NOVEL G-PROTEIN MODULATOR (GPM) PROTEINS AND NUCLEIC ACID MOLECULES AND USES THEREFOR

Abstract: Novel G protein modulator (GPM) polypeptides, proteins, and nucleic acid molecules are disclosed, which stimulate G protein activity in a receptor-independent manner. In addition to isolated, full-length GPM proteins, the invention further provides isolated GPM fusion proteins, antigenic peptides and anti-GPM antibodies. The invention also provides GPM nucleic acid molecules, recombinant expression vectors containing a nucleic acid molecule of the invention, host cells into which the expression vectors have been introduced and non-human transgenic animals in which a GPM gene has been introduced or disrupted. Diagnostic, screening and therapeutic methods utilizing compositions of the invention are also provided.

Description: NOVEL G-PROTEIN MODULATOR (GPM) PROTEINS AND NUCLEIC ACID MOLECULES AND USES THEREFOR Cross Reference to Related Applications This application claims the benefit of U.S. Provisional Application No. 60/084,841, filed May 8, 1998, which is hereby incorporated herein by reference in its entirety. Background of the Invention A number of diverse signaling mechanisms within the cell utilize guanine nucleotide binding proteins ("G proteins") as a molecular switch to propagate and amplify the biological signal. Key components of this molecular switch are the exchange of GDP for GTP and the GTPase activity inherent in the nucleotide binding protein. Membrane receptors, G protein-coupled receptors, sensing external stimuli activate heterotrimeric G (Gαβγ) by facilitating nucleotide exchange and subsequent dissociation of Gβγ from Gα. Several lines of evidence suggest the existence of proteins in addition to G proteins and G protein-coupled receptors that play a role in the regulation G protein- mediated signal transduction. A first line of evidence is the fact that a single G protein coupled receptor can couple to multiple effectors. For example, the α 2A -AR, a typical G protein coupled receptor, may regulate phospholipases A 2 , C and D. calcium flux, Na+/H+ exchangers, p21-ras or adenylyl cyclases. Marjamaki et.al. (1997) J. Biol Chem. 272:16466-16473. The specific regulation of any of these effector molecules often depends upon receptor subtype, receptor density and the environment in which the receptor is operating. The variable efficiency/specificity of coupling observed for a specific receptor in different cells suggests that there are additional unidentified, cell- specific proteins/lipids that contribute to the signaling process. Sato et.al. (1995) J Biol. Chem. 270:15269-15276. For example, the efficiency of G-protein activation by a specific receptor and the influence of guanine nucleotides on receptor-G-protein interactions varies among cell types. Nanoff et.al. (1995) Mol. Pharmacol. 48:806-817; and Duzic and Lanier (1992) J. Biol. Chem. 267:24045-24052. Nanoff et.al. have partially purified a protein ("coupling cofactor") from brain tissue that is suggested to trap the ternary complex and impede further signal propagation. Nanoff et.al. (1995), Mol. Pharmacol. 48:806-817. Using a "signal reconstitution system" Sate et.al. demonstrated that cell-specific differences in the transfer of signal from a_specifιc receptor to G-protein was independent of G-protein type or amount. Sato et.al. (1995) J Biol. Chem. 270:15269-15276. A second line of evidence incorporates several observations suggesting that the exchange of GDP for GTP.and/or subsequent GTP hydrolysis are regulated by accessory proteins. For example, the kinetics of signal termination for many physiological responses if faster than the rate of GTP hydrolysis of purified Gα subunits. A third line of evidence relates to the transfer of signal from receptor to G- protein in a reconstituted system. G-protein activation occurs with homogenous preparations of receptor and G-protein following reconstitution in phospholipid vesicles suggesting that initiation of the cellular response to a biological stimuli involves only receptor and G-protein. However, the efficiency with which the receptor mediates the agonist-induced activation of G-protein and subsequent effector regulation/signal termination is often dramatically less when the purified entities are reconstituted in phospholipid vesicles as compared to what is observed or expected to occur in the intact cell or membrane preparations. Such a discrepancy may reflect technical issues associated with reconstitution studies or the absence of other cellular factors required for driving these events. A fourth line of evidence relates to the ability of nonreceptor proteins/peptides to associate with and regulate the activation state of specific G-proteins. Sato et.al. (1996) J. Biol. Chem. 271 :30052-30060. Overall, these observations indicate the existence of accessory proteins that influence events at the receptor/G-protein or G-protein/effector interface and regulate the key steps of nucleotide exchange and/or GTP hydrolysis. In fact, recent observations in cells transfected with genes encoding components of the signaling cascade or in unperturbed signaling systems endogenous to the cell suggest the existence of cellular factors that augment, direct or brake the transfer of signal from receptor to G-protein. Sato et.al. (1995) J. Biol. Chem. 270:15269-15276; Nanoff et.al. (1995) Mol. Pharmacol. 48:806-817; Koelle and Horvitz (1996) Cell 84:115-125; De Vries et.al. (1995) Proc. Natl. Acad. Sci. 92:11916-11920; Druey et.al. (1996) Nature 379:742-746. Such a thought is given further impetus by the identification of proteins and chemical compounds that directly activate or inhibit G-proteins. Sato et.al. (1996) J. Biol. Chem. 271 :30052-30060. Recently, the existence of a cell-specific factor(s) that regulate the transfer of signal from receptor to G-protein and/or stimulate [ S]GTPγS binding to G-protein independent of receptor activation was demonstrated. Sato et.al. (1996) J. Biol. Chem. 271 :30052-30060. Subsequent efforts involved the biochemical characterization of such a factor in the neuroblastoma glioma hybrid celljine NG108-15, its relationship to other known regulators of G-protein function and the analysis of its functionality. Despite the implication, however, that accessory proteins play an important role in G-protein mediated signal transduction, molecular isolation and characterization of such proteins is still needed. Summary of the Invention This invention provides isolated proteins, and isolated nucleic acid molecules that encode these proteins, that function as modulatory molecules in G protein mediated signal transduction. In particular, the proteins of the invention, referred to herein as G Protein Modulator (GPM) proteins, were identified based on their ability to stimulate signal transduction through the yeast pheromone pathway (mediated by G protein signaling) in a manner independent of G protein-coupled receptor expression. Thus, the GPM proteins of the invention are capable of stimulating G protein activity in a receptor independent manner. In one embodiment, an isolated nucleic acid molecule of the present invention has a nucleotide sequence encoding a G protein modulator (GPM) protein (e.g., a nucleotide sequence selected form the group consisting of SEQ ID NO:l , SEQ ID NO:4 and SEQ ID NO:6). The invention also provides for vectors including nucleotide sequences which encode a GPM, as well as host cells including such vectors. Methods for producing GPM proteins comprising culturing such host cell are also provided by the present invention. In another embodiment, an isolated protein of the present invention is a G protein modulator (GPM) protein (e.g. , a GPM protein having the amino acid sequence of SEQ ID NO:2, SEQ ID NO:3 or SEQ ID NO:5). The invention also provides for pharmaceutical compositions including GPM proteins, fusion proteins including all or a portion of the GPM proteins or the present invention, antibodies that specifically bind GPM proteins (e.g., monoclonal or polyclonal antibodies) as well as pharmaceutical compositions including such antibodies. The present invention also provides methods for identifying a compounds that modulate cellular signal transduction. In one embodiment, a method comprises the steps of (a) contacting a cell that expresses a G protein modulator (GPM) protein with a test compound; (b) determining the effect of the test compound on the activity of the GPM protein; and (c) identifying the test compound as a modulator of signal transduction based on the ability of the compound to modulate the activity of the GPM protein in the cell. In a preferred embodiment, the GPM proteins utilized have an amino acid sequence at least 75% homologous to SEQ ID NO:2 or SEQ ID NO:5. In another preferred embodiment, the GPM proteins utilized have an amino acid sequence at least 75% homologous to SEQ \D NO:2 or SEQ ID NO:5 and comprises at least one tetratricopeptide repeat ("TPR") motif. In another preferred embodiment, the GPM proteins utilized have an amino acid sequence at least 75% homologous to SEQ ID NO:2 or SEQ ID NO:5 and comprises at least one G protein regulatory motif (also referred to herein as a "DDQR" repeat motif or "DDQR" motif. In yet another preferred embodiment, the GPM proteins utilized have an amino acid sequence at least 75% homologous to SEQ ID NO:2 or SEQ ID NO:5, comprises at least one G protein regulatory motif (e.g., a motif having the amino acid sequence of SEQ ID NO:8) and stimulate G protein activity in a receptor-independent manner. In another embodiment, cells used in assay methods of the present invention have been engineered to express a GPM (e.g., a GPM protein having the amino acid sequence of SEQ ID NO:2, SEQ ID NO:3 or SEQ ID NO:5). Preferred cells for use in the assay are yeast cells. In another embodiment, the yeast cells have further been engineered to express a G protein α subunit, a chimeric G protein α subunit, or a Gpal- Gαi2 chimeric G protein α subunit. The activity of a test compound on a GPM of the present invention can be monitored, for example, by measuring the activity of a pheromone responsive promoter in the yeast cells. Alternatively, the activity of a test compound on a GPM can be determined by monitoring the ability of the test compound to bind to the GPM protein or by monitoring the ability of the test compound to modulate the interaction of the GPM protein with a target molecule (e.g., a G protein). The present invention further provides methods for modulating a cell-associated activity (e.g., by contacting a cell with an agent which modulates GPM protein activity or GPM nucleic acid expression). Furthermore, methods for treating subjects having a disorder characterized by aberrant GPM protein activity or nucleic acid expression are provided, as well as methods for detecting the presence of GPM in a biological sample. Brief Description of the Drawing Figure 1 depicts the nucleotide sequence of a GPM II cDNA isolated from the neuroblastoma glioma hybrid cell line NG-108 (SEQ ID NO:l) as well as the predicted amino acid sequences of four peptides (SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, and SEQ ID NO: 13) encoded by the GPM II cDNA. Figure 2 depicts the nucleotide sequence of a GPM II cDNA isolated from a rat brain cDNA library (SEQ ID NO:5) as well as the predicted amino acid sequence amino acid sequence (SEQ ID NO:6). Figure 3 depicts the nucleotide sequence of a GPM I cDNA isolated from the neuroblastoma glioma hybrid cell line NG-108 (SEQ ID NO:7) as well as the predicted amino acid sequence amino acid sequence (SEQ ID NO:8). Figure 4 demonstrates the structural analysis of GPM II. Figure 4 A depicts an alignment of the GPM II amino acid sequence with the human LGN protein (having Accession No.U54999) and the C. elegans protein (having Accession No.U40409) by PILEUP (University of Wisconsin GCG program). Amino acid sequence similarity and identity are indicated below the three sequences by + or residue, respectively. The TPR and DDQR repeat motifs are indicated by shaded and underlined sequences, respectively. TPR refers to the tetratricopeptide repeat motif. Figure 4B depicts the four DDQR repeat domains in the carboxyl terminus half of GPM II, human LGN, the predicted C. elegans protein and related sequences identified by the motif search program MEME. Figure 5 demonstrates the bioactivity of full-length versus truncated GPM II. Figure 5 A depicts a spot growth assay of yeast strain transformed with control plasmid, truncated GPM II (also referred to herein as Activator of G protein Signaling 3 or "AGS3"), or full-length GPM-II/AGS3. Figure 5B depicts an immunoprecipitation of GPM II/AGS3 protein from transformed yeast strains Figure 6 demonstrates the interaction of AGS proteins with G-protein subunits and the relationship of AGS bioactivity to nucleotide binding properties of the Gα subunit. Figure 6A depicts binding of full length GPM I (also referred to herein as "AGS2") and a 74 amino acid peptide beginning at the first in frame MET of frame 1 in the NG108-15 cDNA clone #53 [AGS3 (M577-S650)] to various G-protein subunits (60-80 nM Gα or 40 nM Gβγ). Proteins are adsorbed to glutathione matrix and retained G-protein subunits identified by immunoblotting following gel electrophoresis. Figure 6B depicts the effect of GPM proteins on nucleotide binding to purified brain G-protein. Figure 6C depicts the effect of G204A Giα2 substitution and RGS4 on the functionality of GPM proteins as determined by spot growth assays. Detailed Description of the Invention The present invention is based on the discovery of nucleic acid and protein molecules, referred to herein as G-protein Modulator ("GPM") nucleic acid and protein molecules, which play a role in or function in G protein-mediated signal transduction in the absence of receptor stimulation. In one embodiment, the GPM molecules stimulate the activity of one or more G proteins involved in a G protein-mediated signal transduction pathway, e.g., a pheromone response cascade in yeast, to thereby activate G protein-mediated signal transduction independent of G protein-coupled receptor stimulation. In a preferred embodiment, the GPM molecules of the present invention stimulate the activity of one or more G proteins involved in a G protein-mediated signal transduction pathway, such that G protein coupled receptor-mediated signal transduction is amplified. In a particularly preferred embodiment, the GPM molecules are capable of modulating the activity of Gα subunits, such as a yeast Gpal protein, a mammalian Gαi2 subunit, or a chimeric Gα subunit comprising a portion of the yeast Gpal protein (e.g., the amino-terminal 41 amino acids) linked to a mammalian Gαi2 subunit. According to the present invention, a GPM protein can include one or more tetratricopeptide repeat ("TPR) motifs. As used herein, a TPR motif is an amino acid motif within a protein which comprises an amino acid sequence having a length of about 5-50 amino acid residues, preferably about 10-45, more preferably about 15-35, and more preferably about 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33 or 34 amino acid residues that has at least 50% amino acid homology, preferably about 60-70%, more preferably about 70-80%, and more preferably about 80-90% amino acid homology with a second TPR motif within the same protein which is separated by about 30-1 10 amino acid residues, preferably about 40-100 amino acid residues. Alternatively, a first TPR motif can be separated form a second TPR motif within the same protein by about 60, 70, 80 or 90 amino acid residues. In a preferred embodiment, a TPR motif includes a highly degenerate motif of about 34 ammo acid residues. TPR motifs have been found in as many as 400 proteins and can be present in 3-16 copies per protein (alternatively 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14 or 15 copies per protein) as described, for example, in Chen and Cohen (1997) FEBS Letters 400:136-140; Das et αl. (1998) EMBO J. 17:1 192-1 199 (1998); and Ramarao and Cohen (1998) Proc. Nαtl. Acαd. Sci., USA 95:4007-4012. Particularly preferred TPR motifs can be identified using SMART analysis and are set forth in Figure 4 as they occur in GPM II (AGS3) and human LGN (having Accession No. U54999). Also according to the present invention, a GPM protein can include one or more G protein regulatory ("GPR") motifs, also referred to herein as "DDRQ repeat" motifs or "DDRQ" motifs. As used herein, a GPR motif is an amino acid motif within a protein which comprises an amino acid sequence having a length of about 5-35 amino acid residues, preferably about 10-30, more preferably about 15-25, and more_χjreferably about 17, 18, 19, 20, 21, 22 or 23 amino acid residues that has at least 50% amino acid homology, preferably about 60-70%, more preferably about 70-80%, and more preferably about 80-90% amino acid homology with a second GPR motif within the same protein. Alignment of multiple GPR motifs reveals the GPR majority profile, R-PS P- EEFFDL-K-QSSRMDD QRCPL— P- -AT (SEQ ID NO:9). A generalized GPR consensus sequence can be written as follows: [DE]-XFFX-[LIVM](2)-X(3)-Q-X(2)-R- [LIVM][D/E](2)-QR (SEQ ID NO: 10), wherein X(3) indicates any amino acid residue (n=3); [LIVM] indicates any one of L, I, V, or M. The key features of this stretch of amino acids may be represented by the GPR core majority profile EEFF-X(10-12)- DDQR (SEQ ID NO: 11 ). A generalized GPR core consensus sequence can be written as follows: [DE](2)FF X(10-12)-D[DE]QR (SEQ ID NO:12), wherein X(10-12) indicates any amino acid residue (n=10, 1 1 , or 12); [DE] indicates either of D or E. In another embodiment, a GPR core consensus sequence has the sequence [DE]EX[FL]F[DE][LM][LI]X[RK]XQ[SG]XR[ML]DDQR. Amino acid sequences having all or a majority of the amino acids of the consensus sequences defined herein may be recognized as potentially having a specified motif. For example, an amino acid sequence having all but one amino acid residue of a consensus sequence may be recognized by one of skill in the art as potentially having such a motif. Likewise, an amino acid sequence having all but two amino acid residues of a consensus sequence may be recognized by one of skill in the art as potentially having such a motif. Accordingly, in a preferred embodiment, a GPR motif has the core consensus sequence, [DE](2)FF X(10-12)-D[DE]QR (SEQ ID NO:12). In a more preferred embodiment, a GPR motif has the core majority profile EEFF-X(10-12)-DDQR (SEQ ID NO: 1 1). In an even more preferred embodiment, a GPR motif has the consensus sequence [DE]-XFFX-[LIVM](2)-X(3)-Q-X(2)-R-[LIVM][D/E](2)-QR (SEQ ID NO: 10). In an even more preferred embodiment, a GPR motif has the majority profile R-PS— -P- EEFFDL-K-QSSRMDD QRCPL— P- --AT (SEQ ID NO:9). It is suggested that the above defined consensus sequence(s) arranged in repeats with a defined spatial relationship constitute a structural feature found at the carboxy terminus of a novel family of proteins that interact with G-proteins and regulate nucleotide exchange/GTP hydrolysis or the interaction of the G-protein with other entities involved in signal transduction. In another embodiment, a GPM protein includes at least one G protein regulator ("GPR") motif wherein the GPR motif has at least 50% amino acid homology, preferably about 60-70%, more preferably about 70-80%, and more preferably about 80- 90% amino acid homology with a GPR motif consensus sequence (e.g.. the consensus sequence of SEQ ID NO:9, SEQ ID NO: 10, or SEQ ID NO:l 1). In yet another embodiment, a GPM protein includes at least one G protein regulatory ("GPR") motif wherein the GPR motif has at least 50% amino acid homology, preferably about 60- 70%, more preferably about 70-80%, and more preferably about 80-90% amino acid homology with a GPR motif of GPM II, as described below. A particularly preferred G protein modulator protein, GPM II, is depicted in Figure 1. Figure 1 depicts the nucleotide sequence of a GPM II cDNA which was isolated from the neuroblastoma glioma hybrid cell line NG-108. The predicted amino acid sequences of three peptides encoded by the GPM II cDNA are also depicted in Figure 1. A first open reading frame can be found beginning with the first nucleotide of SEQ ID NO: l and ending with the stop codon, TAA at nucleotides 253-255 of SEQ ID NO:l . Accordingly, in one embodiment, a GPM II protein is encoded by a nucleic acid sequence comprising nucleotides 1-252 of SEQ ID NO:l ("coding region") and comprises amino acids 1 to 84 of SEQ ID NO:2. This peptide (Frame 1, Peptide A of Figure 1) comprises at least two GPRs at about amino acids 6-25 and from about 40-59 of SEQ ID NO:2. In another embodiment, a GPM II protein (Frame 1, Peptide B of Figure 1) is encoded by a nucleic acid sequence comprising nucleotides 31-252 of SEQ ID NO:l ("coding region") and comprises amino acids 1 to 74 of SEQ ID NO:3. This peptide comprises at least one GPR at about amino acids 30-49 of SEQ ID NO:3. A second open reading frame can be found beginning with the second nucleotide of SEQ ID NO:l and ending with the stop codon, TGA at nucleotides 359-361 of SEQ ID NO: l . Accordingly, in another embodiment, a GPM II protein is encoded by a nucleic acid sequence comprising nucleotides 2-358 of SEQ ID NO:l ("coding region") and comprises amino acids 1 to 1 19 of SEQ ID NO:4. In yet another embodiment, a GPM II protein is encoded by a nucleic acid sequence comprising nucleotides 17-358 of SEQ ID NO: 1 and comprises amino acids 1 to 1 14 of SEQ ID NO: 13. Figure 2 depicts the nucleotide sequence of a second GPM II cDNA which was isolated from a rat brain cDNA library. The cDNA encodes a predicted protein which is at least 590 amino acid residues in length and contains at least four GPR motifs at about amino acids 469-490, 524-544, 572-591, and 606-625 of SEQ ID NO:6. In another embodiment, the cDNA encodes a predicted protein which contains at least four GPR motifs at about amino acids 465-492, 519-544, 570-592, and 604-627 of SEQ ID NO:6. Using Northern analysis, GPM II has been found to be expressed in mRNA isolated from rat brain, rat vascular smooth muscle cells, the NG108-15 cell line and the C6 -B4 glioma cell line but not in rat liver. As GPM proteins, e.g., GPMJ.L are involved in activation of the pheromone response cascade in yeast cells, and potentially modulate the MEK pathway in mammalian cells, the GPM molecules of the present invention can be used in methods for identifying antagonists of G protein signaling, either receptor-dependent or receptor independent. The GPM II nuclejc acid molecule of SEQ ID NO:l was identified from an NG108-15 cDNA expression library based on its ability to stimulate G protein signaling in yeast in the absence of a G protein-coupled receptor, as determined using a high throughput library screening method for non-receptor activators of the pheromone response cascade (described in detail in Examples 1 and 2). A GenBank™ search using the GPM nucleotide sequence of SEQ ID NO:l revealed two EST clones, both of murine origin, which were similar to different regions of the nucleotide sequence of SEQ ID NO:l . The mouse EST, va71fl0.rl (Accession Number AA271904), is identical to a portion (from about nucleotides 971 to 1397) of the 3' untranslated sequence of SEQ ID NO: l . The mouse EST, mi70b09.rl (Accession Number AA036169), is identical to a portion (from about nucleotides 853 to 1358) of the 3' untranslated sequence of SEQ ID NO: 1. As no reading frame can be determined from an EST (such as the EST identified in the above database searches), an amino acid sequence encoded by the EST cannot be determined. The GenBank™ search using the GPM nucleotide sequence of SEQ ID NO: l also revealed a murine partial cDNA referred to as mouse C10A (Accession Number L23316). The first 333 nucleotides of the GPM II cDNA exhibit significant homology (one nucleotide difference) to the 3'end of the mouse C10A cDNA. GenPept™ and SwissProt™ database searches of the GPM II amino acid sequence of SEQ ID NO:2 indicated significant homology (one amino acid difference) to the peptide sequence encoded by L23316. Further database searches of the GPM II amino acid sequence of SEQ ID NO:2 revealed a protein sequence which included four GPR motifs which are similar to those found in SEQ ID NO:6. The human polypeptide sequence, LGN (named for the existence of at least 10 leu-gly-asn repeats, (GenPept™ Accession Number U54999), includes at least four GPR motifs which are approximately 50-85% homologous to the GPR motifs of SEQ ID NO:6. (Described in detail in Example 3). A C. elegans open reading frame, (Accession Number U40409) also includes a similar four domain motif. The present invention also pertains to proteins which have an amino acid sequence which is substantially homologous to the amino acid sequence of SEQ ID NO:2, SEQ ID NO:3, or SEQ ID NO:6, comprise at least four GPR motifs, and have a GPM activity. As used herein, a protein which has an amino acid sequence which is substantially homologous to a selected amino_ac id sequence is at least 50% homologous to the selected amino acid sequence, e.g., the entire selected amino acid sequence. A protein which has an amino acid sequence which is substantially homologous to a selected amino acid sequence can also be least 60%, preferably at least 70%, more preferably at least 80%, and even more preferably at least 85, 86, 88, 90%, and most preferably at least 95%, 96, 97, 98, or 99% homologous to a selected amino acid sequence. The GPM protein or a biologically active portion or fragment of the invention can have one or more of the following activities: 1) it can interact with (e.g., bind to) a G protein; 2) it can modulate the activity of a G protein; 3) it can interact with (e.g., bind to) a G protein target molecule; 4) it can modulate the activity of a G protein target molecule; 5) it can modulate a G protein-mediated response in a cell, independent of G protein-coupled receptor activation; and 6) it can augment G protein-coupled receptor signaling by modulating a G protein-mediated response in a cell. Various aspects of the invention are described in further detail in the following subsections: I. Isolated Nucleic Acid Molecules One aspect of the invention pertains to isolated nucleic acid molecules that encode a GPM protein or biologically active portion thereof, as well as nucleic acid fragments sufficient for use as hybridization probes to identify GPM-encoding nucleic acid (e.g., GPM mRNA). As used herein, the term "nucleic acid molecule" is intended to include DNA molecules (e.g., cDNA or genomic DNA) and RNA molecules (e.g., mRNA) and analogs of the DNA or RNA generated using nucleotide analogs. The nucleic acid molecule can be single-stranded or double-strauded, but preferably is double-stranded DNA. An "isolated" nucleic acid molecule is one which is separated from other nucleic acid molecules which are present in the natural source of the nucleic acid. Preferably, an "isolated" nucleic acid is free of sequences which naturally flank the nucleic acid (i.e., sequences located at the 5' and 3' ends of the nucleic acid) in the genomic DNA of the organism from which the nucleic acid is derived. For example, in various embodiments, the isolated GPM nucleic acid molecule can contain less than about 5 kb, 4kb, 3kb, 2kb, 1 kb, 0.5 kb or 0.1 kb of nucleotide sequences which naturally flank the nucleic acid molecule in genomic DNA of the cell from which the nucleic acid is derived. Moreover, an "isolated" nucleic acid molecule, such as a cDNA molecule, can be substantially free of other cellular material, or culture medium when produced by recombinant techniques, or chemical precursors or other chemicals when chemically synthesized. A nucleic acid molecule of the present invention, e.g., a nucleic acid molecule having the nucleotide sequence of SEQ ID NO: 1 , SEQ ID NO:5, SEQ ID NO:7, or a portion thereof, can be isolated using standard molecular biology techniques and the sequence information provided herein. For example, a human GPM II cDNA can be isolated from a human neuronal cDNA library using all or portion of SEQ ID NO: 1 as a hybridization probe and standard hybridization techniques (e.g., as described in Sambrook, J., Fritsh, E. F., and Maniatis, T. Molecular Cloning: A Laboratory Manual. 2nd, ed., Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1989). Moreover, a nucleic acid molecule encompassing all or a portion of SEQ ID NO:l, SEQ ID NO:5, or SEQ ID NO:7 can be isolated by the polymerase chain reaction using oligonucieotide primers designed based upon the sequence of SEQ ID NO: l, SEQ ID NO:5, or SEQ ID NO:7. For example, mRNA can be isolated from normal neuronal cells (e.g., by the guanidinium-thiocyanate extraction procedure of Chirgwin et.al. (1979) Biochemistry 18: 5294-5299) and cDNA can be prepared using reverse transcriptase (e.g., Moloney MLV reverse transcriptase, available from Gibco/BRL, Bethesda, MD; or AMV reverse transcriptase, available from Seikagaku America, Inc., St. Petersburg, FL). Synthetic oligonucieotide primers for PCR amplification can be designed based upon the nucleotide sequence shown in SEQ ID NO:l, SEQ ID NO:5, or SEQ ID NO:7. A nucleic acid of the invention can be amplified using cDNA or, alternatively, genomic DNA, as a template and appropriate oligonucieotide primers according to standard PCR amplification techniques. The nucleic acid so amplified can be cloned into an appropriate vector and characterized by DNA sequence analysis. Furthermore, oligonucleotides corresponding to a GPM nucleotide sequence can be prepared by standard synthetic techniques, e.g., using an automated DNA synthesizer. In a preferred embodiment, an isolated nucleic acid molecule of the invention comprises the nucleotide sequence shown in SEQ ID NO:l. The sequence of SEQ ID NO:l corresponds to a GPM II cDNA isolated from the neuroblastoma glioma hybrid cell line NG-108. This cDNA comprises sequences encoding the NG108-derived GPM II protein. In one embodiment, a GPM protein comprises the peptide encoded by nucleotides 1-252 of SEQ ID NO:l, as well as 3' untranslated sequences (nucleotides 253 to 1478 of SEQ ID NO:l). In another embodiment, a GPM protein comprises the peptide encoded by nucleotides 31-252 of SEQ ID NO:l, as well as 5' untranslated sequences from nucleotides 1-30 of SEQ ID NO: l and 3' untranslated sequences (nucleotides 253-1478 of SEQ ID NO: l). Alternatively, the nucleic acid nolecule can comprise only coding regions of SEQ ID NO:l (e.g., nucleotides 1 to 252 or 31 to 252 of SEQ ID NO:l). In another embodiment, a GPM protein comprises the peptide encoded by nucleotides 2-358 of SEQ ID NO:l, as well as 3' untranslated sequences (nucleotides 359-1478 of SE ID NO:l). In another preferred embodiment, an isolated nucleic acid molecule of the invention comprises the nucleotide sequence shown in SEQ ID NO:5. The sequence of SEQ ID NO:5 corresponds to a GPM II cDNA isolated from rat brain. This cDNA comprises sequences encoding the rat brain GPM II protein (i.e., "the coding region", from nucleotides 1 to 1950), as well as 3' untranslated sequences (nucleotides 1951 to - 2386). Alternatively, the nucleic acid molecule can comprise only the coding region of SEQ ID NO:5 (e.g., nucleotides 1 to 1950). In another preferred embodiment, an isolated nucleic acid molecule of the invention comprises the nucleotide sequence shown in SEQ ID NO:7. The sequence of SEQ ID NO:7 corresponds to a GPM I cDNA isolated from the neuroblastoma glioma hybrid cell line NG-108. This cDNA comprises sequences encoding the NG108-derived GPM I protein (i.e., "the coding region", from nucleotides 102 to 440), as well as 5' untranslated sequences (nucleotides 1 to 101) and 3' untranslated sequences (nucleotides 441 to 770). Alternatively, the nucleic acid molecule can comprise only the coding region of SEQ ID NO:6 (e.g., nucleotides 102 to 440). In another preferred embodiment, an isolated nucleic acid molecule of the invention comprises a nucleic acid molecule which is a complement of the nucleotide sequence shown in SEQ ID NO:l, SEQ ID NO:5, or SEQ ID NO:7, or a portion of any of these nucleotide sequences. A nucleic acid molecule which is the complement of the nucleotide sequence shown in SEQ ID NO:l, SEQ ID NO:5, or SEQ ID NO:7 is one which has a nucleotide sequence that directly pairs with that of SEQ ID NO: 1 or 3, according to the rules of Watson and Crick base pairing, wherein A pairs with T and G pairs with C. For example, the complement of the sequence 5' GGATGC 3' would be 3'CCTACG 5" (which, written in the standard 5' to 3' direction, would be 5' GCATCC 3'). In still another preferred embodiment, an isolated nucleic acid molecule of the invention comprises a nucleotide sequence which is at least 60%, even more preferably at least 70%, even more preferably at least 80%, and even more preferably at least 90%, 95%, 96%, 97%, 98%, or 99% homologous to the nucleotide sequence shown in SEQ ID NO:l, SEQ ID NO:5, or SEQ ID NO:7, or a portion of any of these nucleotide sequences. For example, an isolated nucleotide of the present invention can comprise a nucleotide sequence which is at least 60%, preferably at least 70%, more_rjreferably at least 80%, and even more preferably at least 90%, 95%, 96%, 97%, 98%, or 99% homologous to the 3' untranslated region or to the 5' untranslated region of the nucleotide sequence shown in SEQ ID NO:l, SEQ ID NO:5, or SEQ ID NO:7. In an additional preferred embodiment, an isolated nucleic acid molecule of the invention comprises a nucleotide sequence which hybridizes, e.g., hybridizes under stringent conditions, to the nucleotide sequence shown in SEQ ID NO:l, SEQ ID NO:5, or SEQ ID NO:7, or a portion of any of these nucleotide sequences. Moreover, the nucleic acid molecule of the invention can comprise only a portion of the coding region of SEQ ID NO: l, SEQ ID NO:5, or SEQ ID NO:7, for example a fragment which can be used as a probe or primer or a fragment encoding a biologically active portion of a GPM protein. The nucleotide sequence determined from the cloning of the GPM genes from a mammal, e.g., the mouse, allows for the generation of probes and primers designed for use in identifying and/or cloning GPM homologues in other cell types, e.g. from other tissues, as well as GPM homologues from other mammals, e.g., humans. The probe/primer typically comprises substantially purified oligonucieotide. The oligonucieotide typically comprises a region of nucleotide sequence that hybridizes under stringent conditions to at least about 12, preferably about 25, more preferably about 40, 50 or 75 consecutive nucleotides of SEQ ID NO:l , SEQ ID NO:5, or SEQ ID NO:7 sense, an anti-sense sequence of SEQ ID NO: l , SEQ ID NO:5, or SEQ ID NO:7, or naturally occurring mutants thereof. Primers based on the nucleotide sequence in SEQ ID NO: 1 , SEQ ID NO:5, or SEQ ID NO:7 can be used in PCR reactions to clone GPM homologues. Probes based on the GPM nucleotide sequences can be used to detect transcripts or genomic sequences encoding the same or homologous proteins. In preferred embodiments, the probe further comprises a label group attached thereto, e.g. the label group can be a radioisotope, a fluorescent compound, an enzyme, or an enzyme co-factor. Such probes can be used as a part of a diagnostic test kit for identifying cells or tissue which misexpress a GPM protein, such as by measuring a level of a GPM-encoding nucleic acid in a sample of cells from a subject e.g., detecting GPM mRNA levels or determining whether a genomic GPM gene has been mutated or deleted. In one embodiment, the nucleic acid molecule of the invention encodes a protein or portion thereof which includes an amino acid sequence which is sufficiently homologous to an amino acid sequence of SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO: 8 or SEQ ID NO: 13 such that the protein or portion thereof maintains the ability to modulate a G-protein mediated response in a cell. As used herein, the language "sufficiently homologous" refers to proteins or portions thereof which have amino acid sequences which include a minimum number of identical or equivalent (e.g., an amino acid residue which has a similar side chain as an amino acid residue in SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8 or SEQ ID NO: 13) amino acid residues to an amino acid sequence of SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8 or SEQ ID NO: 13 such that the protein or portion thereof is able to modulate a G-protein mediated response in a cell. In another embodiment, the protein is at least 60%, preferably at least 70%, more preferably at least 80%, more preferably at least 90% and most preferably at least 95, 96, 97, 98, or 99% homologous to the entire amino acid sequence of SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8 or SEQ ID NO:13. Portions of proteins encoded by the GPM nucleic acid molecule of the invention are preferably biologically active portions of the GPM protein. As used herein, the term "biologically active portion of GPM" is intended to include a portion, e.g., a domain/motif, of GPM that has one or more of the following activities: 1) it can interact with (e.g., bind to) a G protein; 2) it can modulate the activity of a G protein; 3) it can interact with (e.g., bind to) a G protein target molecule; 4) it can modulate the activity of a G protein target molecule; 5) it can modulate a G protein-mediated response in a cell, independent of G protein-coupled receptor activation; and 6) it can augment G protein- coupled receptor signaling by modulating a G protein-mediated response in a cell. For example, in one embodiment, a biologically active portion of GPM can comprise at least one GPR motif. Standard binding assays, e.g., immunoprecipitations and yeast two-hybrid assays as described herein, can be performed to determine the ability of a GPM protein or a biologically active portion thereof to interact with (e.g., b ud lu) a G protein. To determine whether a GPM protein or biologically active portion thereof can modulate G- protein mediated response in a cell, the GPM protein or biologically active portion thereof can be introduced into a cell (e.g., transformed or transfected) which has been engineered to grow only in the presence of a GPM protein or biologically active portion thereof, e.g., yeast cell strain 1316/1 183 (described in the Examples) and the ability of the GPM protein or biologically active portion thereof to facilitate growth determined. Alternatively, a cell can be transformed or transfected with a G-protein mediated signal transduction responsive reporter construct (e.g., FUSl-luciferase) which responds to G- protein mediated signaling by expressing luciferase, and a nucleic acid encoding the GPM protein or biologically active portion thereof. The cells can be harvested and lysed and reporter activity, e.g., luciferase activity, can be measured and compared to reporter activity in a control cell. Examples of control cells include cells which include the G- protein mediated signal transduction responsive reporter construct. An alteration in reporter activity in the cells which include nucleic acid encoding the GPM protein, as compared to reporter activity in the cells without nucleic acid encoding the GPM protein is indicative of a modulation of a G-protein mediated response in the cell. In addition to the GPM nucleotide sequences shown in SEQ ID NO:l, SEQ ID NO:5, or SEQ ID NO:7, it will be appreciated by those skilled in the art that DNA sequence polymorphisms that lead to changes in the amino acid sequences of GPM may exist within a population. Such genetic polymorphism in the GPM gene may exist among individuals within a population due to natural allelic variation. As used herein, the terms "gene" and "recombinant gene" refer to nucleic acid molecules comprising an open reading frame encoding a GPM protein, preferably a mammalian GPM protein. Such natural allelic variations can typically result in 1-5% variance in the nucleotide sequence of the GPM gene. Any and all such nucleotide variations and resulting amino acid polymorphisms in GPM that are the result of natural allelic variation and that do not alter the functional activity of GPM are intended to be within the scope of the invention. Moreover, nucleic acid molecules encoding GPM proteins from other species, and thus which have a nucleotide sequence which differs from the sequence of SEQ ID NO:l, SEQ ID NO:5, or SEQ ID NO:7, are intended to be within the scope of the invention. For example, human homologues of the GPM cDNAs of the invention can be isolated based on their homology to the GPM nucleic acid disclosed herein using the murine cDNAs, or a portion thereof, as a hybridization probe according to standard hybridization techniques under stringent hybridization conditions. Accordingly, in another embodiment, an isolated nucleic acid molecule of the invention is at least 15 nucleotides in length and hybridizes under stringent conditions to the nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:l, SEQ ID NO:5, or SEQ ID NO:7. In other embodiments, the nucleic acid is at least 30, 50, 100, 250 or 500 nucleotides in length. As used herein, the term "hybridizes under stringent conditions" is intended to describe conditions for hybridization and washing under which nucleotide sequences at least 60% homologous to each other typically remain hybridized to each other. Preferably, the conditions are such that sequences at least 65%, more preferably at least 70%, and even more preferably at least 75% or more homologous to each other typically remain hybridized to each other. Such stringent conditions are known to those skilled in the art and can be found in Current Protocols in Molecular Biology, John Wiley & Sons, N.Y. (1989), 6.3.1-6.3.6. A preferred, non-limiting example of stringent hybridization conditions are hybridization in 6X sodium chloride/sodium citrate (SSC) at about 45°C, followed by one or more washes in 0.2 X SSC, 0.1% SDS_at 50-65°C. Preferably, an isolated nucleic acid molecule of the invention that hybridizes under stringent conditions to the sequence of SEQ ID NO:l, SEQ ID NO: 5, or SEQ ID NO: 7 corresponds to a naturally-occurring nucleic acid molecule. As used herein, a "naturally-occurring" nucleic acid molecule refers to an RNA or DNA molecule having a nucleotide sequence that occurs in nature (e.g., encodes a natural protein). In one embodiment, the nucleic acid encodes a natural human GPM. In addition to naturally-occurring allelic variants of the GPM sequences that may exist in the population, the skilled artisan will further appreciate that changes can be introduced by mutation into the nucleotide sequence of SEQ ID NO: l, SEQ ID NO:5, or SEQ ID NO:7, thereby leading to changes in the amino acid sequence of the encoded GPM proteins, without altering the functional activity of the GPM proteins. For example, nucleotide substitutions leading to amino acid substitutions at "non-essential" amino acid residues can be made in the sequence of SEQ ID NO:l , SEQ ID NO:5, or SEQ ID NO:7. A "non-essential" amino acid residue is a residue that can be altered from the wild-type sequences of GPM (e.g., the sequence of SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8 or SEQ ID NO: 13) without altering the activity of GPM, whereas an "essential" amino acid residue is required for GPM activity. For example, conserved amino acid residues in the GPR motif of GPM II are most likely important for binding to G proteins and are thus essential residues of GPM II. Other amino acid residues, however, (e.g., those that are not conserved or only semi- conserved in the GPR motif of GPM II) may not be essential for activity and thus are likely to be amenable to alteration without altering GPM activity. Accordingly, another aspect of the invention pertains to nucleic acid molecules encoding GPM proteins that contain changes in amino acid residues that are not essential for GPM activity. Such GPM proteins differ in amino acid sequence from SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8 or SEQ ID NO: 13, yet retain at least one of the GPM activities described herein. In one embodiment, the isolated nucleic acid molecule comprises a nucleotide sequence encoding a protein, wherein the protein comprises an amino acid sequence at least 60% homologous to the amino acid sequence of SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8 or SEQ ID NO:13, and is capable of modulating a G- protein mediated response in a cell. Preferably, the protein encoded by the nucleic acid molecule is at least 70% homologous to SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8 or SEQ ID NO: 13, more preferably at least 80% homologous, even more preferably at least 90% homologous, and most preferably at least 95, 96, 97, 98, or 99% homologous to SEQ ID NO:2, SEQ ID NO-- SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8 or SEQ ID NO:13. To determine the percent homology of two amino acid sequences or of two nucleic acids, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in the sequence of a first amino acid or nucleic acid sequence for optimal alignment with a second aηiino or nucleic acid sequence and non-homologous sequences can be disregarded for comparison purposes). In a preferred embodiment, the length of a reference sequence aligned for comparison purposes is at least 30%, preferably at least 40%, more preferably at least 50%, even more preferably at least 60%, and even more preferably at least 70%, 80%, or 90% of the length of the reference sequence (e.g., when aligning a second sequence to the GPM amino acid sequence of SEQ ID NO:2 having 84 amino acid residues, at least 25, preferably at least 37, more preferably at least 42, even more preferably at least 50, and even more preferably at least 59, 76, or 76 are aligned). The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are homologous at that position (i.e., as used herein amino acid or nucleic acid "homology" is equivalent to amino acid or nucleic acid "identity"). The percent homology between the two sequences is a function of the number of identical positions shared by the sequences (i.e., % homology = # of identical positions/total # of positions x 100). The comparison of sequences and determination of percent homology between two sequences can be accomplished using a mathematical algorithm. A preferred, non- limiting example of a mathematical algorithm utilized for the comparison of sequences is the algorithm of Karlin and Altschul (1990) Proc. Natl. Acad. Sci. USA 87:2264-68, modified as in Karlin and Altschul (1993) Proc. Natl. Acad. Sci. USA 90:5873-77. Such an algorithm is incorporated into the NBLAST and XBLAST programs (version 2.0) of Altschul, et.al. (1990) J. Mol. Biol. 215:403-10. BLAST nucleotide searches can be performed with the NBLAST program, score = 100, wordlength = 12 to obtain nucleotide sequences homologous to GPM nucleic acid molecules of the invention. BLAST protein searches can be performed with the XBLAST program, score = 50, wordlength = 3 to obtain amino acid sequences homologous to GPM protein molecules of the invention. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et.al., (1997) Nucleic Acids Research 25(17):3389-3402. When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used. See http://www.ncbi.nlm.nih.gov. Another preferred, non-limiting example of a mathematical algorithm utilized for the comparison of sequences is the algorithm of Myers and Miller, CABIOS (1989). Such an algorithm is incorporated into the ALIGN program (version 2.0) which is part of the GCG sequence alignment software package. When utilizing the ALIGN program for comparing amino acid sequence (or for comparing nucleic acid sequences), a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4 can be used. Alternatively, a PAM 250 residue weight Table, a GAP penalty of 10, and a GAP length penalty of 10 can be used. Another preferred, non-limiting example of a mathematical algorithm utilized for the comparison of sequences is the algorithm of Wilbur-Lipmann which is part of MegAlign ™ sequence alignment software. When utilizing the Wilbur-Lipmann algorithm, a K- tuple of 1 , a GAP penalty of 3, a window of 5, and diagonals saved set to = 5 can be used. Multiple alignment can be performed using the Clustal algorithm. An isolated nucleic acid molecule encoding a GPM protein homologous to the protein of SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8 or SEQ ID NO: 13, can be created by introducing one or more nucleotide substitutions, additions or deletions into the nucleotide sequence of SEQ ID NO: 1 , SEQ ID NO:5, or SEQ ID NO:7, such that one or more amino acid substitutions, additions or deletions are introduced into the encoded protein. Mutations can be introduced into SEQ ID NO:l, SEQ ID NO:5, or SEQ ID NO:7, by standard techniques, such as site-directed mutagenesis and PCR-mediated mutagenesis. Preferably, conservative amino acid substitutions are made at one or more predicted non-essential amino acid residues. A "conservative amino acid substitution" is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. Those lamilies include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta- branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Thus, a predicted nonessential amino acid residue in a GPM protein is preferably replaced with another amino acid residue from the same side chain family. Alternatively, in another embodiment, mutations can be introduced randomly along all or part of a GPM coding sequence, such as by saturation mutagenesis, and the resultant mutants can be screened for a GPM activity described herein to identify mutants that retain GPM activity. Following mutagenesis of SEQ ID NO:l, SEQ ID NO:5, or SEQ ID NO:7, the encoded protein can be expressed recombinantly and the activity of the protein can be determined using, for example, assays described herein. In addition to the nucleic acid molecules encoding GPM proteins described above, another aspect of tl-je invention pertains to isolated nucleic acid molecules which are antisense thereto. An "antisense" nucleic acid comprises a nucleotide sequence which is complementary to a "sense" nucleic acid encoding a protein, e.g., complementary to the coding strand of a double-stranded cDNA molecule or complementary to an mRNA sequence. Accordingly, an antisense nucleic acid can hydrogen bond to a sense nucleic acid. The antisense nucleic acid can be complementary to an entire GPM coding strand, or to only a portion thereof. In one embodiment, an antisense nucleic acid molecule is antisense to a "coding region" of the coding strand of a nucleotide sequence encoding a GPM protein. The term "coding region" refers to the region of the nucleotide sequence comprising codons which are translated into amino acid residues. In another embodiment, the antisense nucleic acid molecule is antisense to a "noncoding region" of the coding strand of a nucleotide sequence encoding GPM. The term "noncoding region" refers to 5' and 3' sequences which flank the coding region that are not translated into amino acids (i.e., also referred to as 5' and 3' untranslated regions). Given the coding strand sequences encoding GPM proteins disclosed herein (e.g., SEQ ID NO:l, SEQ ID NO:5, or SEQ ID NO:7), antisense nucleic acids of the invention can be designed according to the rules of Watson and Crick base pairing. The antisense nucleic acid molecule can be complementary to the entire coding region of a GPM mRNA, but more preferably is an oligonucieotide which is antisense to only a portion of the coding or noncoding region of a GPM mRNA. For example, the antisense oligonucieotide can be complementary to the region surrounding the translation start site of a GPM mRNA. An antisense oligonucieotide can be, for example, about 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50 nucleotides in length. An antisense nucleic acid of the invention can be constructed using chemical synthesis and enzymatic ligation reactions using procedures known in the art. For example, an antisense nucleic acid (e.g., an antisense oligonucieotide) can be chemically synthesized using naturally occurring nucleotides or variously modified nucleotides designed to increase the biological stability of the molecules or to increase the physical stability of the duplex formed between the antisense and sense nucleic acids, e.g., phosphorothioate derivatives and acridine substituted nucleotides can be used. Examples of modified nucleotides which can be used to generate the antisense nucleic acid include 5-fluorouracil,_5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5- (carboxyhydroxylmethyl) uracil, 5-carboxymethylaminornethyl-2-thiouridine, 5- carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1 -methylguanine, 1 -methylinosine, 2,2-dimethylguanine, 2- methyladenine, 2-methylgμanine, 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. Alternatively, the antisense nucleic acid can be produced biologically using an expression vector into which a nucleic acid has been subcloned in an antisense orientation (i.e., RNA transcribed from the inserted nucleic acid will be of an antisense orientation to a target nucleic acid of interest, described further in the following subsection). The antisense nucleic acid molecules of the invention are typically administered to a subject or generated in situ such that they hybridize with or bind to cellular mRNA and/or genomic DNA encoding a GPM protein to thereby inhibit expression of the protein, e.g., by inhibiting transcription and/or translation. The hybridization can be by conventional nucleotide complementarity to form a stable duplex, or, for example, in the case of an antisense nucleic acid molecule which binds to DNA duplexes, through specific interactions in the major groove of the double helix. An example of a route of administration of an antisense nucleic acid molecule of the invention includes direct injection at a tissue site. Alternatively, an antisense nucleic acid molecule can be modified to target selected cells and then administered systemically. For example, for systemic administration, an antisense molecule can be modified such that it specifically binds to a receptor or an antigen expressed on a selected cell surface, e.g., by linking the antisense nucleic acid molecule to a peptide or an antibody which binds to a cell surface receptor or antigen. The antisense nucleic acid molecule can also be delivered to cells using the vectors described herein. To achieve sufficient intracellular concentrations of the antisense molecules, vector constructs in which the antisense nucleic acid molecule is placed under the control of a strong pol II or pol III promoter are preferred. In yet another embodiment, the antisense nucleic acid molecule of the invention is an α-anomeric nucleic acid molecule. An α-anomeric nucleic acid molecule forms specific double-stranded hybrids with complementary RNA in which^contrary to the usual β-units, the strands run parallel to each other (Gaultier et.al. (1987) Nucleic Acids. Res. 15:6625-6641). The antisense nucleic acid molecule can also comprise a 2'-o- methylribonucleotide (Inoue et. al. (1987) Nucleic Acids Res. 15:6131-6148) or a chimeric RNA-DNA analogue (Inoue et.al. (1987) FEBS Lett. 215:327-330). In still another embodiment, an antisense nucleic acid of the invention is a ribozyme. Ribozymes are catalytic RNA molecules with ribonuclease activity which are capable of cleaving a single-stranded nucleic acid, such as an mRNA, to which they have a complementary region. Thus, ribozymes (e.g., hammerhead ribozymes (described in Haselhoff and Gerlach (1988) Nature 334:585-591)) can be used to catalytically cleave GPM mRΝ A transcripts to thereby inhibit translation of GPM mRΝ As. A ribozyme having specificity for a GPM-encoding nucleic acid can be designed based upon the nucleotide sequence of a GPM cDΝA disclosed herein. For example, a derivative of a Tetrahymena L-19 IVS RΝA can be constructed in which the nucleotide sequence of the active site is complementary to the nucleotide sequence to be cleaved in a GPM-encoding mRΝA. See, e.g., Cech et.al. U.S. Patent No. 4,987,071 and Cech et.al. U.S. Patent No. 5,1 16,742. Alternatively, GPM mRNA can be used to select a catalytic RNA having a specific ribonuclease activity from a pool of RNA molecules. See, e.g., Bartel, D. and Szostak, J.W. (1993) Science 261 :141 1-1418. Alternatively, GPM gene expression can be inhibited by targeting nucleotide sequences complementary to the regulatory region of a GPM gene (e.g., a GPM promoter and/or enhancer) to form triple helical structures that prevent transcription of a GPM gene in target cells. See generally, Helene, C. (1991) Anticancer Drug Des. 6(6):569-84; Helene, C. et.al. (1992) Ann. N Y. Acad. Sci. 660:27-36; and Maher, L.J. (1992) R.o-w_--7y_. 14(12):807-15. II. Recombinant Expression Vectors and Host Cells Another aspect of the invention pertains to vectors, preferably expression vectors, containing a nucleic acid encoding a GPM protein (or a portion thereof). As used herein, the term "vector" refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a "plasmid", which refers to a circular double stranded DNA loop into which additional DNA segments can be ligated. Another type of vector is a viral vector, wherein additional DNA segments can be ligated into the viral genome. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) are integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome. Moreover, certain vectors are capable of directing the expression of genes to which they are operatively linked. Such vectors are referred to herein as "expression vectors". In general, expression vectors of utility in recombinant DNA techniques are often in the form of plasmids. In the present specification, "plasmid" and "vector" can be used interchangeably as the plasmid is the most commonly used form of vector. However, the invention is intended to include such other forms of expression vectors, such as viral vectors (e.g., replication defective retroviruses, adenoviruses and adeno- associated viruses), which serve equivalent functions. The recombinant expression vectors of the invention comprise a nucleic acid of the invention in a form suitable for expression of the nucleic acid in a host cell, which means that the recombinant expression vectors include one or more regulatory sequences, selected on the basis of the host cells to be used for expression, which is operatively linked to the nucleic acid sequence to be expressed. Within a recombinant expression vector, "operably linked" is intended to mean that the nucleotide sequence of interest is linked to the regulatory sequence(s) in a manner which allows for expression of the nucleotide sequence (e.g., in an in vitro transcription/translation system or in a host cell when the vector is introduced into the host cell). The term "regulatory sequence" is intended to includes promoters, enhancers and other expression control elements (e.g., polyadenylation signals). Such regulatory sequences are described, for example, in Goeddel; Gene Expression Technology: Methods in Enzymology 185, Academic Press, San Diego, CA (1990). Regulatory sequences include those which direct constitutive expression of a nucleotide sequence in mrmv types of host cell and those which direct expression of the nucleotide sequence o.-ly in certain host cells (e.g., tissue-specific regulatory sequences). It will be appreciated by those skilled in the art that the design of the expression vector can depend on such factors as the choice of the host cell to be transformed, the level of expression of protein desired, etc. The expression vectors of the invention can be introduced into host cells to thereby produce proteins or peptides, including fusion proteins or peptides, encoded by nucleic acids as described herein (e.g., GPM proteins, mutant forms of GPM proteins, fusion proteins, etc.). The recombinant expression vectors of the invention can be designed for expression of GPM proteins in prokaryotic or eukaryotic cells. For example, a GPM protein can be expressed in bacterial cells such as E. coli, insect cells (using baculovirus expression vectors) yeast cells or mammalian cells. Suitable host cells are discussed further in Goeddel, Gene Expression Technology: Methods in Enzymology 185, Academic Press, San Diego, CA (1990). Alternatively, the recombinant expression vector can be transcribed and translated in vitro, for example using T7 promoter regulatory sequences and T7 polymerase. Expression of proteins in prokaryotes is most often carried out in E. coli with vectors containing constitutive or inducible promoters directing the expression of either fusion or non-fusion proteins. Fusion vectors add a number of amino acids to a protein encoded therein, usually to the amino terminus of the recombinant protein. Such fusion vectors typically serve three purposes: 1) to increase expression of recombinant protein; 2) to increase the solubility of the recombinant protein; and 3) to aid in the purification of the recombinant protein by acting as a ligand in affinity purification. Often, in fusion expression vectors, a proteolytic cleavage site is introduced at the junction of the fusion moiety and the recombinant protein to enable separation of the recombinant protein from the fusion moiety subsequent to purification of the fusion protein. Such enzymes, and their cognate recognition sequences, include Factor Xa. thrombin and enterokinase. Typical fusion expression vectors include pGEX (Pharmacia Biotech Inc; Smith, D.B. and Johnson, K.S. (1988) Gene 67:31-40), pMAL (New England Biolabs. Beverly, MA) and pRIT5 (Pharmacia, Piscataway, NJ) which fuse glutathione S-transferase (GST), maltose E binding protein, or protein A, respectively, to the target recombinant protein. In one embodiment, the coding sequence of a GPM protein is cloned into a pGEX expression vector to create a vector encoding a fusion protein comprising, from the N- terminus to the C-terminus, GST-thrombin cleavage site-GPM protein. The fusion protein can be purified by affinity chromatography using glutathione-agarose resin. Recombinant GPM protein unfused to GST can be recovered by cleavage of the fusion protein with thrombin. Examples of suitable inducible non-fusion E. coli expression vectors include pTrc (Amann et.al., (1988) Gene 69:301-315) and pET l id (Studier et.al., Gene Expression Technology: Methods in Enzymology 185, Academic Press, San Diego, California (1990) 60-89). Target gene expression from the pTrc vector relies on host RNA polymerase transcription from a hybrid trp-lac fusion promoter. Target gene expression from the pET 1 Id vector relies on transcription from a T7 gnl 0-lac fusion promoter mediated by a coexpressed viral RNA polymerase (T7 gnl). This viral polymerase is supplied by host strains BL21(DE3) or HMS174(DE3) from a resident λ prophage harboring a T7 gnl gene under the transcriptional control of the lacUV 5 promoter. One strategy to maximize recombinant protein expression in E. coli is to express the protein in a host bacteria with an impaired capacity to proteolytically_cleave the recombinant protein (Gottesman, S., Gene Expression Technology: Methods in Enzymology 185, Academic Press, San Diego, California (1990) 119-128). Another strategy is to alter the nucleic acid sequence of the nucleic acid to be inserted into an expression vector so that the individual codons for each amino acid are those preferentially utilized in E. coli (Wada et.al. (1992) Nucleic Acids Res. 20:21 1 1-21 18). Such alteration of nucleic acid sequences of the invention can be carried out by standard DNA synthesis techniques. In another embodiment, a GPM expression vector is a yeast expression vector. Examples of vectors for expression in yeast S. cerivisae include pYepSecl (Baldari, et.al., (1987) Embo J. 6:229-234), pMFa (Kurjan and Herskowitz, (1982) Cell 30:933- 943), pJRY88 (Schultz et.al., (1987) Gene 54: 1 13-123), and pYES2 (Invitrogen Corporation, San Diego, CA). Alternatively, a GPM protein can be expressed in insect cells using baculovirus expression vectors. Baculovirus vectors available for expression of proteins in cultured insect cells (e.g., Sf 9 cells) include the pAc series (Smith et.al. (1983) Mol. Cell Biol. 3:2156-2165) and the pVL series (Lucklow and Summers (1989) Virology 170:31-39). In yet another embodiment, a nucleic acid of the invention is expressed in mammalian cells using a mammalian expression vector. Examples of mammalian expression vectors include pCDM8 (Seed, B. (1987) Nature 329:840) and pMT2PC (Kaufman et.al. (1987) EMBO J. 6: 187-195). When used in mammalian cells, the expression vector's control functions are often provided by viral regulatory elements. For example, commonly used promoters are derived from polyoma, Adenovirus 2, cytomegalovirus and Simian Virus 40. For other suitable expression systems for both prokaryotic and eukaryotic cells see chapters 16 and 17 of Sambrook, J., Fritsh, E. F., and Maniatis, T. Molecular Cloning: A Laboratory Manual. 2nd, ed., Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1989. In another embodiment, the recombinant mammalian expression vector is capable of directing expression of the nucleic acid preferentially in a particular cell type (e.g., tissue-specific regulatory elements are used to express the nucleic acid). Tissue- specific regulatory elements are known in the art. Non-limiting examples of suitable tissue-specific promoters include the albumin promoter (liver-specific; Pinkert et.al. (1987) Genes Dev. 1 :268-277), lymphoid-specific promoters (Calame and Eaton (1988) Adv. Immunol. 43:235-275), in particular promoters of T cell receptors (Winoto and Baltimore (1989) EMBO J. 8:729-733) and immunoglobulins (Banerji et.al. (1983) Cell 33:729-740; Queen and Baltimore (1983) Cell 33:741-748), neuron-specific promoters (e.g., the neurofilament promoter; Byrne and Ruddle (1989) PNAS 86:5473-5477), pancreas-specific promoters (Edlund et.al. (1985) Science 230:912-916), and mammary gland-specific promoters (e.g., milk whey promoter; U.S. Patent No. 4,873,316 and European Application Publication No. 264,166). Developmentally-regulated promoters are also encompassed, for example the murine hox promoters (Kessel and Gruss (1990) Science 249:374-379) and the α-fetoprotein promoter (Campes and Tilghman (1989) Genes Dev. 3:537-546). The invention further provides a recombinant expression vector comprising a DNA molecule of the invention cloned into the expression vector in an antisense orientation. That is, the DNA molecule is operatively linked to a regulatory sequence in a manner which allows for expression (by transcription of the DNA molecule) of an RNA molecule which is antisense to a GPM mRNA. Regulatory sequences operatively linked to a nucleic acid cloned in the antisense orientation can be chosen which direct the continuous expression of the antisense RNA molecule in a variety of cell types, for instance viral promoters and/or enhancers, or regulatory sequences can be chosen which direct constitutive, tissue specific or cell type specific expression of antisense RNA. The antisense expression vector can be in the form of a recombinant plasmid, phagemid or attenuated virus in which antisense nucleic acids are produced under the control of a high efficiency regulatory region, the activity of which can be determined by the cell type into which the vector is introduced. For a discussion of the regulation of gene expression using antisense genes see Weintraub, H. et.al., Antisense RNA as a molecular tool for genetic analysis, Reviews - Trends in Genetics, Vol. 1(1) 1986. Another aspect of the invention pertains to host cells into which a recombinant expression vector of the invention has been introduced. The terms "host cell" and "recombinant host cell" are used interchangeably herein. It is understood that such terms refer not only to the particular subject cell but to the progeny or potential progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term as used herein. A host cell can be any prokaryotic or eukaryotic cell. For example, GPM protein can be expressed in bacterial cells such as E. coli, insect cells, yeast or mammalian cells (such as Chinese hamster ovary cells (CHO) or COS cells). Other suitable host cells are known to those skilled in the art. Vector DNA can be introduced into prokaryotic or eukaryotic cells via conventional transformation or transfection techniques. As used herein, the terms "transformation" and "transfection" are intended to refer to a variety of art-recognized techniques for introducing foreign nucleic acid (e.g., DNA) into a host cell, including calcium phosphate or calcium chloride co-precipitation, DEAE-dextran-mediated transfection, lipofection, or electroporation. Suitable methods for transforming or transfecting host cells can be found in Sambrook, et.al. (Molecular Cloning: A Laboratory Manual. 2nd, ed., Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1989), and other laboratory manuals. For stable transfection of mammalian cells, it is known that, depending upon the expression vector and transfection technique used, only a small fraction of cells may integrate the foreign DNA into their genome. In order to identify and select these integrants, a gene that encodes a selectable marker (e.g., resistance to antibiotics) is generally introduced into the host cells along with the gene of interest. Preferred selectable markers include those which confer resistance to drugs, such as G418, hygromycin and methotrexate. Nucleic acid encoding a selectable marker can be introduced into a host cell on the same vector as that encoding GPM or can be introduced on a separate vector. Cells stably transfected with the introduced nucleic acid can be identified by drug selection (e.g., cells that have incorporated the selectable marker gene will survive, while the other cells die). A host cell of the invention, such as a prokaryotic or eukaryotic host cell in culture, can be used to produce (i.e., express) a GPM protein. Accordingly, the invention further provides methods for producing GPM proteins using the host cells of the invention. In one embodiment, the method comprises culturing the host cell of invention (into which a recombinant expression vector encoding a GPM protein has been introduced) in a suitable medium until GPM protein i. produced. In another embodiment, the method further comprises isolating GPM protein from the medium or the host cell. The host cells of the invention can also be used to produce nonhuman transgenic animals. The nonhuman transgenic animals can be used in screening assays designed to identify agents or compounds, e.g., drugs, pharmaceuticals, etc., which are capable of ameliorating detrimental symptoms of selected disorders such as cardiovascular disorders and proliferative disorders. For example, in one embodiment, a host cell of the invention is a fertilized oocyte or an embryonic stem cell into which GPM-coding sequences have been introduced. Such host cells can then be used to create non-human transgenic animals in which exogenous GPM sequences have been introduced into their genome or homologous recombinant animals in which endogenous GPM sequences have been altered. Such animals are useful for studying the function and/or activity of GPM and for identifying and/or evaluating modulators of GPM activity. As used herein, a "transgenic animal" is a nonhuman animal, preferably a mammal, more preferably a rodent such as a rat or mouse, in which one or more of the cells of the animal includes a transgene. Other examples of transgenic animals include nonhuman primates, sheep, dogs, cows, goats, chickens, amphibians, etc. A transgene is exogenous DNA which is integrated into the genome of a cell from which a transgenic animal develops and which remains in the genome of the mature animal, thereby directing the expression of an encoded gene product in one or more cell types or tissues of the transgenic animal. As used herein, a "homologous recombinant animal" is a nonhuman animal, preferably a mammal, more preferably a mouse, in which an endogenous GPM gene has been altered by homologous recombination between the endogenous gene and an exogenous DNA molecule introduced into a cell of the animal, e.g., an embryonic cell of the animal, prior to development of the animal. A transgenic animal of the invention can be created by introducing GPM- encoding nucleic acid into the male pronuclei of a fertilized oocyte, e.g., by microinjection, retroviral infection, and allowing the oocyte to develop in a pseudopregnant female foster animal. The GPM cDNA sequence of SEQ ID NO: l can be used as a transgene. Alternatively, a human homologue of the GPM genes can be isolated based on hybridization to GPM cDNAs (e.g., hybridization to SEQ ID NO:l, SEQ ID NO:5, or SEQ ID NO:7, described further in subsection I above) and used as a transgene. Intronic sequences and polyadenylation signals can also be included in the transgene to increase the efficiency of expression of the transgene. A tissue-specific regulatory sequence(s) can be operably linked to a GPM transgene to direct expression of GPM protein to particular cells. Methods for generating transgenic animals via embryo manipulation and microinjection, particularly animals such as mice, have become conventional in the art and are described, for example, in U.S. Patent Nos. 4,736,866 and 4,870,009, both by Leder et.al., U.S. Patent No. 4,873,191 by Wagner et.al. and in Hogan, B., Manipulating the Mouse Embryo, (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1986). Similar methods are used for production of other transgenic animals. A transgenic founder animal can be identified based upon the presence of a GPM transgene in its genome and/or expression of GPM mRNA in tissues or cells of the animals. A transgenic founder animal can then be used to breed additional animals carrying the transgene. Moreover, transgenic animals carrying a transgene encoding GPM can further be bred to other transgenic animals carrying other transgenes. To create a homologous recombinant animal, a vector is prepared which contains at least a portion of a GPM gene into which a deletion, addition or substitution has been introduced to thereby alter, e.g., functionally disrupt, the GPM gene. The GPM gene can be a human gene (e.g., isolated by hybridization to SEQ ID NO:l , SEQ ID NO:5, or SEQ ID NO:7), but more preferably, is a nonhuman homologue of a huma GPM gene (e.g., SEQ ID NOT , SEQ ID NO:5, or SEQ ID NO:7). For example, a mouse GPM gene can be used to construct a homologous recombination vector suitable for altering an endogenous GPM gene in the mouse genome. In a preferred embodiment, the vector is designed such that, upon homologous recombination, the endogenous GPM gene is functionally disrupted (i.e., no longer encodes a functional protein; also referred to as a "knock out" vector). Alternatively, the vector can be designed such that, upon homologous recombination, the endogenous GPM gene is mutated or otherwise altered but still encodes functional protein (e.g., the upstream regulatory region can be altered to thereby alter the expression of the endogenous GPM protein). In the homologous recombination vector, the altered portion of the GPM gene is flanked at its 5' and 3' ends by additional nucleic acid of the GPM gene to allow for homologous recombination to occur between the exogenous GPM gene carried by the vector and an endogenous GPM gene in an embryonic stem cell. The additional flanking GPM nucleic acid is of sufficient length for successful homologous recombination with the endogenous gene. Typically, several kilobases of flanking DNA (both at the 5' and 3' ends) are included in the vector (see e.g., Thomas, K.R. and Capecchi, M. R. (1987) Cell 51 :503 for a description of homologous recombination vectors). The vector is introduced into an embryonic stem cell line (e.g. , by electroporation) and cells in which the introduced GPM gene has homologously recombined with the endogenous GPM gene are selected (see e.g., Li, E. et.al. (1992) Cell 69:915). The selected cells are then injected into a blastocyst of an animal (e.g., a mouse) to form aggregation chimeras (see e.g., Bradley, A. in Teratocarcinomas and Embryonic Stem Cells: A GPMctical Approach, E.J. Robertson, ed. (IRL, Oxford, 1987) pp. 1 13-152). A chimeric embryo can then be implanted into a suitable pseudopregnant female foster animal and the embryo brought to term. Progeny harboring the homologously recombined DNA in their germ cells can be used to breed animals in which all cells of the animal contain the homologously recombined DNA by germline transmission of the transgene. Methods for constructing homologous recombination vectors and homologous recombinant animals are described further in Bradley, A. (1991) Current Opinion in Biotechnology 2:823-829 and in PCT International Publication Nos.: WO 90/1 1354 by Le Mouellec et.al.; WO 91/01 140 by Smithies et.al.; WO 92/0968 by Zijlstra et.al.; and WO 93/04169 by Berns et.al. In another embodiment, transgenic nonhumans animals can be produced which contain selected systems which allow for regulated expression of the transgene. One example of such a system is the cre/loxP recombinase system of bacteriophage PI . For a description of the cre/loxP recombinase system, see, e.g., Lakso et.al. (1992) PNAS 89:6232-6236. Another example of a recombinase system is the FLP recombinase system of Saccharomyces ςerevisiae (O'Gorman et.al. (1991) Science 251 :1351-1355. If a cre/loxP recombinase system is used to regulate expression of the transgene, animals containing transgenes encoding both the Cre recombinase and a selected protein are required. Such animals can be provided through the construction of "double" transgenic animals, e.g., by mating two transgenic animals, one containing a transgene encoding a selected protein and the other containing a transgene encoding a recombinase. Clones of the nonhuman transgenic animals described herein can also be produced according to the methods described in Wilmut, I. et.al. (1997) Nature 385:810- 813. In brief, a cell, e.g., a somatic cell, from the transgenic animal can be isolated and induced to exit the growth cycle and enter G 0 phase. The quiescent cell can then be fused, e.g., through the use of electrical pulses, to an enucleated oocyte from an animal of the same species from which the quiescent cell is isolated. The reconstructed oocyte is then cultured such that it develops to morula or blastocyst and then transferred to pseudopregnant female foster animal. The offspring borne of this female foster animal will be a clone of the animal from which the cell, e.g., the somatic cell, is isolated. HI. Isolated GPM Proteins and Anti- GPM Antibodies Another aspect of the invention pertains to isolated GPM proteins, and biologically active portions thereof, as well as peptide fragments suitable for use as immunogens to raise anti- GPM antibodies. An "isolated" or "purified" protein or biologically active portion thereof is substantially free of cellular material when produced by recombinant DNA techniques, or chemical precursors or other chemicals when chemically synthesized. The language "substantially free of cellular material" includes preparations of GPM protein in which the protein is separated from cellular components of the cells in which it is naturally or recombinantly produced. In one embodiment, the language "substantially free of cellular material" includes preparations of GPM protein having less than about 30% (by dry weight) of non- GPM protein (also referred to herein as a "contaminating protein"), more preferably less than about 20% of non- GPM protein, still more preferably less than about 10% of non- GPM protein, and most preferably less than about 5% non- GPM protein. When the GPM protein or biologically active portion thereof is recombinantly produced, it is also preferably substantially free of culture medium, i.e., culture medium represents lessjthan about 20%, more preferably less than about 10%. and most preferably less than about 5% of the volume of the protein preparation. The language "substantially free of chemical precursors or other chemicals" includes preparations of GPM protein in which the protein is separated from chemical precursors or other chemicals which are involved in the synthesis of the protein. In one embodiment, the language "substantially free of chemical precursors or other chemicals" includes preparations of GPM protein having less than about 30% (by dry weight) of chemical precursors or non- GPM chemicals, more preferably less than about 20% chemical precursors or non- GPM chemicals, still more preferably less than about 10% chemical precursors or non- GPM chemicals, and most preferably less than about 5% chemical precursors or non- GPM chemicals. In preferred embodiments, isolated proteins or biologically active portions thereof lack contaminating proteins from the same animal from which the GPM protein is derived. Typically, such proteins are produced by recombinant expression of, for example, a huma GPM protein in a nonhuman cell. An isolated GPM protein or a portion thereof of the invention can modulate a G- protein mediated response in a cell. In preferred embodiments, the protein or portion thereof comprises an amino acid sequence which is sufficiently homologous to an amino acid sequence of SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO: 8 or SEQ ID NO: 13 such that the protein or portion thereof maintains the ability to modulate a G-protein mediated response in a cell. The portion of the protein is preferably a biologically active portion as described herein. In another preferred embodiment, the GPM protein has an amino acid sequence shown in SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8 or SEQ ID NO: 13. In yet another preferred embodiment, the GPM protein has an ammo acid sequence which is encoded by a nucleotide sequence which hybridizes, e.g., hybridizes under stringent conditions, to the nucleotide sequence of SEQ ID NOT, SEQ ID NO:5, or SEQ ID NO:7. In still another preferred embodiment, the GPM protein has an amino acid sequence which is encoded by a nucleotide sequence that is at least 60%, preferably at least 70%, more preferably at least 80%, and even more preferably at least 90%, 95, 96, 87, 98, or 99% homologous to the nucleotide sequence of SEQ ID NOT, SEQ ID NO:5, or SEQ ID NO:7. The preferred GPM proteins of the present invention also preferably possess at least one of the GPM activities described herein. For example, a preferred GPM protein of the present invention includes an amino acid sequence encoded by a nucleotide sequence which hybridizes, e.g., hybridizes under stringent conditions, to the nucleotide sequence SEQ ID NOT , SEQ ID NO:5, or SEQ ID NO:7 and which can modulate a G-protein mediated response in a cell. In other embodiments, the GPM protein is substantially homologous to the amino acid sequence of SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8 or SEQ ID NO: 13 and retains the functional activity of the protein of SEQ ID NO:2, SEQ ID NQ:3, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8 or SEQ ID NO: 13 yet differs in amino acid sequence due to natural allelic variation or mutagenesis, as described in detail in subsection I above. Accordingly, in another embodiment, the GPM protein is a protein which comprises an amino acid sequence which is at least 60%, preferably at least 70%, more preferably at least 80%, and even more preferably at least 85%, 86, 88, 90%, and most preferably at least 95%, 96, 97, 98, or 99% homologous to the entire amino acid sequence of SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8 or SEQ ID NO: 13 and which has at least one of the GPM activities described herein. In other embodiment, the invention pertains to a full length human protein which is substantially homologous to the entire amino acid sequence of SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8 or SEQ ID NO:13. Biologically active portions of the GPM protein include peptides comprising amino acid sequences derived from the amino acid sequence of the GPM protein, e.g., the amino acid sequence shown in SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8 or SEQ ID NO: 13 or the amino acid sequence of a protein homologous to the GPM protein, which include less amino acids than the full length GPM protein or the full length protein which is homologous to the GPM protein, and exhibit at least one activity of the GPM protein. Typically, biologically active portions (peptides, e.g., peptides which are, for example, 5, 10, 15, 20, 30, 35, 36, 37, 38, 39, 40, 50, 100 or more amino acids in length) comprise a domain or motif, e.g., a GPR, with at least one activity of the GPM protein. Preferably, the domain is a GPR domain derived from a human and is at least 55%, preferably at least 60%, even more preferably at least 70%, and most preferably at least 80% or more (e.g. 90, 95, 96, 97, 98 or 99%) homologous to SEQ ID NOT or SEQ ID NO:4. In a preferred embodiment, the biologically active portion of the protein which includes the GPR motif can modulate the activity of a G-protein. Moreover, other biologically active portions, in which other regions of the protein are deleted, can be prepared by recombinant techniques and evaluated for one or more of the activities described herein. Preferably, the biologically active portions of the GPM protein include one or more selected domains/motifs or portions thereof having biological activity. GPM proteins are preferably produced by recombinant DNAjechniques. For example, a nucleic acid molecule encoding the protein is cloned into an expression vector (as described above), the expression vector is introduced into a host cell (as described above) and the GPM protein is expressed in the host cell. The GPM protein can then be isolated from the cells by an appropriate purification scheme using standard protein purification technigues. Alternative to recombinant expression, a GPM protein, polypeptide, or peptide can be synthesized chemically using standard peptide synthesis techniques. Moreover, native GPM protein can be isolated from cells (e.g., endothelial cells), for example using an anti- GPM antibody (described further below). The invention also provides GPM chimeric or fusion proteins. As used herein, a GPM "chimeric protein" or "fusion protein" comprises a GPM polypeptide operatively linked to a non- GPM polypeptide. An " GPM polypeptide" refers to a polypeptide having an amino acid sequence corresponding to GPM, whereas a "non- GPM polypeptide" refers to a polypeptide having an amino acid sequence corresponding to a protein which is not substantially homologous to the GPM protein, e.g., a protein which is different from the GPM protein and which is derived from the same or a different organism. Within the fusion protein, the term "operatively linked" is intended to indicate that the GPM polypeptide and the non- GPM polypeptide are fused in-frame to each other. The non- GPM polypeptide can be fused to the N-terminus or C-terminus of the GPM polypeptide. For example, in one embodiment the fusion protein is a GST- GPM fusion protein in which the GPM sequences axe fused to the C-terminus of the GST sequences. Such fusion proteins can facilitate the purification of recombinant GPM. In another embodiment, the fusion protein is a GPM protein containing a heterologous signal sequence at its N-terminus. In certain host cells (e.g.. mammalian host cells), expression and/or secretion of GPM can be increased through use of a heterologous signal sequence. Preferably, a GPM chimeric or fusion protein of the invention is produced by standard recombinant DNA techniques. For example, DNA fragments coding for the different polypeptide sequences are ligated together in-frame in accordance with conventional techniques, for example by employing blunt-ended or stagger-ended termini for ligation, restriction enzyme digestion to provide for appropriate termini, filling-in of cohesive ends as appropriate, alkaline phosphatase treatment to avoid undesirable joining, and enzymatic ligation. In another embodiment, the fusion gene can be synthesized by conventional techniques including automated DNA synthesizers. Alternatively, PCR amplification of gene fragments can be carried out using anchor primers which give rise to complementary overhangs between two consecutive gene fragments which can subsequently be annealed and reamplified to generate a chimeric gene sequence (see, for example, Current Protocols in Molecular Biology, eds. Ausubel et.al. John Wiley & Sons: 1992). Moreover, many expression vectors are commercially available that already encode a fusion moiety (e.g., a GST polypeptide). A GPM- encoding nucleic acid can be cloned into such an expression vector such that the fusion moiety is linked in-frame to the GPM protein. The present invention also pertains to homologues of the GPM proteins which function as either a GPM agonist (mimetic) or a GPM antagonist. In a preferred embodiment, the GPM agonists and antagonists stimulate or inhibit, respectively, a subset of the biological activities of the naturally occurring form of the GPM protein. Thus, specific biological effects can be elicited by treatment with a homologue of limited function. In one embodiment, treatment of a subject with a homologue having a subset of the biological activities of the naturally occurring form of the protein has fewer side effects in a subject relative to treatment with the naturally occurring form of the GPM protein. Homologues of the GPM protein can be generated by mutagenesis, e.g., discrete point mutation or truncation of the GPM protein. As used herein, the term "homologue" refers to a variant form of the GPM protein which acts as an agonist or antagonist of the activity of the GPM protein. An agonist of the GPM protein can retain substantially the same, or a subset, of the biological activities of the GPM protein. An antagonist of the GPM protein can inhibit one or more of the activities of the naturally occurring form of the GPM protein, by, for example, competitively binding to a G-protein or downstream or upstream member of the pheromone response cascade. In an alternative embodiment, homologues of the GPM protein can be identified by screening combinatorial libraries of mutants, e.g., truncation mutants, of the GPM protein for GPM protein agonist or antagonist activity. In one embodiment, a variegated library of GPM variants is generated by combinatorial mutagenesis at the nucleic acid level and is encoded by a variegated gene library. A variegated library of GPM variants can be produced by, for example, enzymatically ligating a mixture of synthetic oligonucleotides into gene sequences such that a degenerate set of potential GPM sequences is expressible as individual polypeptides, or alternatively, as a set of larger fusion proteins (e.g., for phage display) containing the set of GPM sequences therein. There are a variety of methods which can be used to produce libraries of potential GPM homologues from a degenerate oligonucieotide sequence. Chemical synthesis of a degenerate gene sequence can be performed in an automatic DNA synthesizer, and the synthetic gene then ligated into an appropriate expression vector. Use of a degenerate set of genes allows for the provision, in one mixture, of all of the sequences encoding the desired set of potential GPM sequences. Methods for synthesizing degenerate oligonucleotides are known in the art (see, e.g., Narang, S.A. (1983) Tetrahedron 39:3; Itakura et.al. ( 984) Annu. Rev. Biochem. 53:323; Itakura et.al. (1984) Science 198:1056; Ike et.al. (1983) Nucleic Acid Res. 1 1 :477. In addition, libraries of fragments of the GPM protein coding can be used to generate a variegated population of GPM fragments for screening and subsequent selection of homologues of a GPM protein. In one embodiment, a library of coding sequence fragments can be generated by treating a double stranded PCR fragment of a GPM coding sequence with a nuclease under conditions wherein nicking occurs only about once per molecule, denaturing the double stranded DNA, renaturing the DNA to form double stranded DNA which can include sense/antisense pairs from different nicked products, removing single stranded portions from reformed duplexes by treatment with S 1 nuclease, and ligating the resulting fragment library into an expression vector. By this method, an expression library can be derived which encodes N-terminal, C-terminal and internal fragments of various sizes of the GPM protein. Several techniques are known in the art for screening gene products of combinatorial libraries made by point mutations or truncation, and for screening cDNA libraries for gene products having a selected property. Such techniques are adaptable for rapid screening of the gene libraries generated by the combinatorial mutagenesis of GPM homologues. The most widely used techniques, which are amenable to high through-put analysis, for screening large gene libraries typically include cloning the gene library into replicable expression vectors, transforming appropriate cells with the resulting library of vectors, and expressing the combinatorial genes under conditions in which detection of a desired activity facilitates isolation of ti.e encoding the gene whose product was detected. Recursive ensemble mutagenesis (REM), a new technique which enhances the frequency of functional mutants in the libraries, can be used in combination with the screening assays to identify GPM homologues (Arkin and Yourvan (1992) PNAS £9:781 1-7815; Delgrave et.al. (1993) Protein Engineering 6(3):327-331). An isolated GPM protein, or a portion or fragment thereof, can be used as an immunogen to generate antibodies that bind GPM using standard techniques for polyclonal and monoclonal antibody preparation. The full-length GPM protein can be used or, alternatively, the invention provides antigenic peptide fragments of GPM for use as immunogens. The antigenic peptide of GPM comprises at least 8 amino acid residues of the amino acid sequence shown in SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8 or SEQ ID NO: 13 and encompasses_an epitope of GPM such that an antibody raised against the peptide forms a specific immune complex with GPM. Preferably, the antigenic peptide comprises at least 10 amino acid residues, more preferably at least 15 amino acid residues, even more preferably at least 20 amino acid residues, and most preferably at least 30 amino acid residues. Preferred epitopes encompassed by the antigenic peptide are regions of GPM that are located on the surface of the protein, e.g., hydrophilic regions. A GPM immunogen typically is used to prepare antibodies by immunizing a suitable subject, (e.g., rabbit, goat, mouse or other mammal) with the immunogen. An appropriate immunogenic preparation can contain, for example, recombinantly expressed GPM protein or a chemically synthesized GPM peptide. The preparation can further include an adjuvant, such as Freund's complete or incomplete adjuvant, or similar immunostimulatory agent. Immunization of a suitable subject with an immunogenic GPM preparation induces a polyclonal anti- GPM antibody response. Accordingly, another aspect of the invention pertains to anti- GPM antibodies. The term "antibody" as used herein refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, . e. , molecules that contain an antigen binding site which specifically binds (immunoreacts with) an antigen, such as GPM. Examples of immunologically active portions of immunoglobulin molecules include F(ab) and F(ab') 2 fragments which can be generated by treating the antibody with an enzyme such as pepsin. The invention provides polyclonal and monoclonal antibodies that bind GPM. The term "monoclonal antibody" or "monoclonal antibody composition", as used herein, refers to a population of antibody molecules that contain only one species of an antigen binding site capable of immunoreacting with a particular epitope of GPM. A monoclonal antibody composition thus typically displays a single binding affinity for a particular GPM protein with which it immunoreacts. Polyclonal anti- GPM antibodies can be prepared as described above by immunizing a suitable subject with a GPM immunogen. The anti- GPM antibody titer in the immunized subject can be monitored over time by standard techniques, such as with an enzyme linked immunosorbent assay (ELISA) using immobilized GPM. If desired, the antibody molecules directed against GPM can be isolated from the mammal (e.g., from the blood) and further purified by well known techniques, such as protein A chromatography to obtain the IgG fraction. At an appropriate time after immunization, e.g., when the anti- GPM antibody titers are highest, antibody-producing cells can be obtained from the subject and used to prepare monoclonal antibodies by standard techniques, such as the hybridoma technique originally described by Kohler and Milstein (1975) Nature 256:495-497) (see also, Brown et.al. (1981) J. Immunol. 127:539-46; Brown et.al. (1980) J. Biol. Chem .255:4980-83; Yeh et.al. (1976) PNAS 76:2927-31 ; and Yeh et.al. (1982) Int. J. Cancer 29:269-75), the more recent human B cell hybridoma technique (Kozbor et.al. (1983) Immunol Today 4:72), the EBV- hybridoma technique (Cole et.al. (1985), Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc., pp. 77-96) or trioma techniques. The technology for producing monoclonal antibody hybridomas is well known (see generally R. H. Kenneth, in Monoclonal Antibodies: A New Dimension In Biological Analyses, Plenum Publishing Corp., New York, New York (1980); E. A. Lerner (1981) Yale J. Biol. Med, 54:387-402; M. L. Gefter et.al. (1977) Somatic Cell Genet. 3:231-36). Briefly, an immortal cell line (typically a myeloma) is fused to lymphocytes (typically splenocytes) from a mammal immunized with a GPM immunogen as described above, and the culture supernatants of the resulting hybridoma cells are screened to identify a hybridoma producing a monoclonal antibody that binds GPM. Any of the many well known protocols used for fusing lymphocytes and immortalized cell lines can be applied for the purpose of generating an anti- GPM monoclonal antibody (see, e.g., G. Galfre et.al. (1977) Nature 266:55052; Gefter et.al. Somatic Cell Genet., cited suGPM; Lerner, Yale J. Biol. Med., cited suGPM; Kenneth, Monoclonal Antibodies, cited suGPM). Moreover, the ordinarily skilled worker will appreciate that there are many variations of such methods which also would be useful. Typically, the immortal cell line (e.g., a myeloma cell line) is derived from the same mammalian species as the lymphocytes. For example, murine hybridomas can be made by fusing lymphocytes from a mouse immunized with an immunogenic preparation of the present invention with an immortalized mouse cell line. Preferred immortal cell lines are mouse myeloma cell lines that are sensitive to culture medium containing hypoxanthine, aminopterin and thymidine ("HAT medium"). Any of a number of myeloma cell lines can be used as a fusion partner according to standard techniques, e.g., the P3-NSl/l-Ag4-l , P3-x63-Ag8.653 or Sp2/O-Agl4 myeloma lines. These myeloma lines are available from ATCC. Typically, HAT-sensitive mouse myeloma cells are fused to mouse splenocytes using polyethylene glycol ("PEG"). Hybridoma cells resulting from the fusion are then selected using HAT medium, which kills unfused and unproductively fused myeloma cells (unfused splenocytes die after several days because they are not transformed). Hybridoma cells producing a monoclonal antibody of the invention are detected by screening the hybridoma culture supernatants for antibodies that bind GPM, e.g., using a standard ELISA assay. Alternative to preparing monoclonal antibody-secreting hybridomas, a monoclonal anti- GPM antibody can be identified and isolated by screening a recombinant combinatorial immunoglobulin library (e.g., an antibody phage display library) with GPM to thereby isolate immunoglobulin library members that bind GPM. Kits for generating and screening phage display libraries are commercially available (e g., the Pharmacia Recombinant Phage Antibody System, Catalog No. 27-9400-01; and the Stratagene SurfZAP™ Phage Display Kit, Catalog No. 240612). Additionally, examples of methods and reagents particularly amenable for use in generating and screening antibody display library can be found in, for example, Ladner et.al U.S. Patent No. 5,223,409; Kang et al. PCT International Publication No. WO 92/18619; Dower et.al PCT International Publication No. WO 91/17271 ; Winter et.al PCT International Publication WO 92/20791 ; Markland et.al PCT International Publication No. WO 92/15679; Breitling et al PCT International Publication WO 93/01288; McCafferty et al PCT International Publication No. WO 92/01047; Garrard et al PCT International Publication No. WO 92/09690, Ladner et al PCT International Publication No. WO 90/02809; Fuchs et.al (1991) Bio/Technology 9.1370-1372; Hay et.al (1992) Hum Antώod Hybridomas 3:81-85; Huse et al (1989) Science 246: 1275-1281 ; Griffiths et al (1993) EMBO J 12:725-734; Hawkins et al (1992) J Mol Biol 226:889- 896; Clarkson et al (1991) Nature 352:624-628; Gram et al (1992) PNAS 89:3576- 3580; Garrad et.al (1991) Bio/Technology 9:1373-1377; Hoogenboom et.al (1991) Nuc Acid Res 19:4133-4137; Barbas et al (1991) PNAS 88:7978-7982; and McCafferty et.al Nature (1990) 348:552-554. Additionally, recombinant anti- GPM antibodies, such as chimeπc and humanized monoclonal antibodies, comprising both human and non-human portions, which can be made using standard recombinant DNA techniques, are within the scope of the invention. Such chimeric and humanized monoclonal antibodies can be produced by recombinant DNA techniques known in the art, for example using methods described in Robinson et al International Application No. PCT/US 86/02269; Akira, et.al European Patent Application 184,187; Taniguchi, M., European Patent Application 171,496, Morrison et al European Patent Application 173.494; Neuberger et.al PCT International Publication No. WO 86/01533; Cabilly et al U.S. Patent No. 4,816,567, Cabilly et al European Patent Application 125,023; Better et.al (1988) Science 240:1041-1043; Liu et al (1987) EN-4S 84:3439-3443; Liu et al (1987) J Immunol 139:3521-3526; Sun et.al (1987) PNAS 84:214-218; Νishimura et.al (1987) Cane Res 47:999-1005; Wood et.al (1985) Nature 314:446-449; and Shaw et.al (1988) J Natl Cancer Inst 80:1553-1559); Morrison. S. L (1985) Science 229: 1202-1207; Oi et.al (1986) BioTechniques 4:214; Winter U.S. Patent 5,225,539; Jones et al. £1986) Nature 321 :552-525; Verhoeyan et.al. (1988) Science 239:1534; and Beidler et.al. (1988) J Immunol. 141 :4053-4060. An anti- GPM antibody (e.g., monoclonal antibody) can be used to isolate GPM by standard techniques, such as affinity chromatography or immunoprecipitation. An anti- GPM antibody can facilitate the purification of natural GPM from cells and of recombinantly produced GPM expressed in host cells. Moreover, an anti- GPM antibody can be used to detect GPM protein (e.g., in a cellular lysate or cell supernatant) in order to evaluate the abundance and pattern of expression of the GPM protein. Anti- GPM antibodies can be used diagnostically to monitor protein levels in tissue as part of a clinical testing procedure, e.g., to, for example, determine the efficacy of a given treatment regimen. Detection can be facilitated by coupling (i.e. , physically linking) the antibody to a detectable substance. Examples of detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, and radioactive materials. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, β-galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin, and aequorin, and examples of suitable radioactive material include 12 V 3 I I, 35 S or 3 H. IV. Pharmaceutical Compositions The GPM nucleic acid molecules, GPM proteins, GPM modulators, and anti- GPM antibodies (also referred to herein as "active compounds") of the invention can be incorporated into pharmaceutical compositions suitable for administration to a subject, e.g., a human. Such compositions typically comprise the nucleic acid molecule, protein, modulator, or antibody and a pharmaceutically acceptable carrier. As used herein the language "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, such media can be used in the compositions of the invention. Supplementary active compounds can also be incorporated into the compositions. A pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as manitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions can be prepared by incorporating the active compound (e.g., a GPM protein or anti- GPM antibody) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. For administration by inhalation, the compounds are delivered in the form of an aerosol sGPMy from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer. Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sGPMys or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art. The compounds can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides]_or retention enemas for rectal delivery. In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,81 1. It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals. The nucleic acid molecules of the invention can be inserted into vectors and used as gene therapy vectors. Gene therapy vectors can be delivered to a subject by, for example, intravenous injection, local administration (see U.S. Patent 5,328,470) or by stereotactic injection (see e.g., Chen et.al (1994) PNAS 91 :3054-3057). The pharmaceutical preparation of the gene therapy vector can include the gene therapy vector in an acceptable diluent, or can comprise a slow release matrix in which the gene delivery vehicle is imbedded. Alternatively, where the complete gene delivery vector can be produced intact from recombinant cells, e g. retroviral vectors, the pharmaceutical preparation can include one or more cells which produce the gene delivery system. The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration. V. Uses and Methods of the Invention A GPM protein of the invention has one or more of the activitiesjiescribed herein and can thus be used, for example, to screen drugs or compounds which modulate GPM protein activity as well as to treat disorders characterized by insufficient production of GPM protein or production of GPM protein forms which have decreased activity compared to wild type GPM. The isolated nucleic acid molecules of the invention can be used to express GPM protein (e.g., via a recombinant expression vector in a host cell in gene therapy applications), to detect GPM mRNA (e.g., in a biological sample) or a genetic lesion in a GPM gene, and to modulate GPM activity, as described further below. Moreover, the anti- GPM antibodies of the invention can be used to detect and isolate GPM protein and modulate GPM protein activity. a. Drug Screening Assays: The invention provides methods for identifying compounds or agents which modulate GPM protein activity and/or GPM nucleic acid expression. These methods are also referred to herein as drug screening assays and typically include the step of screening a candidate/test compound or agent for the ability to interact with (e.g., bind to) a GPM protein, to modulate the interaction of a GPM protein and a target molecule, and/or to modulate GPM nucleic acid expression and/or GPM protein activity, and or to modulate signal transduction mediated at least in part by a GPM protein. Candidate/test compounds or agents which have one or more of these abilities can be used to develop drugs to treat disorders characterized by aberrant or abnormal GPM protein activity and/or GPM nucleic acid expression. Candidate/test compounds such as small molecules, e.g., small organic molecules, and other drug candidates can be obtained, for example, from combinatorial and natural product libraries. In a preferred embodiment, the invention provides ,- n-α-iυd for identifying a compound that modulates signal transduction in a cell, comprising: contacting a cell that expresses a G protein modulator (GPM) protein with a test compound; determining the effect of the test compound on the activity of the GPM protein; and identifying the test compound as a modulator of signal transduction based on the ability of the compound to modulate the activity of the GPM protein in the cell. As used herein, the term "identify" as used in the context of "identifying a compound" refers to the identification of compounds for which an activity as a G protein modulator has not been previously recognized or demonstrated. The term "identifying" according to the methods of the present invention is intended to refer to identifying, screening and/or selecting of test compound, for example selecting active compounds not previously recognized as a modulator of G protein activity for further analysis and testing. In a preferred non-limiting example, compounds "identified" according to the methods of the present invention can be used as test compounds in a second assay to confirm a G protein modulatory activity. Alternatively, compounds "identified" according to the methods of the present invention can be tested for other desireable activities or can be tested, for example, at varying doses to determine the effecacy of the compound. Compounds "identified" according to the methods of the present invention can be also tested in cell culture models or in animal models of disease. In a preferred embodiment, the GPM protein comprises an amino acid sequence at least 75% homologous to SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:6„ SEQ ID NO:8 or SEQ ID NO: 13, comprises at least one G protein regulatory motif (e.g., a GPR motif having at least 75% homology to SEQ ID NO: 10), and stimulates G protein activity in a receptor-independent manner. Alternatively, the GPM protein can comprise a structure as described above in the sections discussing GPM proteins and nucleic acids. In a preferred embodiment of the cell-based screening method, the cell has been engineered to express the GPM protein by introducing into the cell an expression vector encoding the GPM protein. The cell can be further engineered to express other proteins, such as a G protein α subunit. In a preferred embodiment, the cell is a yeast cell that has been engineered to express a GPM protein and a mammalian or chimeric G protein α subunit and the effect of the test compound on the activity of the GPM protein is determined by monitoring a pheromone response pathway in the yeast cells. A preferred chimeric G protein subunit which the yeast cell is engineered to express is a Gpal-Gαi2 chimeric G protein α subunit (preferably comprising 41 amino-terminal amino acids from yeast Gpal operatively linked to a mammalian Gαi2). The pheromone response pathway in the yeast cells can be monitored, for example, by measuring the activity of a pheromone responsive promoter in the yeast cells. Yeast cell compositions and methods that can be used for screening modulators of GPM proteins are described in further detail below and in the Examples. In an alternative embodiment, the effect of the test compound on the activity of the GPM protein is determined by monitoring the ability of the test compound to bind to the GPM protein. In another alternative embodiment, the effect of the test compound on the activity of the GPM protein is determined by monitoring the ability of the test compound to modulate the interaction of the GPM protein with a target molecule. Preferably, the target molecule is a G protein. In another embodiment, the invention provides assays for screening candidate/test compounds which interact with (e.g., bind to) GPM protein. Typically, the assays are cell-free assays which include the steps of combining a GPM protein or a biologically active portion. thereof, and a candidate/test compound, e.g., under conditions which allow for interaction of (e.g., binding of) the candidate/test compound to the GPM protein or portion thereof to form a complex, and detecting the formation of a complex, in which the ability of the candidate compound to interact with (e.g., bind to) the GPM protein or portion thereof is indicated by the presence of the candidate compound in the complex. Formation of complexes between the GPM protein and the candidate compound can be quantitated, for example, using standard immunoassays. In another embodiment, the invention provides screening assays to identify candidate/test compounds which modulate (e.g., stimulate or inhibit) the interaction (and most likely GPM activity as well) between a GPM protein and a molecule (target molecule) with which the GPM protein normally interacts. Examples of such target molecules includes proteins in the same signaling pathway as the GPM protein, e.g.. G proteins, or proteins which may function upstream (including both stimulators and inhibitors of activity) or downstream of the G protein in the pheromone response pathway. Typically, the assays are cell-free assays which include the steps of combining a GPM protein or a biologically active portion thereof, a GPM target molecule (e.g., a G protein) and a candidate/test compound, e.g., under conditions wherein but for the presence of the candidate compound, the GPM protein or biologically active portion thereof interacts with (e.g., binds to) the target molecule, and detecting the formation of a complex which includes the GPM protein and the target molecule or detecting the interaction/reaction of the GPM protein and the target molecule. Detection of complex formation can include direct quantitation of the complex by, for example, measuring inductive effects of the GPM protein. A statistically significant change, such as a decrease, in the interaction of the GPM and target molecule (e.g., in the formation of a complex between the GPM and the target molecule) in the presence of a candidate compound (relative to what is detected in the absence of the candidate compound) is indicative of a modulation (e.g., stimulation or inhibition) of the interaction between the GPM protein and the target molecule. Modulation of the formation of complexes between the GPM protein and the target molecule can be quantitated using, for example, an immunoassay. To perform the above drug screening assays, it may be desirable to immobilize either GPM or its target molecule to facilitate separation of complexes from uncomplexed forms of one or both of the proteins, as well as to accommodate automation of the assay. Interaction (e.g., binding of) of GPM to a target molecule, in the presence and absence of a candidate compound, can be accomplished in any vessel suitable for containing the reactants. Examples of such vessels include microtitre plates, test tubes, and micro-centrifuge tubes. In one embodiment, a fusion protein can be provided which adds a domain that allows the protein to be bound to a matrix. For example, glutathione-S-transferase/ GPM fusion proteins can be adsorbed onto glutathione sepharose beads (Sigma Chemical, St. Louis, MO) or glutathione derivatized microtitre plates, which are then combined with the cell lysates (e.g. 35s-. l beled) and the candidate compound, and the mixture incubated under conditions conducive to complex formation (e.g., at physiological conditions for salt and pH). Following incubation, the beads are washed to remove any unbound label, and the matrix immobilized and radiolabel determined directly, or in the supernatant after the complexes are dissociated. Alternatively, the complexes can be dissociated from the matrix, separated by SDS-PAGE, and the level of GPM-binding protein found in the bead fraction quantitated from the gel using standard electrophoretic techniques. Other techniques for immobilizing proteins on matrices can also be used in the drug screening assays of the invention. For example, either GPM or its target molecule can be immobilized utilizing conjugation of biotin and streptavidin. Biotinylated GPM molecules can be prepared from biotin-NHS (N-hydroxy-succinimide) using techniques well known in the art (e.g., biotinylation kit, Pierce Chemicals, Rockford, IL), and immobilized in the wells of streptavidin-coated 96 well plates (Pierce Chemical). Alternatively, antibodies reactive with GPM but which do not interfere with binding of the protein to its target molecule can be derivatized to the wells of the plate, and GPM trapped in the wells by antibody conjugation. As described above, preparations of a GPM-binding protein and a candidate compound are incubated in the GPM-presenting wells of the plate, and the amount of complex trapped in the well can be quantitated. Methods for detecting such complexes, in addition to those described above for the GST-immobilized complexes, include immunodetection of complexes using antibodies reactive with the GPM target molecule, or which are reactive with GPM protein and compete with the target molecule; as well as enzyme-linked assays which rely on detecting an enzymatic activity associated with the target molecule. The invention also provides cell-based assays for identifying compounds which modulate GPM activity. In one embodiment, the cell-based assay involves a method for identifying a compound which modulates (e.g.. stimulates or inhibits) GPM activity including contacting a cell which contains a GPM protein with a test compound and determining the ability of the test compound to modulate the activity of the GPM protein. In a preferred embodiment, determining the ability of the test compound to modulate GPM activity includes determining the ability of the test compound to effect (e.g., upregulate or down regulate) G-protein mediated signaling in the cell. For example, G-protein mediated signaling can be determined in a GPM-containing cell prior to contacting the cell with a test compound and compared to the signaling after contacting the cell with a test compound. Compounds which reduce the G-protein mediated signaling can be identified as GPM antagonists whereas compounds which increase the G-protein mediated signaling can be identified as antagonists. Alternatively, modulators of GPM expression can be identified in a method wherein a cell is contacted with a candidate compound and the expression of GPM mRNA or protein in the cell is determined. The level of expression of GPM mRNA or protein in the presence of the candidate compound is compared to the level of expression of GPM mRNA or protein in the absence of the candidate compound. The candidate compound can then be identified as a modulator of GPM nucleic acid expression based on this comparison. For example, when expression of GPM mRNA or protein is greater (statistically significantly greater) in the presence of the candidate compound than in its absence, the candidate compound is identified as a stimulator of GPM mRNA or protein expression. Alternatively, when expression of GPM mRNA or protein is less (statistically significantly less) in the presence of the candidate compound than in its absence, the candidate compound is identified as an inhibitor of GPM mRNA or protein expression. The level of GPM mRNA or protein expression in the cells can be determined by methods described herein for detecting GPM mRN A. or protein. The present invention also provides cell-based assa s foi identifying compounds which modulate the activity of a GPM. Cells for use in cell based assays are engineered to express a heterologous GPM protein. In preferred embodiments, the cells may be further engineered such that the endogenous GPM protein is not expressed in functional form. Cells used to express a heterologous GPM can be, for example, mammalian or yeast in origin. In preferred embodiments, the engineered cells of the present invention are yeast cells. In certain embodiments, the cells for use in the instant assays are further engineered to express a heterologous G protein coupled receptor which is functionally integrated into the signaling pathway of the cell in which it is expressed. In the case of yeast cells, heterologous GPCRs can be expressed in yeast cells and can be made to couple to yeast G proteins resulting in the transduction of signals via the endogenous yeast pheromone system signaling pathway which is normally activated by STE2 or STE3. In certain embodiments, such heterologous receptors can be made to couple more effectively to the yeast pheromone system signaling pathway by coexpressing a heterologous G protein subunit or subunits, by expressing a chimeric G protein subunit, or by expressing a chimeric G protein coupled receptor. Methods for preparing engineered yeast cells, and engineered yeast cells themselves, are described in U.S. Patent No. 5,482,835 by King et.al. and PCT Publication WO 94/23025 by Fowlkes et.al., the contents of both of which are hereby expressly incorporated herein by reference. In one embodiment of the assay, the effect of a test compound on GPM induced G protein activation can be measured by detecting changes in second messenger generation. A variety of intracellular effectors have been identified as being G-protein- regulated, including adenylyl cyclase, cyclic GMP, phosphodiesterases, phosphoinositidase C, and phospholipase A2- In addition, G proteins interact with a range of ion channels and are able to inhibit certain voltage-sensitive Ca ++ transients, as well as stimulating cardiac K + channels. For example, in yeast cells a reduction in the generation of GPM-induced second messengers or mating factor responses (e.g., growth arrest or shmoo formation) could be measured. In one embodiment, the GTPase enzymatic activity by G proteins can be measured in plasma membrane preparations by determining the breakdown of γ3 p GTP using techniques that are known in the art (For example, see Signal Transduction: A GPMctical Approach. G. Milligan, Ed. Oxford University Press, Oxford England). When receptors that modulate cAMP are tested, it will be possible to use standard techniques for cAMP detection, such as competitive assays which quantitate HJcAMP in the presence of unlabelled cAMP. Certain receptors stimulate the activity of phospholipase C which stimulates the breakdown of phosphatidylinositol 4,5, bisphosphate to 1 ,4,5-IP3 (which mobilizes intracellular Ca++) and diacylglycerol (DAG) (which activates protein kinase C). Inositol lipids can be extracted and analyzed using standard lipid extraction techniques. DAG can also be measured using thin-layer chromatography. Water soluble derivatives of all three inositol lipids (IP 1 , IP2, IP3) can also be quantitated using radiolabelling techniques or HPLC. The mobilization of intracellular calcium or the influx of calcium from outside the cell can be measured using standard techniques. The choice of the appropriate calcium indicator, fluorescent, bioluminescent, metallochromic, or Ca++-sensitive microelectrodes depends on the cell type and the magnitude and time constant of the event under study (Borle (1990) Environ Health Perspect 84:45-56).— As-en exemplary method of Ca++ detection, cells could be loaded with the Ca++sensitive fluorescent dye fura-2 or indo-1, using standard methods, and any change in Ca++ measured using a fluorometer. The other product of PIP2 breakdown, DAG can also be produced from phosphatidyl choline. The breakdown of this phospholipid in response to receptor- mediated signaling can also be measured using a variety of radiolabelling techniques. The activation of phospholipase A2 can easily be quantitated using known techniques, including, for example, the generation of arachadonate in the cell. In the case of certain receptors, it may be desirable to screen for changes in cellular phosphorylation. Such assay formats may be useful when the receptor of interest is a receptor tyrosine kinase. For example, yeast transformed with the FGF receptor and a ligand which binds the FGF receptor could be screened using colony immunoblotting (Lyons and Nelson (1984) Proc. Natl. Acad. Sci. USA 81 :7426-7430) using anti-phosphotyrosine. In addition, tests for phosphorylation could be useful when a receptor which may not itself be a tyrosine kinase, activates protein kinases that function downstream in the signal transduction pathway. Likewise, it is noted that protein phosphorylation also plays a critical role in cascades that serve to amplify signals generated at the receptor. Multi-kinase cascades allow not only signal amplification but also signal divergence to multiple effectors that are often cell-type specific, allowing a growth factor to stimulate mitosis of one cell and differentiation of another. One such cascade is the MAP kinase pathway that appears to mediate both mitogenic, differentiation and stress responses in different cell types. Stimulation of growth factor receptors results in Ras activation followed by the sequential activation of c-Raf, MEK, and p44 and p42 MAP kinases (ERK1 and ERK2). Activated MAP kinase then phosphorylates many key regulatory proteins, including p90RSK and Elk-1 that are phosphorylated when MAP kinase translocates to the nucleus. Homologous pathways exist in mammalian and yeast cells. For instance, an essential part of the S. cerevisiae pheromone signaling pathway is comprised of a protein kinase cascade composed of the products of the STE1 1, STE7, and FUS3/KSS 1 genes (the latter pair are distinct and functionally redundant). Accordingly, phosphorylation and/or activation of members of this kinase cascade can be detected and used to quantitate receptor engagement. Phosphotyrosine specific antibodies are available to measure increases in tyrosine phosphorylation and phospho-specific antibodies are commercially available (New England Biolabs, Beverly, MA). Modified methods for detecting receptor-mediated signal transduction exist and one of skill in the art will recognize suitable methods that may be used to substitute for the example methods listed. In another embodiment, an indicator gene can be used for detection. In one embodiment, an indicator gene is an unmodified endogenous gene. For example, in yeast cells, the instant method can rely on detecting the transcriptional level of such pheromone system pathway responsive endogenous genes as the Barl or Fusl. Fus 2, mating factor, Ste3 Stel3, Kexl, Ste2, Ste6, Stel, sSst2, or Chsl. (Appletauer and Zchstetter (1989) Eur. J. Biochem. 181 :243). In other embodiments, the sensitivity of an endogenous indicator gene can be enhanced by manipulating the promoter sequence at the natural locus for the indicator gene. Such manipulation may range from point mutations to the endogenous regulatory elements to gross replacement of all or substantial portions of the regulatory elements. For example, in the case of the Barl gene, the promoter of the gene can be modified to enhance the transcription of Barl upon activation of the yeast pheromone system pathway. Barl gene transcription is activated upon exposure of yeast cells to mating factor. The sequence of the Barl gene is known in the art (see e.g., U.S. patent 4,613,572). Moreover, the sequences required for α-factor-enhanced expression of the Barl, and other pheromone responsive genes have been identified. (Appeltauer and Achstetter (1989) Eur. J. Biochem. 181 :243; Hagen et. al. ( 1991 ) Mol. Cell. Biol. 1 1 :2952). In an exemplary embodiment, the yeast Barl promoter can be engineered by mutagenesis to be more responsive, e.g., to more strongly promoter gene transcription, upon stimulation of the yeast pheromone pathway. Standard techniques for mutagenizing the promoter can be used. In such embodiments, it is desirable that the conserved oligonucieotide motif described by Appeltaure et.al. be conserved. In yet other embodiments, rather than measuring second messenger production or alterations in transcription, the activity of endogenous yeast proteins can be assayed. For example, in one embodiment, the signal transduction pathway of the receptor upregulates expression or otherwise activates an enzyme which is capable of modifying a substrate which can be added to the cell. The signal can be detected by using a detectable substrate, in which case loss of the substrate signal is monitored, or alternatively, by using a substrate which produces a detectable product. In certain embodiments, the substrate is naturally occurring. Alternatively, the substrate can be non-naturally occurring. In preferred embodiments, BAR1 activity can be measured. In other embodiments, the modulation of a receptor by a test compound can result in a change in the transcription of a gene, which is not normally pheromone responsive. In preferred embodiments, the gene is easily detectable. For example, in a preferred embodiment, the subject assay can be used to measure Pho5, a secreted acid phosphatase. Acid phosphatase activity can be measured using standard techniques. In other embodiments, reporter gene constructs can be used. Reporter gene constructs are prepared by operatively linking a reporter gene with at least one transcriptional regulatory element. If only one transcriptional regulatory element is included it must be a regulatable promoter. At least one of the selected transcriptional regulatory elements must be indirectly or directly regulated by the activity of the selected cell-surface receptor whereby activity of the receptor can be monitored via transcription of the reporter genes. Many reporter genes and transcriptional regulatory elements are known to those of skill in the art and others may be identified or synthesized by methods known to those of skill in the art. Reporter genes include any gene that expresses a detectable gene product, which may be RNA or protein. Preferred reporter genes are those that are readily detectable. The reporter gene may also be included in the construct in the form of a fusion gene with a gene that includes desired transcriptional regulatory sequences or exhibits other desirable properties. Examples of reporter genes include, but are not limited to CAT (chloramphenicol acetyl transferase) (Alton and Vapnek (1979) Nature 282:864-869) luciferase, and other enzyme detection systems, such as beta-galactosidase; firefly luciferase (deWet et.al. (1987) Mol. Cell. Biol. 7:725-737); bacterial luciferase (Engebrecht and Silverman (1984), Proc. Natl. Acad. Sci. 1 :4154-4158; Baldwin et.al. (1984) Biochemistry 23:3663-3667); alkaline phosphatase (Toh et.al. (1989) Eu. J. b iochem.182:231-238, Hall et.al. (1983) J. Mol. Appl. Gen. 2:101), human placental secreted alkaline phosphatase (Cullen and Malim (1992) Methods in Enzymol. 216:362-368) and green fluorescent protein (U.S. patent 5,491,084; WO96/23898). Transcriptional control elements include, but are not limited to, promoters, enhancers, and repressor and activator binding sites. Suitable transcriptional regulatory elements may be derived from the transcriptional regulatory regions of genes whose expression is rapidly induced, generally within minutes, of contact between the cell surface protein and the effector protein that modulates the activity of the cell surface protein. Examples of such genes include, but are not limited to, the immediate early genes (see, Sheng et.α/.(1990) Neuron 4:477-485), such as c-fos. Immediate early genes are genes that are rapidly induced upon binding of a ligand to a cell surface protein. The transcriptional control elements that are preferred for use in the gene constructs include transcriptional control elements from immediate early genes, elements derived from other genes that exhibit some or all of the characteristics of the immediate early genes, or synthetic elements that are constructed such that genes in operative linkage therewith exhibit such characteristics. The characteristics of preferred genes from which the transcriptional control elements are derived include, but are not limited to, low or undetectable expression in quiescent cells, rapid induction at the transcriptional level within minutes of extracellular simulation, induction that is transient and independent of new protein synthesis, subsequent shut-off of transcription requires new protein synthesis, and mRNAs transcribed from these genes have a short half-life. It is not necessary for all of these properties to be present. Other promoters and transcriptional control elements, in addition to those described above, include the vasoactive intestinal peptide (VIP) gene promoter (cAMP responsive; Fink et.al. (1988) Proc Natl. Acad. Sci 85:6662-6666); the somatostatin gene promoter (cAMP responsive; Montminy et.al (1986) Proc Natl Acad Sci 8.3:6682-6686); the proenkephalin promoter (responsive to cAMP, nicotinic agonists, and phorbol esters; Comb et.al (1986) Nature 323:353-356); the phosphoenolpyruvate carboxy-kinase gene promoter (cAMP responsive; Short et.al. (1986) J. Biol. Chem. 261 :9721-9726); the NGFI-A gene promoter (responsive to NGF, cAMP, and serum; Changelian et.al. (1989). Proc. Natl. Acad. Sci. 86:377-381); and others that may be known to or prepared by those of skill in the art. In certain assays it may be desirable to use changes in growth in the screening procedure. For example, one of the consequences of activation of the pheromone signal pathway in wild-type yeast is growth arrest. If one is testing for an antagonist of a G protein-coupled receptor, this normal response of growth arrest can be used to select cells in which the pheromone response pathway is inhibited. That is, cells exposed to both a known agonist and a peptide of unknown activity will be growth arrested if the peptide is neutral or an agonist, but will grow normally if the peptide is an antagonist. Thus, the growth arrest response can be used to advantage to discover peptides that function as antagonists. However, when searching for compounds which can function as modulators of GPMs, the growth arrest consequent to activation of the pheromone response pathway is an undesirable effect since cells that bind agonists stop growing while surrounding cells that fail to bind agonists will continue to grow. The cells of interest, then, will be overgrown or their detection obscured by the background cells, confounding identification of the cells of interest. To overcome this problem the present invention teaches engineering the cell such that: 1) growth arrest does not occur ^ as_a result of exogenous signal pathway activation (e.g., by inactivating the FAR1 gene); and or 2) a selective growth advantage is conferred by activating the pathway (e.g., by transforming an auxotrophic mutant with a HIS3 gene under the control of a pheromone-responsive promoter, and applying selective conditions). Alternatively, the promoter may be one which is repressed by the receptor pathway, thereby preventing expression of a product which is deleterious to the cell. With a receptor repressed promoter, one screens for agonists by linking the promoter to a deleterious gene, and for antagonists, by linking it to a beneficial gene. Repression may be achieved by operably linking a receptor- induced promoter to a gene encoding mRNA which is antisense to at least a portion of the mRNA encoded by the marker gene (whether in the coding or flanking regions), so as to inhibit translation of that mRNA. Repression may also be obtained by linking a receptor-induced promoter to a gene encoding a DNA binding repressor protein, and incorporating a suitable operator site into the promoter or other suitable region of the marker gene. In the case of yeast, exemplary positively selectable (beneficial) genes include the following: URA3, LYS2, HIS3, LEU2, TRPl; ADE1, 2,3,4,5, 1,8; ARGl, 3, 4, 5, 6, 8; HIS1, 4, 5; ILV1, 2, 5; THR1, 4; TRP2, 3, 4, 5; LEU1, 4; MET2, 3, 4,8,9, 14, 16,19; URA1, 2,4,5, 10; H0M3,6; ASP3; CHOI; ARO 2, 1; CYS3; OLE1; IN01,2,4; PR01,3. Countless other genes are potential selective markers. The above are involved in well-characterized biosynthetic pathways. The imidazoleglycerol phosphate dehydratase (IGP dehydratase) gene (HIS3) is preferred because it is both quite sensitive and can be selected over a broad range of expression levels. In the simplest case, the cell is auxotrophic for histidine (requires histidine for growth) in the absence of activation. Activation leads to synthesis of the enzyme and the cell becomes prototrophic for histidine (does not require histidine). Thus the selection is for growth in the absence of histidine. Since only a few molecules per cell of IGP dehydratase are required for histidine prototrophy, the assay is very sensitive. In another embodiment a reporter gene, e.g., the fusl-lacZ reporter plasmid can be introduced along with the GPM. The addition of an antagonist should result in a decrease in β-galactosidase units over that observed in the absence of the GPM, demonstrating the ability of the antagonist to interact in a negative fashion with the GPM. In another version of the assay, cells can be selected for resistance to aminotriazole (AT), a drug that inhibits the activity of IGP dehydratase. Cells with low, fixed level of expression of HIS3 are sensitive to the drug, while cells with higher levels are resistant. The amount of AT can be selected to inhibit cells with a_basal level of HIS3 expression (whatever that level is) but allow growth of cells with an induced level of expression. In this case selection is for growth in the absence of histidine and in the presence of a suitable level of AT. In appropriate assays, so-called counterselectable or negatively selectable genes may be used. Suitable genes include: URA3 (orotidine-5'-phosphate decarboxylase; inhibits growth on 5-fluoroorotic acid), LYS2 (2-aminoadipate reductase; inhibits growth on α-aminoadipate as sole nitrogen source), CYH2 (encodes ribosomal protein L29; cycloheximide-sensitive allele is dominant to resistant allele), CAN1 (encodes arginine permease; null allele confers resistance to the arginine analog canavanin), and other recessive drug-resistant markers. In one example, the reporter gene affects yeast cell growth. The natural response to signal transduction via the yeast pheromone system response pathway is for cells to undergo growth arrest. This is a preferred way to select for antagonists of a ligand/receptor pair that stimulates a the pathway. An antagonist would inhibit the activation of the pathway; hence, the cell would be able to grow. Thus, the FAR1 gene may be considered an endogenous counterselectable marker. The FAR1 gene is preferably inactivated when screening for agonist activity. The reporter gene may also be a screenable gene. The screened characteristic may be a change in cell morphology, metabolism or other screenable features. Suitable markers include beta-galactosidase (Xgal, C12FDG, Salmon-gal, Magenta-Gal (latter two from Biosynth Ag)), alkaline phosphatase. horseradish peroxidase. exo-glucanase (product of yeast exbl gene; nonessential, secreted); luciferase; bacterial green fluorescent protein; (human placental) secreted alkaline phosphatase (SEAP); and chloramphenicol transferase (CAT). Some of the above can be engineered so that they are secreted (although not β-galactosidase). A preferred screenable marker gene is beta-galactosidase; yeast cells expressing the enzyme convert the colorless substrate Xgal into a blue pigment. Again, the promoter may be receptor-induced or receptor-inhibited. In another example using yeast cells, a screen can take advantage of the fact that a gpalfusl -HIS3 colony expressing wild type Gas can grow upon replica plating to media lacking histidine and containing ImM 3-aminotriazole (AT). The growth of this strain occurs due to the partially constitutive state of the pheromone pathway, which leads to partial derepression of Xhe fusl-HlS3 reporter gene. AT inhibits the activity of IGP dehydratase. Cells with low, fixed level of expression of HIS3 are sensitive to the drug, while cells with higher levels are resistant. The amount of AT can be selected to inhibit cells with a basal level of HIS3 expression (whatever that levej. is)_but allow growth of cells with an induced level of expression. A colony to which an antagonist of a GPM has been added will presumably fail to grow on this media due to the reduced signaling via the pheromone pathway. In certain embodiments, a peptide library can be expressed to test for modulators of a GPM. In one embodiment, the peptide library is expressed by the cell that also expresses the GPM, thereby creating an "autocrine" system, wherein the peptide to be tested for GPM-modulating activity is made by the same cell expressing the GPM protein. For a general description of yeast cell autocrine systems for screening peptide, see PCT Publication WO 94/23025 by Fowlkes et.al, the contents of which are expressly incorporated herein by reference. In certain embodiments in which yeast cells are used, such a library can be expressed using a leader sequence for periplasmic expression, e.g., a yeast mating factor leader sequence. Yeast cells are bounded by a lipid bilayer called the plasma membrane. Between this plasma membrane and the cell wall is the periplasmic space. Peptides secreted by yeast cells cross the plasma membrane through a variety of mechanisms and thereby enter the periplasmic space. The secreted peptides are then free to interact with other molecules that are present in the periplasm or displayed on the outer surface of the plasma membrane. The peptides then either undergo re-uptake into the cell, diffuse through the cell wall into the medium, or become degraded within the periplasmic space. The test polypeptide library may be secreted into the periplasm by any of a number of exemplary mechanisms, depending on the nature of the expression system to which they are linked. In one embodiment, the peptide may be structurally linked to a yeast signal sequence, such as that present in the α-factor precursor, which directs secretion through the endoplasmic reticulum and Golgi app --rat _,'... Since this is the same route that the receptor protein follows in its journey to the plasma membrane, opportunity exists in cells expressing both the receptor and the peptide library for a specific peptide to interact with the receptor during transit through the secretory pathway. This has been postulated to occur in mammalian cells exhibiting autocrine activation. S uch interaction could yield activation of the response pathway during transit, which would still allow identification of those cells expressing a peptide agonist. For situations in which peptide antagonists to externally applied receptor agonist are sought, this system would still be effective, since both the peptide antagonist and receptor would be delivered to the outside of the cell in concert. Thus, those cells producing an antagonist would be selectable, since the peptide antagonist would be properly and timely situated to prevent the receptor from being stimulated by the externally applied agonist. An alternative mechanism for delivering peptides to the periplasmic space is to use the ATP-dependent transporters of the STE6/MDR1 class. This transport pathway and the signals that direct a protein or peptide to this pathway are not as well characterized as is the endoplasmic reticulum-based secretory pathway. Nonetheless, these transporters apparently can efficiently export certain peptides directly across the plasma membrane, without the peptides having to transit the ER/Golgi pathway. It is anticipated that at least a subset of peptides can be secreted through this pathway by expressing the library in context of the α-factor prosequence and terminal tetrapeptide. The possible advantage of this system is that the receptor and peptide do not come into contact until both are delivered to the external surface of the cell. Thus, this system strictly mimics the situation of an agonist or antagonist that is normally delivered from outside the cell. Use of either of the described pathways is within the scope of the invention. The present invention does not require periplasmic secretion of peptides, or, if such secretion is provided, any particular secretion signal or transport pathway. In certain embodiments, peptides expressed with a signal sequence may bind to and activate receptors prior to their transport to the cell surface. In other embodiments, a heterologous G-protein coupled receptor can be coexpressed with a heterologous GPM protein. In embodiments in which yeast cells are used, it may be desirable to use the leader sequence of a yeast secreted protein to direct transport of G-protein coupled receptors to the plasma membrane. In certain embodiments, the compounds to be tested in the subject assays can be derived from libraries. While the use of libraries of peptides is well established in the art, new techniques have been developed which have allowed the production of mixtures of other compounds, such as benzodiazepines (Bunin et.al (1992) J. Am. Chem. Soc. 114:10987; DeWitt et.al. (1993) Proc. Natl. Acad. Sci. USA 90:6909) peptoids (Zuckermann. (1994) J. Med. Chem. 37:2678) oligocarbamates (Cho et.al. (1993) Science 261 :1303), and hydantoins (DeWitt et.al. supra). Rebek et.al. have described an approach for the synthesis of molecular libraries of small organic molecules with a diversity of 104-105 (Carell et.al. (1994) Angew. Chem. Int. Ed. Engl. 33:2059; Carell et.al. ( 994) Angew. Chem. Int. Ed. Engl. 33:2061). The compounds of the present invention can be obtained using any of the numerous approaches in combinatorial library methods known in the art, including: biological libraries; spatially addressable parallel solid phase or solution phase libraries, synthetic library methods requiring deconvolution, the 'one-bead one-compound' library method, and synthetic library methods using affinity chromatography selection. The biological library approach is limited to peptide libraries, while the other four approaches are applicable to peptide, non-peptide oligomer or small molecule libraries of compounds (Lam, K.S. (1997) Anticancer Drug Des. 12:145). In one embodiment, the test compound is a peptide or peptidomimetic. In another, preferred embodiment, the compounds are small, organic non-peptidic compounds. Other exemplary methods for the synthesis of molecular libraries can be found in the art, for example in: Erb et.al (1994) Proc. Natl Acad. Sci. USA 91 : 1 1422; Horwell et.al. (1996) Immunopharmacology 33:68; and in Gallop et.al (1994) J. Med. Chem. 37:1233. In addition, libraries such as those described in the commonly owned applications U.S.S.N. 08/864,241, U.S.S.N. 08/864,240 and U.S.S.N. 08/835,623 can be used to provide compounds for testing in the present invention. The contents of each of these applications is expressly incorporated herein by this reference. Libraries of compounds may be presented in solution (e.g., Houghten (1992) Biotechniques 13:412-421), or on beads (Lam (1991) Nature 354:82-84). chips (Fodor (1993) Nature 364:555-556), bacteria (Ladner USP 5,223,409), spores (Ladner USP '409), plasmids (Cull et.al. (1992) Proc Natl Acad Sci USA 89:1865-1869) or on phage (Scott and Smith (1990) Science 249:386-390); (Devlin (1990)Sc/e«ce 249:404-406); (Cwirla et.al. (1990) Proc. Natl Acad. Sci. 87:6378-6382); (Felici (1991) J. Mol. Biol. 222:301-310); (Ladner suGPM.). In certain embodiments, the test compounds are exogenously added to the yeast cells expressing a recombinant receptor and compounds that modulate signal transduction via the receptor are selected. In other embodiments, the yeast cells express the compounds to be tested. For example, a culture of the subject yeast cells can be further modified to collectively express a peptide library as described in more detail in PCT Publication WO 94/23025 the contents of which is expressly incorporated herein by this reference. Other types of peptide libraries may also be expressed, see, for example, U.S. Patents 5,270,181 and 5,292,646; and PCT publication WO 94/02502). In still another embodiment, the combinatorial polypeptides are produced from a cDΝA library. Exemplary compounds which can be screened for activity include, but are not limited to, peptides, nucleic acids, carbohydrates, small organic molecules, and natural product extract libraries. In such embodiments, both compounds which agonize or antagonize the receptor- or channel-mediated signaling function can be selected and identified. In certain other embodiments, cells can be engineered to produce the compounds to be tested. This assay system has the advantage of increasing the effective concentration of the compound to be tested. In one embodiment, a method such as that described in WO 94/23025 can be utilized. Other methods can also be used. For example, peptide libraries are systems which simultaneously display, in a form which permits interaction with a target, a highly diverse and numerous collection of peptides. These peptides may be presented in solution (Houghten (1992) Biotechniques 13:412-421), or on beads (Lam (1991) Nature 354:82-84), chips (Fodor (1993) Nature 364:555-556), bacteria (Ladner USP 5,223,409), spores (Ladner USP '409), plasmids (Cull et.al. (1992) Proc Natl Acad Sci USA 89: 1865-1869) or on phage (Scott and Smith (1990) Science 249:386-390); (Devlin (1990)Sc/ ' e-ϊee 249:404-406); (Cwirla et.al. (1990) Proc. Natl. Acad. Sci. 87:6378- 6382); (Felici (1991) J Mol. Biol. 222:301-310); (Ladner suGPM.). Many of these systems are limited in terms of the maximum length of the peptide or the composition of the peptide (e.g., Cys excluded). Steric factors, such as the proximity of a support, may interfere with binding. Usually, the screening is for binding in vitro to an artificially presented target, not for activation or inhibition of a cellular signal transduction pathway in a living cell. While a cell surface receptor may be used as a target, the screening will not reveal whether the binding of the peptide caused an allosteric change in the conformation of the receptor. The Ladner et.al. patent, USSN 5,096,815, describes a method of identifying novel proteins or polypeptides with a desired DNA binding activity. Semi-random ("variegated") DNA encoding a large number of different potential binding proteins is introduced, in expressible form, into suitable yeast cells. The target DNA sequence is incorporated into a genetically engineered operon such that the binding of the protein or polypeptide will prevent expression of a gene product that is deleterious to the gene under selective conditions. Cells which survive the selective conditions are thus cells which express a protein which binds the target DNA. While it is taught that yeast cells may be used for testing, bacterial cells are preferred. The interactions between the protein and the target DNA occur only in the cell (and then only in the nucleus), not in the periplasm or cytoplasm, and the target is a nucleic acid, and not a receptor protein. Substitution of random peptide sequences for functional domains in cellular proteins permits some determination of the specific sequence requirements for the accomplishment of function. Though the details of the recognition phenomena which operate in the localization of proteins within cells remain largely unknown, the constraints on sequence variation of mitochondrial targeting sequences and protein secretion signal sequences have been elucidated using random peptides (Lemire et.al, J. Biol. Chem.(l989) 264, 20206 and Kaiser et.al (1987) Science 235:312, respectively). In certain embodiments of the instant invention, the compounds tested are in the form of peptides from a peptide library. The peptide library of the present invention takes the form of a cell culture, in which essentially each cell expresses one, and usually only one, peptide of the library. While the diversity of the library is maximized if each cell produces a peptide of a different sequence, it is usually prudent to construct the library so there is some redundancy. Depending on size, the combinatorial peptides of the library can be expressed as is, or can be incorporated into larger fusion proteins. The fusion protein can provide, for example, stability against degradation or denaturation, as well as a secretion signal if secreted. In an exemplary embodiment of a library for intracellular expression, e.g., for use in conjunction with intracellular target receptors, the polypeptide library is expressed as thioredoxin fusion proteins (see. for example, U.S. Patents 5,270,181 and 5,292,646; and PCT publication WO94/ 02502). The combinatorial peptide can be attached one the terminus of the thioredoxin protein, or, for short peptide libraries, inserted into the so-called active loop. In one embodiment, the peptide library is derived to express a combinatorial library of polypeptides which are not based on any known sequence, nor derived from cDNA. That is, the sequences of the library are largely random. In preferred embodiments, the combinatorial polypeptides are in the range of 3-100 amino acids in length, more preferably at least 5-50, and even more preferably at least 10, 13, 15, 20 or 25 amino acid residues in length. Preferably, the polypeptides of the library are of uniform length. It will be understood that the length of the --omhinatorial peptide does not reflect any extraneous sequences which may be present in order to facilitate expression, e.g., such as signal sequences or invariant portions of a fusion protein. In another embodiment, the peptide- library is a combinatorial library of polypeptides which are based at least in part on a known polypeptide sequence or a portion thereof (not a cDNA library). That is, the sequences of the library is semi- random, being derived by combinatorial mutagenesis of a known sequence. See, for example, Ladner et.al PCT publication WO 90/02909; Garrard et.al. , PCT publication WO 92/09690; Marks et.al. (1992) J. Biol Chem. 267:16007-16010: Griffths et.al. (1993) EMBO J 12:725-734; Clackson et.al. (1991) Nature 352:624-628; and Barbas et.al (1992) PNAS 89:4457-4461. Accordingly, polypeptide(s) which are known ligands for a target receptor can be mutagenized by standard techniques to derive a variegated library of polypeptide sequences which can further be screened_for agonists and/or antagonists. In still another embodiment, the combinatorial polypeptides are produced from a cDNA library. In a preferred embodiment of the present invention, the cells collectively produce a "peptide library", preferably including at least 10 3 to 10 7 different peptides, so that diverse peptides may be simultaneously assayed for the ability to interact with the exogenous receptor. In an especially preferred embodiment, at least some peptides of the peptide library are secreted into the periplasm, where they may interact with the "extracellular" binding site(s) of an exogenous receptor. They thus mimic more closely the clinical interaction of drugs with cellular receptors. This embodiment optionally may be further improved (in assays not requiring pheromone secretion) by preventing pheromone secretion, and thereby avoiding competition between the peptide and the pheromone for signal peptidase and other components of the secretion system. In certain embodiments of the present invention, the peptides of the library are encoded by a mixture of DNA molecules of different sequence. Each peptide-encoding DNA molecule is ligated with a vector DNA molecule and the resulting recombinant DNA molecule is introduced into a yeast cell. Since it is a matter of chance which peptide encoding DNA molecule is introduced into a particular cell, it is not predictable which peptide that cell will produce. However, based on a knowledge of the manner in which the mixture was prepared, one may make certain statistical predictions about the mixture of peptides in the peptide library. The peptides of the library can be composed of constant and variable residues. If the nth residue is the same for all peptides of the library, it is said to be constant. If the nth residue varies, depending on the peptide in question, the residue is a variable one. The peptides of the library will have at least one, and usually more than one, variable residue. A variable residue may vary among any of two to all twenty of the genetically encoded amino acids; the variable residues of the peptide may vary in the same or different manner. Moreover, the frequency of occurrence of the allowed amino acids at a particular residue position may be the same or different. The peptide may also have one or more constant residues. There are two principal ways in which to prepare the required DNA mixture. In one method, the DNAs are synthesized a base at a time. When variation is desired, at a base position dictated by the Genetic Code, a suitable mixture of nucleotides is reacted with the nascent DNA, rather than the pure nucleotide reagent of conventional polynucleotide synthesis. The second method provides more exact control over the amino acid variation. First, trinucleotide reagents are prepared, each trinucleotide being a codon of one (and only one) of the amino acids to be featured in the peptide library. When a particular variable residue is to be synthesized, a mixture is made of the appropriate trinucleotides and reacted with the nascent DNA. Once the necessary "degenerate" DNA is complete, it must be joined with the pNA sequences necessary to assure the expression of the peptide, as discussed in more detail below, and the complete DNA construct must be introduced into the yeast cell. In the case of yeast cells, test polypeptide library may be secreted into the periplasm by any of a number of exemplary mechanisms, depending on the nature of the expression system to which they are linked. In one embodiment, the peptide may be structurally linked to a yeast signal sequence, such as that present in the α-factor precursor, which directs secretion through the endoplasmic reticulum and Golgi apparatus. Since this is the same route that the receptor protein follows in its journey to the plasma membrane, opportunity exists in cells expressing both the receptor and the peptide library for a specific peptide to interact with the receptor during transit through the secretory pathway. This has been postulated to occur in mammalian cells exhibiting autocrine activation. Such interaction could yield activation of the response pathway during transit, which would still allow identification of those cells expressing a peptide agonist. For situations in which peptide antagonists to externally applied receptor agonist are sought, this system would still be effective, since both the peptide antagonist and receptor would be delivered to the outside of the cell in concert. Thus, those cells producing an antagonist would be selectable, since the peptide antagonist would be properly and timely situated to prevent the receptor from being stimulated by the externally applied agonist. An alternative mechanism for delivering peptides to the periplasmic space is to use the ATP-dependent transporters of the STE6/MDR1 class. This transport pathway and the signals that direct a protein or peptide to this pathway are not as well characterized as is the endoplasmic reticulum-based secretory pathway. Nonetheless, these transporters apparently can efficiently export certain peptides directly across the plasma membrane, without the peptides having to transit the ER/Golgi pathway. It is anticipated that at least a subset of peptides can be secreted through this pathway by expressing the library in context of the a-factor prosequence and terminal tetrapeptide. The possible advantage of this system is that the receptor and peptide do not come into contact until both are delivered to the external surface of the cell. Thus, this system strictly mimics the situation of an agonist or antagonist that is normally delivered from outside the cell. Use of either of the described pathways is within the_scope of the invention. The present invention does not require periplasmic secretion, or, if such secretion is provided, any particular secretion signal or transport pathway. After identifying certain test compounds as potential modulators of GPMs, the practitioner of the subject assay will continue to test the efficacy and specificity of the selected compounds both in vitro and in vivo. Whether for subsequent in vivo testing, or for administration to an animal as an approved drug, agents identified in the subject assay can be formulated in pharmaceutical preparations for in vivo administration to an animal, preferably a human. The compounds selected in the subject assay, or a pharmaceutically acceptable salt thereof, may accordingly be formulated for administration with a biologically acceptable medium, such as water, buffered saline, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol and the like) or suitable mixtures thereof. The optimum concentration of the active ingredient(s) in the chosen medium can be determined empirically, according to procedures well known to medicinal chemists. As used herein, "biologically acceptable medium" includes any and all solvents, dispersion media, and the like which may be appropriate for the desired route of administration of the pharmaceutical preparation. The use of such media for pharmaceutically active substances is known in the art. Except insofar as any conventional media or agent is incompatible with the activity of the compound, its use in the pharmaceutical preparation of the invention is contemplated. Suitable vehicles and their formulation inclusive of other proteins are described, for example, in the book Remington's Pharmaceutical Sciences (Remington's Pharmaceutical Sciences. Mack Publishing Company, Easton, Pa., USA 1985). These vehicles include injectable "deposit formulations". Based on the above, such pharmaceutical formulations include, although not exclusively, solutions or freeze-dried powders of the compound in association with one or more pharmaceutically acceptable vehicles or diluents, and contained in buffered media at a suitable pH and isosmotic with physiological fluids. In preferred embodiment, the compound can be disposed in a sterile preparation for topical and/or systemic administration. In the case of freeze-dried preparations, supporting excipients such as, but not exclusively, mannitol or glycine may be used and appropriate buffered solutions of the desired volume will be provided so as to obtain adequate isotonic buffered solutions of the desired pH. Similar solutions may also be used for the pharmaceutical compositions of compounds in isotonic solutions of the desired volume and include, but not exclusively, the use of buffered saline solutions with phosphate or citrate at suitable concentrations so asjo obtain at all times isotonic pharmaceutical preparations of the desired pH, (for example, neutral pH). In yet another aspect of the invention, the GPM proteins can be used as "bait proteins" in a two-hybrid assay (see, e.g., U.S. Patent No. 5,283,317; Zervos et.al. (1993) Cell 72:223-232; Madura et.al. (1993) J Biol. Chem. 268:12046-12054; Bartel et.al. (1993) Biotechniques 14:920-924; Iwabuchi et.al. (1993) Oncogene 8: 1693-1696; and Brent WO94/10300), to identify other proteins, which bind to or interact with GPM (" GPM-binding proteins" or " GPM-bp") and modulate GPM protein activity. Such GPM-binding proteins are also likely to be involved in the propagation of signals by the GPM proteins as, for example, upstream or downstream elements of the pheromone response pathway. The two-hybrid system is based on the modular nature of most transcription factors, which consist of separable DNA-binding and activation domains. Briefly, the assay utilizes two different DNA constructs. In one construct, the gene that codes for GPM is fused to a gene encoding the DNA binding domain of a known transcription factor (e.g., GAL-4). In the other construct, a DNA sequence, from a library of DNA sequences, that encodes an unidentified protein ("prey" or "sample") is fused to a gene that codes for the activation domain of the known transcription factor. If the "bait" and the "prey" proteins are able to interact, in vivo, forming a GPM-dependent complex, the DNA-binding and activation domains of the transcription factor are brought into close proximity. This proximity allows transcription of a reporter gene (e.g., LacZ) which is operably linked to a transcriptional regulatory site responsive to the transcription factor. Expression of the reporter gene can be detected and cell colonies containing the functional transcription factor can be isolated and used to obtain the cloned gene which encodes the protein which interacts with GPM. Modulators of GPM protein activity and or GPM nucleic acid expression identified according to these drug screening assays can be to treat, for example, diseases or disorders characterized by excessive or insufficient G-protein mediated signal transduction. Examples of such diseases or disorders which can be treated using modulators of GPM protein activity and/or nucleic acid expression include inflammatory disorders/diseases, immune diseases/disorders, proliferative diseases/disorders (e.g., cancer), developmental disordesr/diseases, and or differentiative diseases/disorders. These methods of treatment include the steps of administering the GPM molecules of the present invention or modulators of GPM protein activity and/or nucleic acid expression, e.g., in a pharmaceutical composition as described above, to a subject in need of such treatment. b. Detection and Diagnostic Assays: The invention further provides a method for detecting the presence of GPM in a biological sample. The method involves contacting the biological sample with a compound or an agent capable of detecting GPM protein or mRNA such that the presence of GPM is detected in the biological sample. A preferred agent for detecting GPM mRNA is a labeled or labelable nucleic acid probe capable of hybridizing to GPM mRNA. The nucleic acid probe can be, for example, the full-length GPM cDNA of SEQ ID NOT, SEQ ID NO:5, or SEQ ID NO:7, or a portion thereof, such as an oligonucieotide of at least 15, 30, 50, 100, 250 or 500 nucleotides in length and sufficient to specifically hybridize under stringent conditions to GPM mRNA. A preferred agent for detecting GPM protein is a labeled or labelable antibody capable of binding to GPM protein. Antibodies can be polyclonal, or more preferably, monoclonal. An intact antibody, or a fragment thereof (e.g., Fab or F(ab')2) can be used. The term "labeled or labelable", with regard to the probe or antibody, is intended to encompass direct labeling of the probe or antibody by coupling (i.e., physically linking) a detectable substance to the probe or antibody, as well as indirect labeling of the probe or antibody by reactivity with another reagent that is directly labeled. Examples of indirect labeling include detection of a primary antibody using a fluorescently labeled secondary antibody and end-labeling of a DNA probe with biotin such that it can be detected with fluorescently labeled streptavidin. The term "biological sample" is intended to include tissues, cells and biological fluids isolated from a subject, as well as tissues, cells and fluids present within a subject. That is, the detection method of the invention can be used to detect GPM mRNA or protein in a biological sample in vitro as well as in vivo. For example, in vitro techniques for detection of GPM mRNA include Northern hybridizations and in situ hybridizations. In vitro techniques for detection of GPM protein include enzyme linked immunosorbent assays (ELISAs), Western blots, immunoprecipitations and immunofluorescence. Alternatively, GPM protein can be detected in vivo in a subject by introducing into the subject a labeled anti- GPM antibody. For example, the antibody can be labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques. In one preferred embodiment of the detection method, the biological sample is a cell sample, a tissue section, for example, a freeze-dried or fresh frozen section of tissue removed from a patient, or a biological fluid obtained from a subject. The invention also encompasses kits for detecting the presence of GPM in a biological sample. For example, the kit can comprise a labeled or labelable compound or agent capable of detecting GPM protein or mRNA in a biological sample; means for determining the amount of GPM in the sample; and means for comparing the amount of GPM in the sample with a standard. The compound or agent can be packaged in a suitable container. The kit can further comprise instructions for using the kit to detect GPM mRNA or protein. c. Methods of Treatment: Additional methods of the invention include methods for treating a subject having a disorder characterized by aberrant GPM activity or expression. These methods include administering to the subject a GPM modulator such that treatment of the subject occurs. The terms "treating" or "treatment", as used herein, refer to reduction or alleviation of at least one adverse effect or symptom of a disease or disorder, e.g., a disease or disorder characterized by or associated with abnormal or aberrant GPM protein activity or GPM nucleic acid expression. As used herein, a GPM modulator is a molecule which can modulate GPM nucleic acid expression and or GPM protein activity. For example, a GPM modulator can modulate, e.g., upregulate (activate) or downregulate (suppress), GPM nucleic acid expression. In another example, a GPM modulator can modulate (e.g., stimulate or inhibit) GPM protein activity. If it is desirable to treat a disease or disorder characterized by (or associated with) aberrant or abnormal (non- wild-type) GPM nucleic acid expression and/or GPM protein activity by inhibiting GPM nucleic acid expression, a GPM modulator can be an antisense molecule, e.g., a ribozyme, as described herein. Examples of antisense molecules which can be used to inhibit GPM nucleic acid expression include antisense molecules which are complementary to a portion of the 5' untranslated region of SEQ ID NOT, SEQ ID NO:5, or SEQ ID NO:7, which also includes the start codon and antisense molecules which are complementary to a portion of the 3' untranslated region of SEQ ID NOT, SEQ ID NO:5, or SEQ ID NO:7. A GPM modulator which inhibits GPM nucleic acid expression can also be a small molecule or other drug, e.g., a small molecule or drug identified using the screening assays described herein, which inhibits GPM nucleic acid expression. If it is desirable to treat a disease or disorder characterized by (or associated with) aberrant or abnormal (non-wild-type) GPM nucleic acid expression and/or GPM protein activity by stimulating GPM nucleic acid expression, a GPM modulator can be, for example, a nucleic acid molecule encoding GPM (e.g., a nucleic acid molecule comprising a nucleotide sequence homologous to the nucleotide sequence of SEQ ID NOT) or a small molecule or other drug, e.g., a small molecule (peptide) or drug identified using the screening assays described herein, which stimulates GPM nucleic acid expression. Alternatively, if it is desirable to treat a disease or disorder characterized by (or associated with) aberrant or abnormal (non-wild-type) GPM nucleic acid expression and/or GPM protein activity by inhibiting GPM protein activity, a GPM modulator can be an anti- GPM antibody or a small molecule or other drug, e.g., a small molecule or drug identified using the screening assays described herein, which inhibits GPM protein activity. If it is desirable to treat a disease or disorder characterized by (or associated with) aberrant or abnormal (non-wild-type) GPM nucleic acid expression and/or GPM protein activity by stimulating GPM protein activity, a GPM modulator can be an active GPM protein or portion thereof (e.g., a GPM protein or portion thereof having an amino acid sequence which is homologous to the amino acid sequence of SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8 or SEQ ID NO: 13 or a portion thereof) or a small molecule or other drug, e.g., a small molecule or drug identified using the screening assays described herein, which stimulates GPM protein activity. Other aspects of the invention pertain to methods for modulating a cell associated activity. These methods include contacting the cell with an agent (or a composition which includes an effective amount of an agent) which modulates GPM activity or GPM expression such that a cell associated activity is altered relative to a cell associated activity of the cell in the absence of the agent. As used herein, "a cell associated activity" refers to a normal or abnormal activity or function of a cell. Examples of cell associated activities include proliferation, migration, differentiation, production or secretion of molecules, such as proteins, and cell survival. In a preferred embodiment, the cell-associated activity is mediated by a G-protein signaling pathway. The term "altered" as used herein refers to a change, e.g., an increase or decrease, of a cell associated activity. In one embodiment, the agent stimulates GPM protein activity or GPM nucleic acid expression. Examples of such stimulatory agents include an active GPM protein, a nucleic acid molecule encoding GPM that has been introduced into the cell, and a modulatory agent which stimulates GPM protein activity or GPM nucleic acid expression and which is identified using the drug screening assays described herein. In another embodiment, the agent inhibits GPM protein activity or GPM nucleic acid expression. Examples of such inhibitory agents include an antisense GPM nucleic acid molecule, an anti- GPM antibody, and a modulatory agent which inhibits GPM protein activity or GPM nucleic acid expression and which is identified using the drug screening assays described herein. These modulatory methods can be performed in vitro (e.g., by culturing the cell with the agent) or, alternatively, in vivo (e.g., by administering the agent to a subject). In a preferred embodiment, the modulatory methods are performed in vivo, i.e., the cell is present within a subject, e.g., a mammal, e.g., a human, and the subject has a disorder or disease characterized by or associated with abnormal or aberrant GPM activity or expression. A nucleic acid molecule, a protein, a GPM modulator etc. used in the methods of treatment can be incorporated into an appropriate pharmaceutical composition described herein and administered to the subject through a route which allows the molecule, protein, modulator etc. to perform its intended function. Examples of routes of administration are also described herein. Particular GPM inhibitory agents and GPM stimulatory agents are described further below. Inhibitory Agents According to a modulatory method of the invention, GPM activity is inhibited in a cell by contacting the cell with an inhibitory agent. Inhibitory agents of the invention can be, for example, intracellular binding molecules that act to inhibit the expression or activity of GPM. As used herein, the term "intracellular binding molecule" is intended to include molecules that act in tracellularly to inhibit the expression or activity of a protein by binding to the protein itself, to a nucleic acid (e.g., an mRNA molecule) that encodes the protein or to a target with which the protein indirectly interacts. Examples of intracellular binding molecules, described in further detail below, include antisense GPM nucleic acid molecules (e.g., to inhibit translation of GPM mRNA), intracellular anti-GPM antibodies (e.g., to inhibit the activity of GPM protein) and chemical inhibitors of the GPM protein. In one embodiment, an inhibitory agent of the invenuon is an antisense nucleic acid molecule that is complementary to a gene encoding AGSor to a portion of said gene, or a recombinant expression vector encoding said antisense nucleic acid molecule. The use of antisense nucleic acids to downregulate the expression of a particular protein in a cell is well known in the art (see e.g., Weintraub, H. et.al, Antisense RNA as a molecular tool for genetic analysis, Reviews - Trends in Genetics, Vol. 1(1) 1986; Askari, F.K. and McDonnell, W.M. (1996) N. Eng. J. Med. 334:316-318; Bennett, M.R. and Schwartz, S.M. (1995) Circulation 92: 1981-1993; Mercola, D. and Cohen, J.S. (1995) Cancer Gene Ther. 2:47-59; Rossi, J.J. (1995) Br. Med. Bull 51_:217-225; Wagner, R.W. (1994) Nature 372:333-335). An antisense nucleic acid molecule comprises a nucleotide sequence that is complementary to the coding strand of another nucleic acid molecule (e.g., an mRNA sequence) and accordingly is capable of hydrogen bonding to the coding strand of the other nucleic acid molecule. Antisense sequences complementary to a sequence of an mRNA can be complementary to a sequence found in the coding region of the mRNA, the 5 ' or 3' untranslated region of the mRNA or a region bridging the coding region and an untranslated region (e.g., at the junction of the 5' untranslated region and the coding region). Furthermore, an antisense nucleic acid can be complementary in sequence to a regulatory region of the gene encoding the mRNA, for instance a transcription initiation sequence or regulatory element. Preferably, an antisense nucleic acid is designed so as to be complementary to a region preceding or spanning the initiation codon on the coding strand or in the 3' untranslated region of an mRNA. An antisense nucleic acid for inhibiting the expression of GPM protein in a cell can be designed based upon the nucleotide sequence encoding the GPM protein (e.g., SEQ ID NO: 1), constructed according to the rules of Watson and Crick base pairing (e.g., as described above in subsection I). An antisense nucleic acid can exist in a variety of different forms. For example, the antisense nucleic acid can be an oligonucieotide that is complementary to only a portion of an GPM gene. An antisense oligonucleotides can be constructed using chemical synthesis procedures known in the art. An antisense oligonucieotide can be chemically synthesized using naturally occurring nucleotides or variously modified nucleotides designed to increase the biological stability of the molecules or to increase the physical stability of the duplex formed between the antisense and sense nucleic acids, e.g. phosphorothioate derivatives and acridine substituted nucleotides can be used. To inhibit GPM expression in cells in culture, one or more antisense oligonucleotides can be added to cells in culture media, typically at about 200 μg oligonucleotide/ml. Alternatively, an antisense nucleic acid can be produced biologically using an expression vector into which a nucleic acid has been subcloned in an antisense orientation (i.e., nucleic acid transcribed from the inserted nucleic acid will be of an antisense orientation to a target nucleic acid of interest). Regulatory sequences operatively linked to a nucleic acid cloned in the antisense orientation can be chosen which direct the expression of the antisense RNA molecule in a cell of interest, for instance promoters and/or enhancers or other regulatory sequences can be chosen which direct constitutive, tissue specific or inducible expression of antisense RNA. For example, for inducible expression of antisense RNA, an inducible eAGSaryotic regulatory system, such as the Tet system (e.g., as described in Gossen. M. and Bujard, H. (1992) Proc. Natl Acad. Sci. USA 89:5547-5551 ; Gossen, M. et.al. (1995) Science 268:1766-1769; PCT Publication No. WO 94/29442; and PCT Publication No. WO 96/01313) can be used. The antisense expression vector is prepared as described above for recombinant expression vectors, except that the cDNA (or portion thereof) is cloned into the vector in the antisense orientation. The antisense expression vector can be in the form of, for example, a recombinant plasmid, phagemid or attenuated virus. The antisense expression vector is introduced into cells using a standard transfection technique, as described above for recombinant expression vectors. In another embodiment, an antisense nucleic acid for use as an inhibitory agent is a ribozyme. Ribozymes are catalytic RNA molecules with ribonuclease activity which are capable of cleaving a single-stranded nucleic acid, such as an mRNA, to which they have a complementary region (for reviews on ribozymes see e.g., Ohkawa, J. et.al. (1995) J. Biochem. 1 18:251-258; Sigurdsson, ST. and Eckstein, F. (1995) Trends Biotechnol 13:286-289; Rossi, J.J. (1995) Trends Biotechnol. 0:301-306; Kiehntopf, M. et.al. (1995) J. Mol. Med. 73:65-71). A ribozyme having specificity for GPM mRNA can be designed based upon the nucleotide sequence of the GPM cDNA. For example, a derivative of a Tetrahymena L-19 IVS RNA can be constructed in which the base sequence of the active site is complementary to the base sequence to be cleaved in an GPM mRNA. See for example U.S. Patent Nos. 4,987,071 and 5,1 16,742, both by Cech et.al. Alternatively, GPM mRNA can be used to select a catalytic RNA having a specific ribonuclease activity from a pool of RNA molecules. See for example Bartel, D. and Szostak, J.W. (1993) Science 261 : 141 1-1418. Another type of inhibitory agent that can be used to inhibit the expression and/or activity of GPM in a cell is an intracellular antibody specific for the GPM protein. The use of intracellular antibodies to inhibit protein function in a cell is known in the art (see e.g., Carlson, J. R. (1988) Mol. Cell. Biol. 8:2638-2646; Biocca, S. et.al. (1990) EMBO J. 9:101-108; Werge, T.M. et.al. (1990) FEBS Letters 274:193-198; Carlson, J.R. (1993) Proc. Natl Acad. Sci. USA 90:7427-7428; Marasco, W.A. et.al. (1993) Proc. Natl. Acad. Sci. USA 90:7889-7893; Biocca, S. et.al. (1994) Bio/Technology 12:396-399; Chen, S-Y. et.al. (1994) Human Gene Therapy 5:595-601; Duan, L et.al. (1994) Proc. Natl. Acad. Sci. USA 9L5075-5079; Chen, S-Y. et.al (1994) Proc. Natl Acad. Sci. USA 9j_:5932-5936; Beerli, R.R. et.al. (1994) J Biol. Chem. 269:23931-23936; Beerli, R.R. et.al (1994) Biochem. Biophys. Res. Commun. 204:666-672; Mhashilkar, A.M. et.al (1995) EMBO J. 14:1542-1551; Richardson, J.H. et.al. (1995) Proc. Natl Acad. Sci. USA 92:3137-3141; PCT Publication No. WO 94/02610 by Marasco et.al ; and PCT Publication No. WO 95/03832 by Duan et.al). To inhibit protein activity using an intracellular antibody, a recombinant expression vector is prepared which encodes the antibody chains in a form such that, upon introduction of the vector into a cell, the antibody chains are expressed as a functional antibody in an intracellular compartment of the cell. For inhibition of GPM activity according to the inhibitory methods of the invention, an intracellular antibody that specifically binds the GPM protein is expressed in the cytoplasm of the cell. To prepare an intracellular antibody expression vector, antibody light and heavy chain cDNAs encoding antibody chains specific for the target protein of interest, e.g., GPM, are isolated, typically frorn a hybridoma that secretes a monoclonal antibody specific for the GPM protein. Hybridomas secreting anti-GPM monoclonal antibodies, or recombinant anti-GPM monoclonal antibodies, can be prepared as described above. Once a monoclonal antibody specific for GPM protein has been identified (e.g., either a hybridoma-derived monoclonal antibody or a recombinant antibody from a combinatorial library), DNAs encoding the light and heavy chains of the monoclonal antibody are isolated by standard molecular biology techniques. For hybridoma derived antibodies, light and heavy chain cDNAs can be obtained, for example, by PCR amplification or cDNA library screening. For recombinant antibodies, such as from a phage display library, cDNA encoding the light and heavy chains can be recovered from the display package (e.g., phage) isolated during the library screening process. Nucleotide sequences of antibody light and heavy chain genes from which PCR primers or cDNA library probes can be prepared are known in the art. For example, many such sequences are disclosed in Kabat, E.A., et.al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242 and in the "Vbase" human germline sequence database. Once obtained, the antibody light and heavy chain sequences are cloned into a recombinant expression vector using standard methods. To allow for cytoplasmic expression of the light and heavy chains, the nucleotide sequences encoding the hydrophobic leaders of the light and heavy chains are removed. An intracellular antibody expression vector can encode an intracellular antibody in one of several different forms. For example, in one embodiment, the vector encodes full-length antibody light and heavy chains such that a full-length antibody is expressed intracellularly. In another embodiment, the vector encodes a full-length light chain but only the VH CH1 region of the heavy chain such that a Fab fragment is expressed intracellularly. In the most preferred embodiment, the vector encodes a single chain antibody (scFv) wherein the variable regions of the light and heavy chains are linked by a flexible peptide linker (e.g., (Gly 4 Ser) 3 ) and expressed as a single chain molecule. To inhibit GPM activity in a cell, the expression vector encoding the anti-GPM intracellular antibody is introduced into the cell by standard transfection methods, as discussed hereinbefore. Other inhibitory agents that can be used to inhibit the activity of an GPM protein are chemical compounds that directly inhibit GPM activity or inhibit the interaction between GPM and target molecules. Such compounds can be identified using screening assays that select for such compounds, as described in detail above. Stimulatory Agents ^ According to a modulatory method of the invention, GPM activity is stimulated in a cell by contacting the cell with a stimulatory agent. Examples of such stimulatory agents include active GPM protein and nucleic acid molecules encoding GPM that are introduced into the cell to increase GPM activity in the cell. A preferred stimulatory agent is a nucleic acid molecule encoding an GPM protein, wherein the nucleic acid molecule is introduced into the cell in a form suitable for expression of the active GPM protein in the cell. To express an GPM protein in a cell, typically an GPM-encoding DNA is first introduced into a recombinant expression vector using standard molecular biology techniques, as described herein. AN GPM-encoding DNA can be obtained, for example, by amplification using the polymerase chain reaction (PCR), using primers based on the GPM nucleotide sequence. Following isolation or amplification of GPM- encoding DNA, the DNA fragment is introduced into an expression vector and transfected into target cells by standard methods, as described herein. Other stimulatory agents that can be used to stimulate the activity of an GPM protein are chemical compounds that stimulate GPM activity in cells, such as compounds that directly stimulate GPM protein and compounds that promote the interaction between GPM and target molecules. Such compounds can be identified using screening assays that select for such compounds, as dc cril ed in detail above. The modulatory methods of the invention can be performed in vitro (e.g., by culturing the cell with the agent or by introducing the agent into cells in culture) or, alternatively, in vivo (e.g., by administering the agent to a subject or by introducing the agent into cells of a subject, such as by gene therapy). For practicing the modulatory method in vitro, cells can be obtained from a subject by standard methods and incubated (i.e., cultured) in vitro with a modulatory agent of the invention to modulate GPM activity in the cells. If desired, cells treated in vitro with a modulatory agent of the invention can be readministered to the subject. For administration to a subject, it may be preferable to first remove residual agents in the culture from the cells before administering them to the subject. For further discussion oϊ ex vivo genetic modification of cells followed by readministration to a subject, see also U.S. Patent No. 5,399,346 by W.F. Anderson et.al. For practicing the modulatory method in vivo in a subject, the modulatory agent can be administered to the subject such that GPM activity in cells of the subject is modulated. The term "subject" is intended to include living organisms in which an GPM-dependent cellular response can be elicited. Preferred subjects are mammals. Examples of subjects include humans, monkeys, dogs, cats, mice, rats, cows, horses, goats and sheep. For stimulatory or inhibitory agents that comprise nucleic acids (including recombinant expression vectors encoding GPM protein, antisense RNA and intracellular antibodies), the agents can be introduced into cells of the subject using methods known in the art for introducing nucleic acid (e.g., DNA) into cells in vivo. Examples of such methods encompass both non-viral and viral methods, including: Direct Injection: Naked DNA can be introduced into cells in vivo by directly injecting the DNA into the cells (see e.g., Acsadi et.al. (1991 ) Nature 332:815-818; Wolff et.al. (1990) Science 247:1465-1468). For example, a delivery apparatus (e.g., a "gene gun") for injecting DNA into cells in vivo can be used. Such an apparatus is commercially available (e.g., from BioRad). Cationic Lipids: Naked DNA can be introduced into cells in vivo by complexing the DNA with cationic lipids or encapsulating the DNA in cationic liposomes. Examples of suitable cationic lipid formulations include N-[-l-(2,3- dioleoyloxy)propyl]N,N,N-triethylammonium chloride (DOTMA) and a 1 : 1 molar ratio of l,2-dimyristyloxy-propyl-3-dimethylhydroxyethylammonium bromide (DMRIE) and dioleoyl phosphatidylethanolamine (DOPE) (see e.g., Logan, J.J. et.al. (1995) Gene Therapy 2:38-49; San, H. et.al. (1993) Human Gene Therapy 4:781-788). Receptor-Mediated DNA Uptake: Naked DNA can also be introduced into cells in vivo by complexing the DNA to a cation, such as polylysine, which is coupled to a ligand for a cell-surface receptor (see for example Wu, G. and Wu, CH. (1988) J. Biol Chem. 263:14621 ; Wilson et.al. (1992) J. Biol. Chem. 267:963-967; and U.S. Patent No. 5,166,320). Binding of the DNA-ligand complex to the receptor facilitates uptake of the DNA by receptor-mediated endocytosis. A DNA-ligand complex linked to adenovirus capsids which naturally disrupt endosomes, thereby releasing material into the cytoplasm can be used to avoid degradation of the complex by intracellular lysosomes (see for example Curiel et.al. (1991) Proc. Natl. Acad. Sci. USA 88:8850; Cristiano et.al. (1993) Proc. Natl Acad. Sci. USA 90:2122-2126). Retroviruses: Defective retroviruses are well characterized for use in gene transfer for gene therapy purposes (for a review see Miller, A.D. (1990) Blood 76:271). A recombinant retrovirus can be constructed having a nucleotide sequences of interest incorporated into the retroviral genome. Additionally, portions of the retroviral genome can be removed to render the retrovirus replication defective. The replication defective retrovirus is then packaged into virions which can be used to infect a target cell through the use of a helper virus by standard techniques. Protocols for producing recombinant retroviruses and for infecting cells in vitro or in vivo with such viruses can be found in Current Protocols in Molecular Biology, Ausubel, F.M. et.al. (eds.) Greene Publishing Associates, (1989), Sections 9.10-9.14 and other standard laboratory manuals. Examples of suitable retroviruses include pLJ, pZIP, pWE and pEM which are well known to those skilled in the art. Examples of suitable packaging virus lines include ψ Crip, ψCre, ψ2 and ψ Am. Retroviruses have been used to introduce a variety of genes into many different cell types, including epithelial cells, endothelial cells, lymphocytes, myoblasts, hepatocytes, bone marrow cells, in vitro and/or in vivo (see for example Eglitis, et.al. (1985) Science 230:1395-1398; Danos and Mulligan (1988) Proc. Natl. Acad. Sci. USA 85:6460-6464; Wilson et.al. (1988) Proc. Natl Acad. Sci. USA 85:3014- 3018; Armentano et.al. (1990) Proc. Natl. Acad. Sci. USA 87:6141-6145; Huber et.al. (1991) Proc. Natl. Acad. Sci. USA 88:8039-8043; Ferry et.al. (1991 ) Proc. Natl. Acad. Sci. USA 88:8377-8381; Chowdhury et.α/. (1991) Science 254:1802-1805; van Beusechem et.al. (1992) Proc. Natl. Acad. Sci. USA 89:7640-7644; Kay et.al. (1992) Human Gene Therapy 3:641-647; Dai et.al. (1992) Proc. Natl. Acad. Sci. USA 89:10892-10895; Hwu et.al (1993) J. Immunol. 150:4104-4115; U.S. Patent No. 4,868,116; U.S. Patent No. 4,980,286; PCT Application WO 89/07136; PCT Application WO 89/02468; PCT Application WO 89/05345; and PCT Application WO 92/07573). Retroviral vectors require target cell division in order for the retroviral genome (and foreign nucleic acid inserted into it) to be integrated into the host genome to stably introduce nucleic acid into the cell. Thus, it may be necessary to stimulate replication of the target cell. Adenoviruses: The genome of an adenovirus can be manipulated such that it encodes and expresses a gene product of interest but is inactivated in terms of its ability to replicate in a normal lytic viral life cycle. See for example Berkner et.al. (1988) BioTechniques 6:616; Rosenfeld et.al. (1991) Science 252:431-434; and Rosenfeld et.al. (1992) Cell 68:143-155. Suitable adenoviral vectors derived from the adenovirus strain Ad type 5 dl324 or other strains of adenovirus (e.g., Ad2, Ad3, Ad7 etc.) are well known to those skilled in the art. Recombinant adenoviruses are advantageous in that they do not require dividing cells to be effective gene delivery vehicles and can be used to infect a wide variety of cell types, including airway epithelium (Rosenfeld et.α _(1992) cited supra), endothelial cells (Lemarchand et.al. (1992) Proc. Natl. Acad. Sci. USA 89:6482- 6486), hepatocytes (Herz and Gerard (1993) Proc. Natl. Acad. Sci. USA 90:2812-2816) and muscle cells (Quantin et.al. (1992) Proc. Natl. Acad. Sci. USA 89:2581-2584). Additionally, introduced adenoviral DNA (and foreign DNA contained therein) is not integrated into the genome of a host cell but remains episomal, thereby avoiding potential problems that can occur as a result of insertional mutagenesis in situations where introduced DNA becomes integrated into the host genome (e.g., retroviral DNA). Moreover, the carrying capacity of the adenoviral genome for foreign DNA is large (up to 8 kilobases) relative to other gene delivery vectors (Berkner et.al. cited supra; Haj- Ahmand and Graham (1986) J. Virol. 57:267). Most replication-defective adenoviral vectors currently in use are deleted for all or parts of the viral El and E3 genes but retain as much as 80 % of the adenoviral genetic material. Adeno-Associated Viruses: Adeno-associated virus (AAV) is a naturally occurring defective virus that requires another virus, such as an adenovirus or a herpes virus, as a helper virus for efficient replication and a productive life cycle. (For a review see Muzyczka et.al Curr. Topics in Micro, and Immunol. (1992) 158:97-129). It is also one of the few viruses that may integrate its DNA into non-dividing cells, and exhibits a high frequency of stable integration (see for example Flotte et.al. (1992) Am. J. Respir. Cell. Mol. Biol. 7:349-356; Samulski et.al (1989) J. Virol. 63:3822-3828; and McLaughlin et.al (1989) J. Virol. 62: 1963-1973). Vectors containing as little as 300 base pairs of AAV can be packaged and can integrate. Space for exogenous DNA is limited to about 4.5 kb. An AAV vector such as that described in Tratschin et.al. (1985) Mol. Cell. Biol. 5:3251-3260 can be used to introduce DNA into cells. A variety of nucleic acids have been introduced into different cell types using AAV vectors (see for example Hermonat et.al (1984) Proc. Natl. Acad. Sci. USA 81_:6466-6470; Tratschin et.al. (1985) Mol. Cell Biol. 4:2072-2081 ; Wondisford et.al. (1988) Mol Endocrinol 2:32-39; Tratschin et.al. (1984) J. Virol. 5L61 1-619; and Flotte et.al. (1993) J. Biol. Chem. 268:3781-3790). The efficacy of a particular expression vector system and method of introducing nucleic acid into a cell can be assessed by standard approaches routinely used in the art. For example, DNA introduced into a cell can be detected by a filter hybridization technique (e.g., Southern blotting) and RNA produced by transcription of introduced DNA can be detected, for example, by Northern blotting, RNase protection or reverse transcriptase-polymerase chain reaction (RT-PCR). The gene product can be detected by an appropriate assay, for example by immunological detection of a produced protein, such as with a specific antibody, or by a functional assay to detect a functional activity of the gene product. In a preferred embodiment, a retroviral expression vector encoding GPM is used to express GPM protein in cells in vivo, to thereby stimulate GPM protein activity in vivo. Such retroviral vectors can be prepared according to standard methods known in the art (discussed further above). A modulatory agent, such as a chemical compound, can be administered to a subject as a pharmaceutical composition. Such compositions typically comprise the modulatory agent and a pharmaceutically acceptable carrier. As used herein the term "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary' active compounds can also be incorporated into the compositions. Pharmaceutical compositions can be prepared as described above. This invention is further illustrated by the following examples which should not be construed as limiting. The contents of all references, patent applications, patents, and published patent applications cited throughout this application are hereby incorporated by reference. EXAMPLES The following yeast strains were used in the EXAMPLES described herein. TABLE 1 : YEAST STRAINS *Strain 1316/3856 serves as a control. Full length Gαi2 does not effectively couple to yeast Gβγ. 1 Growth on medium lacking tryptophan. 2 Growth on medium lacking tryptophan and histidine. containing 1 mM AT. EXAMPLE 1 : NG108-15 cDNA LIBRARY GENERATION The NG108-15 cell line was propagated as previously described. Sato et.al (1995) J. Biol. Chem. 270: 15269-15276. mRNA was prepared from 20 100 mm confluent plates of cells using the Stratagene mRNA isolation kit. The mRNA was processed for cDNA library construction using the cDNA kit from Stratagene using an oligo dT primer that contained an Xho I restriction site. The 5' end of the cDNA was modified with Eco RI adaptors. Both size fractionated and non-size fractionated cDNA was restricted with the enzymes Eco RI and Xho I and ligated into the Eco RI and Xhol restrictions sites of the yeast expression vector pYES2 to generate three independent libraries. This strategy allowed the directional insert of cDNAs into the expression vector in the sense orientation downstream of a galactose-inducible promoter. Aliquots of the ligated cDNA in pYES2 was used to transform ultracompetent XL 1 -Gold bacteria (Stratagene) to determine optimal conditions for large scale transformation. Typically five ul aliquots of the ligation mixture were used to transform 10 to 20 100 ul aliquots of ultracompetent XL-1 gold bacteria to generate a population of primary transformants. Analysis of individual transformants indicated cDNA inserts ranging from 400 to 3000 nt with ~70-80% of the transformants containing cDNA inserts. TABLE 1: NG108-15 LIBRARY CHARACTERISTICS The primary transformants were then amplified by solid phase agarose growth for 48 hrs and plasmid DNA was isolated using column fractionation using the Qaigen 7 system. EXAMPLE 2: YEAST TRANSFORMATION AND SCREENING Each cDNA library was then used to transform the yeast strain CY1316/1183, which expresses a chimeric Gpal-Gαi2 G protein α subunit and is auxotrophic for histidine (described above). The screen took advantage of the inducible expression of the library cDNAs by differential plating of transformants on glucose or galactose containing plates. Based on a series of preliminary experiments using different amounts of cDNA and yeast, the primary screen was optimized to generate 100,000 to 300,000 transformants. Primary transformants were first plated on sucrose containing medium and subsequently transferred to selective medium by replica plating . The selective medium lacks histidine and thus growth is inhibited in the yeast strain. This growth inhibition is reversed by activation of the pheromone response pathway which results in the activation of a Fusl-HIS3 construct. Expression of HIS3 restores histidine prototrophy to the yeast. The selective medium also contained galactose to induce the expression of cDNA in the pYES2 vector. Thus, cDNA clones that activated the pheromone response pathway grew on the selective medium and hence were considered to be positive clones. Transformants exhibiting growth in the primary screen were rescreened by spot growth assays. Transformants exhibiting growth in the primary screen were re-screened on medium lacking histidine and containing either glucose or galactose as carbon source. Transformants were identified as positive in the second screen if they exhibited a galactose-dependent growth phenotype. These were then further propagated to isolate plasmid DNA. The isolated plasmid was then used to retransform yeast and verify that the cDNA conferred galactose dependent growth in the selective media. The cDNAs conferring such a response were considered positive and were further evaluated by nucleotide sequencing, RNA blot analysis and epistatic experiments in different yeast strains. TABLE 2: CHARACTERIZATION OF YEAST STRAINS "analysis of 10/14 isolated N/D Primary Screen: Cultures of CY1316/1 183 (see Table 1 for list of strains) were grown in medium lacking tryptophan to an OD 60o of approximately 1 and transformed in the presence of lithium acetate. Approximately 20 μg pYES2 (2 μ URA3 GAL lp Amp ) carrying size-selected neuroblastoma-glioma NG108-15 cDNA libraries was used to transform 1 x 10 yeast cells. Transformation mixtures were plated onto sucrose medium lacking uracil and tryptophan (approximately 5 x 10 cells/plate; 1 x 10 5 transformants/plate) and grown at 30° for 22 hours. Replicas of each plate were then made onto galactose medium lacking uracil, tryptophan and histidine, and containing 1 mM aminotriazole (AT). Replica plates were incubated at 30° for 3 days and scored for growth. - 7o - Secondary Screen: Colonies growing on galactose replica plates were patched onto sucrose medium lacking uracil and tryptophan and allowed to grow for 24 hours. Cells from each path were then resuspended in sterile water. Equal numbers of cells were spotted onto 3 plates: sucrose medium lacking uracil and tryptophan; glucose medium lacking uracil, tryptophan and histidine, and containing 1 mM AT; and galactose medium lacking uracil, tryptophan and histidine, and containing 1 mM AT. Plates were grown at 30° for 2 days. Isolates showing a galactose-dependent phenotype were studied further. Spot tests: Strains CY1316/1 183, CY1316/1 127, CY1316/5533, Y1316/1 179, and CY1316Δste5/l 183 (see Table 1) were transformed with pYES2 recombinants and plated onto sucrose medium lacking uracil and tryptophan. Identical yeast cultures were transformed with the parent vector pYES2 as a control. Independent transformants from each plate were patched onto fresh sucrose medium lacking uracil and tryptophan and grown at 30°. Cells from each patch were resuspended in sterile water, and equal numbers of cells were spotted onto both glucose and galactose plates lacking uracil, tryptophan and histidine, and containing 1-2 mM AT (aminotrazole). Plates incubated at 30° for 2 days prior to photographing. Miscellaneous procedures - Nucleotide sequencing was performed by standard procedures. cDNA sequences were evaluated for open reading frames, protein motifs and homologous sequences in various data bases using the University of Wisconsin GCG Sequence analysis programs. RNA blot analysis was ; rfoπrιed as previously described Duzic and Lanier (1992) J. Biol. Chem. 267:24045-24052. The lambdaZapII ™ rat brain cDNA library was screened and isolated clones processed as previously described (Lanier et.al. 1989). EXAMPLE 3: ANALYSIS OF POSITIVE CLONES The following methodology in addition to that described previously, is used throughout the following Example. Sequence analysis Sequence retrieval and analyses were conducted via Genetics Computer Group version 9.1 software licensed to the Medical University of South Carolina ("MUSC") and funded through the Biomolecular Computing Resource of the University's Research Resource Facilities. Multiple alignments were performed by the GCG PILEUP program using default settings for gap insertion and elongation. Domain searches were performed by the GCG COMPARE/DOTPLOT PROFILESEARCH and MOTIFS commands, via internet access to the Simple Modular Architecture Research Tool (SMART) databases. Schultz et al. (1998) Proc. Natl Acad. Sci., USA 95:5857- 5864. Multiple Expectation Maximization for motif Elucidation version 2.2 (MEME), Motif Alignment and Search Tool (MAST) and Profile searches were performed via web resources at the San Diego Supercomputer Center. Bailey and Gribskov (1997) J. Comput. Biol 4:45-59. Secondary structure analysis was performed with the GCG PEPPLOT, HELICAL WHEEL and MOMENT programs as well as by the PROBE program and the PredictProtein network server at EMBL-Heidelberg. Holbrook et al. (1993) Biotechniques 14:984-989. No known fold patterns were identified in the AGS2 protein by SMART analysis, the PROBE program or the UCLA/DOE Fold Prediction server. Fischer and Eisenberg (1997) Proc. Natl. Acad. Sci., USA 94: 1 1929-1 1934. Sequencing, Immunoblotting, G-protein activation and interaction assays. Nucleotide binding assays, protein interaction assays and immunoblotting were conducted according to standard procedures. Dideoxy nucleotide sequencing was performed in the MUSC DNA sequencing facility. The peptide C- VDLAGSPEQEASGLPDPQQQYPPGαS, used for generation of GPM II antisera, was synthesized in the MUSC peptide synthesis facility and rabbits immunized through the MUSC antibody production facility. Northern Blot Alnalysis A Multiple Tissue Northern Blot (CLONTECH ® ) was hybridized with radiolabeled random-primed probes (GPM I - coding region, GPM II - nt 2261 to 2692) and the film exposed for four days. The Multiple Tissue Northern Blot includes mRNA samples form the following tissues: heart, brain, spleen, lung, liver, skeletal muscle, kidney and testis. Results Two NG108-15 cDNA clones (#37, #53) were isolated by the expression cloning strategy and thus were capable of activating the pheromone response pathway by a mechanism that did not require receptor activation. These clones were termed G protein modulators I and II (GPM I and II). Subsequent experiments using various strains of yeast expressing defective signaling molecules or in which the pheromone response pathway was interrupted by deletion of genes encoding key proteins in this signaling cascade indicated that both GPM I and GPM II acted at the level of G-protein. Thus, the clones were inactive in yeast strains null for STE5, STE4 or STE20, which function just distal to activated G-protein in this system. Strains 1316/1183 (WT) and 1316Δ steS/1 183 (Δste5), 4600/1 183 (Δste4) and 1290/1 183 (Δste20) were transformed with plasmids 3-37 and 3-53, and transformants plated on sucrose medium lacking uracil and tryptophan (S-UT). Equal numbers of cells from two independent isolates were spotted onto S-UT, as well as glucose and galactose plates lacking uracil, tryptophan and histidine and containing 1 mM AT. Plates were grown 2 days, 30°. Whereas WT- transformants grew on all medium, Δste5, Δste4, and Δste20-transformants all grew only on S-UT medium. Immunoblot analysis indicated that neither cDNA altered the levels of Gα or Gβγ subunits. Though GPM1 and GPM2 were also not functional in a yeast strain expressing its native Gα, Gpal (1316/1 179), both activators were functional in a yeast strain expressing a Gpal/Gαi2 chimeric mutant that cannot exchange GDP for GTP (1316/5533). Yeast strains 1316/1 183 (Gpal/Gα-2), 1316/5533 (Gpal/Gαi2-G204A), 1316/1127 (no Gα), and 1316/1179 (Gpal) were transformed with plasmids pYES, 3- 37, and 3-53, and transformants plated on sucrose medium lacking uracil and tryptophan (S-UT). Equal numbers of cells from independent isolates were spotted onto S-UT, as well as glucose and galactose plates lacking uracil, tryptophan and histidine, containing 1, 2, 5, or lO mM AT. Plates were grown 2 days, 30°. Whereas transformants expressing 3-37 or 3-53 and carrying either no Gα, the Gpal/Gαi2 chimera or the mutant Gpal/Gαi2-G204A chimera were all able to grow at all concentrations of AT tested, transformants expressing 3-37 or 3-53 and carrying yeast Gpal were unable to grow. Therefore, though the activators 3-37 and 3-53 both require the presence of an intact heterotrimeric G protein in order to function, and though this function appears to show some specificity for different G alpha subunits, neither activator appears to require GTP exchange on the Gα in order to function. Thus, these activators appear to be functioning through a novel pathway, one that does not require nucleotide exchange at the Gα subunit. General description of Clone #31 insert Clone #37 contained an insert of -770 nt. A polyadenylation site was found at nt 768. The first 73 nt contain GA repeats followed by an open reading frame encoding a peptide of 1 13 amino acids. The translational start methionine is found at nt 102-104 and the stop codon is at nt 441-443. Clone #37 is also referred to herein as GPM I (Figure 3). Northern blot analysis GPM I mRNA (~900nt) is enriched in lung, kidney and testis. Data base analysis A blastn search of the data bases for homologous sequences indicated that GPM I is identical to mouse tctexl (M25825). The data base search also indicated significant amino acid sequence homology with the human RP3 gene (U02556, P51808). Role of GPM I in signal processing The tctexl gene is a component of the mouse T complex and is implicated in the generation of sterile mouse due to chromosome 17 inversion. Lader et.al. (1989) Cell 58(5):969-79. The functional role of tctex in this phenotype is unclear but may involve a defect in sperm motility. Recent data indicate that the tctex 1 protein subserves functions in tissues other than sperm. The tctexl exhibits homology to the RP3 gene that encodes a protein of unknown function but which is implicated in X-linked retinal pigmentosa type 3. Roux et.al. (1994) Human Mol. Genetics 3(2):257-63. In addition, the tctexl protein was isolated from a rat brain cDNA library in a yeast two hybrid screen in which the cytosolic tyrosine kinase fyn was used as bait indicating a potential role tctexl in signal transduction. Kai et.al. (1997) J. Neurosci. Res. 48(5):407-424. Subsequently, the tctex protein was identified as a light chain of the cytoplasmic motor protein dynein. Patelking et.al. (1997) J. Cell Biol. 137(5): 1081-1090; and King et.al. (1996) J. Biol. Chem. 271(50):32281 -32287. Dynein along with kinensin and myosin represent a family of motor proteins that perform critical functions in the cell including the shuttling of vesicles within the cell, the organization of cytoskeletal components and the alignment of chromosomes during meiosis. It is of interest to note that vesicular transport and actin/tubulin dynamics are associated with GTP hydrolysis and nucleotide exchange. Indeed, the G-protein Go plays a critical role in vesicular transport in neuronal cells. Immunoblots indicate expression of tctex in rat brain, skeletal muscle and sperm cells. The identification of tctexl as a stoichiometric component of cytoplasmic dynein and the bioactivity associated with GPM I suggests a regulatory role of tctexl in dynein function that involves a heterotrimeric G-protein. Indeed, both Giα3 and Goβγ are implicated in various aspects of membrane trafficking and vesicular transport. Denker et al. (1996) J. Cell. Biol. 1333:1027-1040 and Devries et al. (1998) Mol. Biol. Cell 9:1 123-1134. Tctexl also exists in the cytoplasm free of dynein where it may subserve as yet undefined roles in cellular signaling. Tai et al. ,Supra and Campbell et al. (1998) J. Immunol. 161 :1728-1737. One such role may involve a direct regulation of heterotrimeric G-protein signaling pathways. ANALYSIS OF GPM II General description of insert Clone #53 included an insert of 1.478 kb which contained a truncated open reading frame at its 5' terminus. Clone #53 is also referred to herein as GPM II (SEQ ID NOT). A potential polyadenylation site is found at ~nt 1460. Analysis of potential open reading frames at the 5' end of the insert indicated peptide sequences of 84 or 1 19 amino acids (Figure 1 and SEQ ID NO:s 2 and 4, respectively). Thus, it appears that clone #53 contains a large segment of the 3' untranslated regions of the mRNA. Indeed, truncation of the 3' end of clone #53 to nt 480 resulted in a clone that again conferred galactose dependent growth in the selective media indicating the importance of the first 480 nt of the clone in the biological activity. The 84 amino acid reading frame (Frame 1, SEQ ID NO:2) began at nt 1 and terminated at nt 252. The 84 amino acid peptide contained a methionine at amino acid residue #1 1 and this ATG codon is positioned with an adenine at position -3. Thus this methionine is placed in the context of Kozak's consensus sequence for translational initiation and may represent a true translational start site for Frame 1. In this case the peptide encoded by Frame 1 would be 74 amino acids beginning at nt 31 , the peptide having a predicted molecular weight of -8266 Da (SEQ ID NO:3). For Frame 2, the first methionine (residue #6 of the 119 amino acid coding sequence; nt 17-19) is positioned with a guanine at position - 3 to the ATG and thus is also in the context of a Kozak's consensus sequence for translational initiation and would lead to translation of a peptide 1 14 amino acids in length that terminated at nt 358 (stop codon at 359-361 ; calculated molecular weight -12081 (SEQ ID NO-13). Distribution of GPM II mRNA Northern blot analysis using a random-primed probe derived from a DNA fragment representing the first 480 nt of clone #53 indicated expression of a -3000- 3500 nt mRNA in rat brain, rat vascular smooth muscle cells, the NG108-15 cell line and the C6 -B4 glioma cell line. An additional mRNA species of - 2000 nt was observed in rat brain. Data base analysis A blastn search of the data bases for sequences homologous to clone #53 indicated the following: 1) The first 333 nt exhibits significant homology to the 3' end of a mouse mRNA in GenBank (L23316.gb_ro), termed C10A (SEQ ID NO: 14). Only one nt differs when the sequences of GPM II and C10A are aligned for comparison purposes ^ The-guanine appearing at nucleotide 236 in the GPM II cDNA described herein is replaced by an adenine at the equivalent position in the C10A cDNA sequence. 2) Nt 844-1391 - exhibited significant homology to EST clones AA271904, AA036169. A blastp search using the peptide sequence encoded by open reading frame 1 indicated identity (with one amino acid change) to the incomplete protein encoded by L23316.gb_ro, termed C10A, which was isolated by subtractive cloning of murine erythroleukemia mRNAs. The C10A cDNA sequence (SEQ ID NOT 1) encodes a predicted protein which is at least 255 amino acid residues in length and contains at least four GPR motifs from about gly66 - alal03, about ala 1 17 - prol54, about leul 66 - pro 199, and about asp200 - glu237 (amino acids 66-103, 1 17-154, 166-199, and 200-237 of SEQ ID NOT 1, respectively). The one nucleotide difference in the two sequences results in a tyrosine in the L23316.gb_ro encoded protein and a cysteine in clone #53. The one nucleotide difference in clone #53 was confirmed in both directions with multiple primers suggesting three possibilities 1) species difference, 2) sequencing error in the genebank entry of L23316.gb_ro or 3) a point mutation in clone #53. L23316.gb_ro cDNA clone appears to be a partial clone incomplete at both the 3' and 5' end. The longest open reading frame encoded by L23316.gb_ro generates a peptide of 256 amino acids. The 84 amino acid peptide encoded by clone #53 frame 1 aligns to the carboxy terminus of L23316.gb_ro with the exception of the C/Y discrepancy. From this analysis, it appears that both clone #53 and L23316.gb_ro represent partial transcripts of longer entire gene sequences, with the last 84 amino acids of the L23316.gb_ro protein sharing significant homology to GPM II. With regards to the truncation of GPM II, it is possible that the truncation is due to incomplete extension of the 1 st strand synthesis during library construction. Alternatively, the GPM II gene truncated gene products may represent biologically active peptides expressed by NG108-15 cells. A blastp search using the peptide sequence encoded by open reading frame 1 did not reveal any high homology with any entry in the data base. The highest scoring sequence in this search was a C. elegans gene (U41544) (36% identity, 51% similarity over a 41 amino acid span) of unknown function. This degree of homology is low and of unclear significance. To isolate a full length GPM II a rat brain cDNA library was jscreened with a 40 nt oligomer corresponding to nt 98-141 of clone #53 isolated from the yeast screen. GTGGCCCTACCATGCCTGATGAGGATTTCTTCAGCCTTAT (SEQ ID NO: 12) Three sets of overlapping phage clones were isolated. Two of the clones contained inserts of -2.4 kb while the third clone contained an insert of -1 kb. The shorter clone corresponded to nt 1225 - nt 2338 of clone #53. Relative to clone #53 the larger clones exhibited 92% nt sequence identity that encompassed nt 1 to 676 of clone #53. The largest insert extended the 5' end of clone #53 by 566 in-frame amino acids. The extended amino acid sequence was identical to L23316.gb_ro with the exception of a D/E at residue 632, R/Q at residue 642, and C/Y at residue 645. The 5' end of the rat cDNA was further extended by 5'RACE to yield a full length protein of 650 amino acids with a calculated molecular weight of 72,048. The full-length nucleotide sequence is set forth as SEQ ID NO:5. The complete rat brain GPM II sequence is shown in Figure 2. Blastp analysis of non-redundant GenBank CDS translations, PDB, SwissProt and PIR indicates that the full length GPM II exhibits homology with the partial mouse cDNA 123316 (96% identity, 97% similarity) and is related to the human LGN protein (59% identity, 66% similarity) and a predicted C elegans protein (PID:gl 065449; gene F32A6.4, U40409) (30% identity, 42% similarity) (Figure 4A). The human LGN protein was originally isolated as a truncated carboxyl terminus fragment in a two- hybrid screen using Giα2 as "bait". Mochizuki et al. (1996) Gene 181 :39-43. RNA blot analysis using a 3' probe identified mRNAs of -2,300 and -4000 nt that were differentially enriched in heart and brain. Blastn analysis of human EST databases with the GPM II sequence identified cDNAs that exhibited greater homology with GPM II than with human LGN indicating that these genes likely encode two members of a family of proteins with shared structural motifs. Structural Analysis of GPM II GPM II, human LGN and the predicted C. elegans proteins are characterized two defined cassettes - LGN repeats in the amino terminus half of the protein and DDQR repeats in the carboxyl terminus half of the protein (Figure 4A,B). "SMART" analysis of the rat cDNA and human LGN sequences predicts that the amino terminus half of the molecule exists as a series of six tetratricopeptide repeats (TPR). The TPR is a highly degenerate motif of 34 amino acids found in at least 400 proteins and may be present in 3-16 copies per protein. Chen and Cohen (1997) FEBS Letters 400: 136-140; Das et al. (1998) EMBO J. 17: 1 192-1 199; and Ramero and Cohen ( 1998) Proc. Natl. Acad. Sci., USA 95:4007-4012. The six TPRs in GPM II are separated by -40, fθO, θ , 40 and 40 amino acids respectively. In contrast to the bioactivity observed with cDNA #53, which encodes 74 amino acids at the carboxyl terminus, full length GPM II was inactive in the yeast growth assay. Briefly, the 5' sequence of GPM II identified by 5'RACE was amplified by PCR using primers that allowed in frame connection with the longest phage clone identified by library screening to generate a full length GPM II cDNA. This construct was subsequently inserted into the galactose-inducible yeast expression vector pYES2. The bioactivity of full length GPM II was then compared with cDNA #53-490 (GPM-II-490 in spot growth assays and the expression of the two proteins determined by immunoblotting with the specific antiserum described previously, Figure 5A). Proteins were electrophoresed on denaturing gels (SDS, 12% polyacrylamide) and the numbers to the left of the immunoblot indicate the migration of BioRad low range molecular weight markers (x 10 3 ). The arrow indicates the slowest migrating and major immunodetected species (Mr - 70,000) for full length AGS3 (calculated molecular weight = 72,0548). The smaller peptides detected in the full length AGS3 yeast extracts likely represent proteolysis during extract preparation. Similar results were obtained in three experiments. In spot growth assays, only GPM 11-490 grew under induced selection conditions (Figure 5B). Non-induced/selection = glucose media lacking uracil/tryptophan/histidine (UTH) and containing the histidine analog aminotriazole (AT) at 1 mM. Induced/selection = galactose media lacking UTH and containing 1 mM AT. Control (Non-induced/no selection) = glucose media lacking uracil and tryptophan (UT). The carboxy terminal half of GPM II contains four repeated sequences of 18-19 amino acids that exhibit 80-85% homology: Domain I - E470 to R489, Domain II - E524 to R542, Domain III - D572 to R590, Domain IV - D606 to R624 (Figure 4A). The four repeated domains are also found in human LGN and the predicted C. elegans protein. Each of the four repeated domains regions can exist as an amphipathic helix. An amphipathic helix is also observed in the juxtamembrane portions of the 13 loop of several G-protein coupled receptors where it is involved in G-protein recognition activation. Carlson et al. (1998) Mol. Pharm. 53:451-458. Repeat domains I-IV were evaluated by MAST (Motif Alignment and Search Tool) to determine their existence in other proteins in the databases. The complete 18-19 amino acid repeat or the carboxyl half of the repeat is also found in three proteins that influence the nucleotide binding properties or GTPase activity of G-proteins (Figure 4B). Analysis of the four repeated DDQR domains in GPM II, human LGN, the predicted T. elegans protein and the single DDQR motifs in RGS12, RGS14 and rapip indicated a consensus sequence of E/DEXF/LFD/EL/ML/IXK/RXQS/GS/K/RRM/LDDQR (Figure 4B). The presence of such a repeated structural motif infers functionality and we refer to this consensus sequence as a G-protein regulatory (GPR) motif. This structural feature may be shared in proteins that interact with G-proteins and regulate subunit interactions, nucleotide exchange, GTP hydrolysis and/or the interaction of the G-protein with other entities involved in signal transduction. Mechanisms of G-protein activation. GPM I and GPM II do not share any apparent structural similarities that suggest common mechanisms of G-protein activation. To define the mechanism of G-protein activation by GPM I and GPM II, the following issues were investigated: 1) Selectivity of GPM I and GPM II for different Gα subunits; 2) Specificity of interact of GPM I and GPM II with Gα or Gβγ subunits; and 3) Alteration of nucleotide binding of GPM I and GPM II by Gα subunits? The selectivity of GPM I and GPM II for different Gα was determined using yeast strains that expressed Gpal (yeast Gα), Gsα, Giα2 Gpa , ( | ) , Giα3 Gpa ι ( ,. 4| ) and Gαl6 Gpa | ( 1 ) . GPM I and GPM II exhibited distinct selectivity profiles for the different Gα subunits. In β-galactosidase reporter assays, GPM II was only active in the Giα2 and Giα3 genetic backgrounds, whereas GPM I was active in each of the genetic backgrounds except Gpal . The Gαl6 yeast strain exhibited an elevated background signaling due to its relatively lower affinity for yeast Gβγ. These data indicated that recognition of the Gα subunit is important for the action of GPM II, whereas the effect of GPM I was qualitatively independent of the type of Gα. GPM I either recognizes features conserved in all Gα subunits or else may interact wi:.-_ Gβγ which is common to each of the yeast strains. This issue was addressed in protein interaction assays with G- protein subunits. GPM I and the active carboxyl terminus region of GPM II were generated as glutathione-S-transferase fusion proteins, expressed in bacteria or yeast and purified using a glutathione affinity matrix. The GST-GPM II construct, when expressed in yeast, was functionally similar to the original GPM II isolate in terms of its ability to promote growth. In contrast, the GST-GPM I fusion protein did not promote growth in the yeast spot growth assay suggesting that the amino terminus region of GPM I has an important functional role. GPM II specifically bound recombinant Giα2, transducin α and purified brain Gα, but it did not interact with purified brain Gβγ (Figure 6A). GPM II preferred the GDP bound conformation of Gα. In contrast to GPM II, GPM I selectively interacted with purified brain Gβγ (Figure 6A). Thus, both the functional and the protein interaction data indicated that GPM I and GPM II interact with different G-protein subunits. GPM I binding to Gβγ may also have further functional implications unrelated to subunit interactions per se, as GPM I activated the system in the absence of any Gα subunit and this action required Gβγ. Despite the ability of GPM I and GPM II to interact with the G-protein subunits, neither GPM I or GPM II influenced GTPγ 35 S binding to heterotrimeric brain G-protein (Figure 6B) or Giα2. Moreover, GPM I and GPM II were still active in a yeast strain in which the Giα2 subunit was replaced with a G204A site-directed mutant Giα2 (Figure 6C; WT strain = CY1316/1 183). Giα2 G204A behaves as a dominant negative Gα subunit by virtue of its predicted low affinity for GTP and it is incapable of supporting signal propagation by an activated receptor in our yeast system used. Lee et al. (1992) J. Biol Chem. 267:1212-1218; Wall et al (1998) Structure 6:1 169-1 183; and Hermouet et al. (1991) Proc. Natl. Acad. Sci., USA 88:10455-10459. Consistent with system activation in the absence of apparent nucleotide exchange, the actions of GPM I and GPM II were not antagonized by coexpression of the GTPase activating protein RGS4 (Figure 6C). These data indicate that GPM I and GPM II activated G-protein mediated signaling by distinct mechanisms. GPM I and GPM II activate heterotrimeric G-protein signaling by a mechanism independent of nucleotide exchange. By binding to GαGDP, GPM II may actively promote subunit dissociation and "stabilize" GαGDP, transiently preventing the interaction of GαGDP with Gβγ. Alternatively, GPM II may simply compete with Gβγ for binding to the Gα subunit. Signal duration would then depend upon the half-life of the GPM II-GαGDP complex and reassociation of GαGDP with Gβγ. In contrast to GPM II, GPM I interacts with the Gβγ subunit. Again, the interaction of GPM I with Gβγ may actively promote subunit dissociation independent of nucleotide exchange or GPM I may simply compete with Gα for interaction with Gβγ. Such mechanisms of G- protein activation dramatically differ from that involving a typical G-protein coupled receptor and might lead to selective activation of Gβγ-regulated effectors. GPM proteins are indicative of a growing number of accessory proteins that influence signal propagation by heterotrimeric G-protein systems. Lanier: The Construction of Recombinant Receptor Systems and Their Use to Gain Insight Into Receptor Events at the Receptor-G-Protein and G-Protein-Effector Interface. In General Pharmacology - Handbook of Experimental Pharmacology Series. Eds. Born et al. Springer-Verlag (1998). As is the case with GPM proteins, several of the accessory proteins directly influence the activation state of the G-protein. Sato et al. (1995) J. Biol Chem. 270:15269-15276; Sato et al. (1996) J. Biol. Chem. 271 :30052-30060; Chen et al. (1997) Genes Dev. 1 1 :3218-3231 ; Dohlman and ThornerjT 9_97) J. Biol. Chem. 272:3871-3874; Lanier et al, Supra; Strittmatter et al (1993) Proc. Natl. Acad. Sci., USA 90:5327-5331 ; Li et al. (1995). J. Biol Chem. 270:15693-15701 ; Okamoto et al. (1995) J. Biol. Chem. 270:4205-4208; Boekhoff et al (1997) J. Biol Chem. 272:4606-4612. Such entities may: 1) provide a cell-specific mechanism for signal amplification by acting in concert with G-protein coupled receptors; 2) influence the population of activated G-protein effector within the cell independent of external stimuli; 3) serve as "effectors" subject to receptor regulation and/or 4) serve as a mechanism to provide signal input to heterotrimeric G-protein signaling systems that is distinct from that initiated by a seven-membrane span hormone receptor. Equivalents Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims: What is claimed is: 1. An isolated nucleic acid molecule comprising a nucleotide sequence encoding a G protein modulator (GPM) protein, wherein the nucleotide sequence is selected form the group consisting of SEQ ID NOT, SEQ ID NO:4 and SEQ ID NO:6. A vector comprising the nucleotide sequence of claim 1. 3. A host cell containing the vector of claim 2. 4. A method for producing a GPM protein comprising culturing the host cell of claim 3 in a suitable medium until GPM is produced. 5. The method of claim 4, further comprising i •olaLiug GPM from the medium or the host cell. 6. An isolated G protein modulator (GPM) protein comprising the amino acid sequence of SEQ ID NO:2, SEQ ID NO:3 or SEQ ID NO:5. 7. A pharmaceutical composition comprising the protein of claim 6 and a pharmaceutically acceptable carrier. 8. A fusion protein comprising the GPM protein of claim 6 operatively linked to a non-GPM polypeptide. 9. Antibodies that specifically bind the GPM protein of claim 6. 10. The antibodies of claim 9, which are monoclonal. 1 1. The antibodies of claim 9, which are polyclonal. 12. A pharmaceutical composition comprising the antibodies of claim 9 and a pharmaceutically acceptable carrier. 13. A method for identifying a compound that modulates signal transduction in a cell, comprising: contacting a cell that expresses a G protein modulator (GPM) protein with a test compound; determining the effect of the test compound on the activity of the GPM protein; and identifying the test compound as a modulator of signal transduction based on the ability of the compound to modulate the activity of the GPM protein in the cell. 14. The method of claim 13, wherein the GPM protein comprises an amino acid sequence at least 75% homologous to SEQ ID NO:2 or SEQ ID NO:5, comprises at least one G protein regulatory motif having the amino acid sequence of SEQ ID NO: 8 and stimulates G protein activity in a receptor-independent manner. 15. The method of claim 13, wherein the cell has been engineered to express the GPM protein by introducing into the cell an expression vector encoding the GPM protein. 16. The method of claim 15, wherein the cell has further been engineered to express a G protein α subunit. 17. The method of claim 16, wherein the cell is a yeast cell that has been engineered to express a mammalian or chimeric G protein α subunit and the effect of the test compound on the activity of the GPM protein is determined by monitoring a pheromone response pathway in the yeast cells. 18. The method of claim 17, wherein the yeast cell has been engineered to express a Gpal-Gαi2 chimeric G protein α subunit. 19. The method of claim 17, wherein the pheromone response pathway in the yeast cells is monitored by measuring the activity of a pheromone responsive promoter in the yeast cells. 20. The method of claim 13, wherein the effect of the test compound on the activity of the GPM protein is determined by monitoring the ability of the test compound to bind to the GPM protein. 21. The method of claim 13 , wherein the effect of the test compound on the activity of the GPM protein is determined by monitoring the ability of the test compound to modulate the interaction of the GPM protein with a target molecule. 22. The method of claim 21, wherein the target molecule is a G protein. 23. A method for modulating a cell associated activity comprising contacting a cell with an agent which modulates GPM protein activity or GPM nucleic acid expression such that a cell associated activity is altered in the cell, relative to a cell associated activity of the cell in the absence of the agent. 24. The method of claim 23, wherein the cell-associated activity is a G- protein mediated activity. 25. The method of claim 23, wherein the agent stimulates GPM activity or expression. 26. The method of claim 23, wherein the agent is an active GPM protein. 27. The method of claim 23, wherein the agent is a nucleic acid encoding GPM that has been introduced into the cell. 28. The method of claim 23, wherein the agent inhibits GPM activity or expression. 29. The method of claim 23, wherein the agent is an antisense GPM nucleic acid molecule. 30. The method of claim 23, wherein the agent is an antibody that specifically binds to GPM. 31. The method of claim 23, wherein the cell is present within a subject and the agent is administered to the subject. 32. A method for treating a subject having a disorder characterized by aberrant GPM protein activity or nucleic acid expression comprising administering to the subject a GPM modulator such that treatment of the subject occurs. 33. A method for detecting the presence of GPM in a biological sample comprising contacting a biological sample with an agent capable of detecting GPM protein or mRNA such that the presence of GPM is detected in the biological sample. 34. The method of claim 33, wherein the agent is a labeled or labelable nucleic acid probe capable of hybridizing to GPM mRNA. 35. The method of claim 33, wherein the agent is a labeled or labelable antibody capable of specifically binding to GPM protein.

Inventors: CISMOWSKI MARY, DUZIC EMIR, LANIER STEPHEN M, TAKESONO AYA, CISMOWSKI, MARY, DUZIC, EMIR, LANIER, STEPHEN, M., TAKESONO, AYA
Applicants: MUSC FOUND FOR RES DEV, OSI PHARM INC, MUSC FOUNDATION FOR RESEARCH DEVELOPMENT, OSI PHARMACEUTICALS, INC.
Application year: 2000
Main classification: C07K
IPC codes: A61K38, C07K14, C12P21