote homologous recombination. 86. A method of identifying a tumor suppressor gene comprising (a) identifying an overproliferation phenotype in a genetic mosaic; and (b) isolating a gene that is mutated in cells exhibiting said overproliferation phenotype. 87. The method of claim 86 in which the genetic mosaic is an animal containing (a) a nucleic acid encoding and capable of expressing a recombinase, and (b) intrachromosomal insertions of a target site at which the recombinase promotes recombination, on the homologous arms of both of a set of parental chromosomes; and the genetic mosaic has been produced by a method comprising inducing expression of the recombinase. 88. The method of claim 87 in which the recombinase is an FLP recombinase, and the target site is an FRT site. 89. The method according to claim 87 in which the recombinase is a Cre recombinase, and the target site is a lox site. 90. The method of claim 86 in which the overproliferation phenotype is the formation of overproliferated outgrowth tissue. 91. The method of claim 86 in which the overproliferation phenotype is the formation of a normal structure of larger than normal size. 92. A non-human mammal comprising (a) a nucleic acid sequence encoding a recombinase operably linked to a promoter; and (b) intrachromosomal insertions into the - 163 - homologous arms of both of a set of parental chromosomes, of a target site at which the recombinase can promote recombination. 93. The mammal of claim 92 which is heterozygous for an induced mutation. 94. The mammal of claim 93 in which the sequence encoding the recombinase is operably linked to an inducible promoter. 95. A method of making a genetic mosaic comprising inducing expression of the recombinase in the mammal of claim 93. 96. A method for identifying a gene with an identifiable mutant phenotype comprising: (a) identifying a mutant phenotype in a genetic mosaic animal, said genetic mosaic animal having been produced by a method comprising recombinantly expressing a recombinase within a cell of the animal so as to promote recombination at intrachromosomally inserted target sites on the homologous arms of both of a set of parental chromosomes; and (b) isolating a gene that is mutated in cells exhibiting said mutant phenotype. 97. A method for identifying a gene with an identifiable mutant phenotype comprising: (a) identifying a mutant phenotype in a cultured cell, said cultured cell having been produced by a method comprising recombinantly expressing a recombinase within said cultured cell so as to promote recombination at intrachromosomally inserted target sites on - 164 - the homologous arms of both of a set of parental chromosomes; and (b) isolating a gene that is mutated in cells exhibiting said mutant phenotype. 98. The method of claim 97 in which the mutant phenotype is a transformed phenotype. 99. The mammal of claim 92 in which the promoter is not a native recombinase gene promoter. 100. A method of inhibiting cellular senescence in a subject comprising administering to a subject in which such inhibition is desired an amount of a molecule that inhibits lats function, effective to inhibit cellular senescence. 101. A method of inhibiting cellular senescence in cells in vitro comprising contacting cells in vitro with an amount of a molecule that inhibits lats function, effective to inhibit cellular senescence. 102. The method according to claim 100 in which the molecule that inhibits lats function is selected from the group consisting of an anti-lats antibody or a fragment or derivative thereof containing the binding region thereof, a lats derivative or analog that is capable of being bound by an anti-lats antibody and that is a dominant-negative protein kinase, a latε antisense nucleic acid, and a nucleic acid comprising at least a portion of a lats gene into which a heterologous nucleotide sequence has been inserted such that said heterologous sequence inactivates the biological activity of the at least a portion of the lats gene, in which the latε gene portion flanks the heterologous sequence so as to promote homologous recombination with a genomic lats gene. 103. The method according to claim 101 in which the molecule that inhibits lats function is selected from the - 165 - group consisting of an anti-lats antibody or a fragment cr derivative thereof containing the binding region thereo: a lats derivative or analog that is capable of being bounc ry an anti-lats antibody and that is a dominant-negative pr::ein kinase, a lats antisense nucleic acid, and a nucleic ac. comprising at least a portion of a lats gene into which heterologous nucleotide sequence has been inserted sue; :t said heterologous sequence inactivates the biological activity of the at least a portion of the latε gene, ιr ^ch the latε gene portion flanks the heterologous sequence ∑ .s to promote homologous recombination with a genomic l a t. ne. BAD ORIGINAL - 166 -

Inventors: TAO WUFAN, WANG WEIYI, XU TIAN, YU WAN, ZHANG SHENG, TAO, WUFAN, WANG, WEIYI, XU, TIAN, YU, WAN, ZHANG, SHENG
Applicants: TAO WUFAN, UNIV YALE, WANG WEIYI, XU TIAN, YU WAN, ZHANG SHENG, TAO, WUFAN, WANG, WEIYI, XU, TIAN, YALE UNIVERSITY, YU, WAN, ZHANG, SHENG
Application year: 1996
Main classification: C07K11
IPC codes: A61K38, A61K48, C07K14, C12N9, C12N15, C12P21