MINIREVIEW
The Pathways Connecting G Protein-coupled Receptors to the Nucleus through Divergent Mitogen-activated Protein Kinase Cascades*

J. Silvio GutkindDagger

From the Oral and Pharyngeal Cancer Branch, NIDR, National Institutes of Health, Bethesda, Maryland 20892

    INTRODUCTION
Top
Introduction
References

Receptors coupled to heterotrimeric GTP-binding proteins (G proteins) are integral membrane proteins involved in the transmission of signals from the extracellular environment to the cytoplasm. The best known family of G protein-coupled receptors (GPCRs),1 currently comprising more than 1000 members, exhibits a common structural motif consisting of seven membrane-spanning regions (1) (Fig. ins;1873f1}1). A diverse array of external stimuli including neurotransmitters, hormones, phospholipids, photons, odorants, certain taste ligands, and growth factors can activate specific members of this receptor family and promote interaction between the receptor and the G protein on the intracellular side of the membrane. This causes the exchange of GDP for GTP bound to the G protein alpha  subunit and apparently the dissociation of the beta gamma heterodimers. In turn, GTP-bound G protein alpha  subunits or beta gamma complexes initiate intracellular signaling responses by acting on effector molecules such as adenylate cyclases or phospholipases or directly regulating ion channel or kinase function (Fig. 1, and see below). Sixteen distinct mammalian G protein alpha  subunits have been molecularly cloned and are divided into four families based upon sequence similarity: alpha s, alpha i, alpha q, and alpha 12. Similarly, eleven G protein gamma  subunits and five G protein beta  subunits have been identified. Thus, GPCRs are likely to represent the most diverse signal transduction systems in eukaryotic cells. The biochemical and biological consequences of such diversity in subunit composition and coupling specificity for each receptor have just begun to be elucidated. In this review, we will briefly describe the role of G proteins and their coupled receptors in normal growth control and tumorigenesis and then focus on current efforts to elucidate the signaling pathways connecting this class of cell surface receptors to nuclear events regulating gene expression.


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Fig. 1.   Diversity of the G protein-coupled receptor signal transduction system. See text for details. DAG, diacylglycerol; IP3, inositol trisphosphate.

    Proliferative Signaling through G Protein-coupled Receptors

Proliferative signaling has generally been associated with polypeptide growth factor receptors that possess an intrinsic protein tyrosine kinase activity (2). A variety of oncogenes have been found to code for mutated forms of these receptors (3) and their ligands (4) or for molecules that participate in their growth-promoting pathways (5). On the other hand, GPCRs have been traditionally linked to tissue-specific, fully differentiated cell functions (1). However, GPCRs are also expressed in proliferating cells, and they have been implicated in embryogenesis, tissue regeneration, and growth stimulation (reviewed in Ref. 6). In this regard, many ligands acting via GPCRs, including thrombin, bombesin, bradykinin, substance P, endothelin, serotonin, acetylcholine, gastrin, prostaglandin F2alpha , and lysophosphatidic acid, are known to elicit a mitogenic response in a variety of cell types (reviewed in Refs. 6 and 7), and recent gene knock-out studies indicate that certain GPCRs are essential for cell growth under physiological conditions (8). Furthermore, accumulating evidence indicates that GPCRs and their signaling molecules can harbor oncogenic potential. For example, the mas oncogene, which encodes a putative GPCR, was initially cloned using standard transfection assays by virtue of its ability to induce tumors in mice (9). Subsequently, serotonin 1C (10), muscarinic m1, m3, and m5 (11), and adrenergic alpha 1 (12) receptors were shown effectively to transform contact-inhibited cultures of rodent fibroblasts when persistently activated. Together these studies demonstrated that GPCRs can behave as agonist-dependent oncogenes and prompted several groups to explore the transforming potential of G protein alpha  subunits. In recent studies, constitutively active mutants of Galpha i, Galpha q, Galpha 0, Galpha 12, and Galpha 13 were shown to behave as transforming genes in a variety of cell types (reviewed in Ref. 13).

The recent discovery of activating mutations in GPCRs and G proteins in several disease states, including cancer, further supports a role for GPCRs in normal and aberrant growth control. For example, mutationally activated Galpha s results in hyperplasia of endocrine cells and has been found in human thyroid and pituitary tumors (reviewed in Ref. 13) and in the McCune-Albright syndrome, a disease in which multiple endocrine glands exhibit autonomous hyperproliferation (14). Interestingly, activated Galpha s contributes significantly to hyperplasia only in tissues where cAMP stimulates proliferation, thus acting as an oncogene referred to as the gsp oncogene (15). Activating mutations have also been identified for Galpha i2, referred to as the gip2 oncogene, in a subset of ovarian sex cord stromal tumors and adrenal cortical tumors (16). On the other hand, Galpha 12, referred as the gep oncogene (17, 18), was isolated as a transforming gene from a soft tissue sarcoma-derived cell (19), although its role in tumorigenesis remains unclear. Naturally occurring activated mutations in members of the Galpha q family have not yet been described.

At the receptor level, the identification of constitutively active thyroid-stimulating hormone receptor mutations in 30% of thyroid adenomas (20) provided a direct link between this class of receptors and human cancer. Similarly, mutationally activated luteinizing hormone receptors have been identified in a form of familial male precocious puberty, which results from hyperplastic growth of Leydig cells (21). Perhaps more frequently than activating mutations, paracrine and autocrine stimulation of multiple GPCRs for neuropeptides and prostaglandins has been implicated in a number of human neoplasias, including small cell lung carcinoma (22), colon adenomas and carcinomas (23), and gastric hyperplasia and cancer (24). Sequences encoding functional GPCRs have also been found in the genome of transforming DNA viruses, including herpesvirus saimiri (25) and Kaposi's sarcoma-associated herpesvirus (26). Currently available evidence suggests that, at least for Kaposi's sarcoma-associated herpesvirus, these viral GPCRs are sufficient to subvert normal growth control.

The mechanism(s) whereby GPCRs regulate cell proliferation remain poorly understood. Although inhibition of adenylyl cyclase has been observed in cells responding to growth-promoting agents acting on Gi-coupled receptors, there is no formal proof that induction of DNA synthesis results from decreasing intracellular levels of cAMP. Conversely, several lines of investigation have implicated phosphatidylinositol bisphosphate (PIP2) hydrolysis as a critical component of mitogenesis (6). However, recent studies using mutant tyrosine kinase receptors suggested that PIP2 hydrolysis is neither necessary nor sufficient for mitogenesis (27, 28). Furthermore, a number of GPCR agonists induce the PIP2 turnover pathway but fail to stimulate growth when added alone to quiescent cells (29). Although the interpretation of this body of information can be hampered by the fact that each study has been performed in a different cell line, collectively it indicates that additional effector pathways might participate in the proliferative response to GPCR stimulation.

    Role of MAP Kinase in Proliferative Pathways

Critical molecules participating in the transduction of proliferative signals have just begun to be identified. One such example is the family of extracellular signal-regulated kinases (ERKs) or MAP kinases, whose enzymatic activity increases in response to mitogenic stimulation. These kinases play a central role in mitogenic signaling, as impeding their function prevents cell proliferation in response to a number of growth-stimulating agents (30). Furthermore, aberrant functioning of proteins known to be upstream of MAPK can induce cells to acquire the transformed phenotype, and constitutive activation of the MAPK pathway is itself sufficient for tumorigenesis (31, 32). Thus, MAPKs appear to be a critical component of growth-promoting pathways. The stimulation of tyrosine kinase receptors provokes the activation of MAPKs in a multistep process. For example, essential molecules linking epidermal growth factor receptors to MAP kinase include the adaptor protein GRB2/SEM-5, a guanine nucleotide exchange protein such as SOS, the small GTP-binding protein p21ras, and a cascade of protein kinases defined sequentially as MAP kinase kinase kinase, represented by c-Raf-1, and MAP kinase kinase such as MEK1 and MEK2 (reviewed in Ref. 32). MEKs ultimately phosphorylate p44mapk and p42mapk, also known as ERK1 and ERK2, respectively, on both threonine and tyrosine residues, thereby increasing their enzymatic activity. In turn, MAP kinases phosphorylate and regulate the activity of key enzymes and nuclear proteins, which ultimately regulate the expression of genes essential for proliferation (reviewed in Ref. 33). Because of the proposed central role of MAPK in proliferative pathways, many laboratories have recently addressed the nature of those molecules connecting GPCRs to MAP kinases.

    Signaling from G Protein-coupled Receptors to MAP Kinase Involves beta gamma Subunits of Heterotrimeric G Proteins Acting on a Ras-dependent Pathway

As an approach to explore the mechanism of MAPK activation by GPCRs, several laboratories have used the transient coexpression of an epitope-tagged form of MAPK together with GPCRs in readily transfectable cell lines, such as COS-7 cells. In this cellular setting, it was observed that MAPK was potently activated upon ligand addition by either Gq-coupled or Gi-coupled receptors, respectively, in a pertussis toxin-insensitive and -sensitive fashion (34-36). However, under identical experimental conditions, activated forms of Galpha i2, Galpha q, Gs, or G12 were not able to induce MAPK activation (35).

The failure of activated Galpha subunits to mimic receptor stimulation of MAPK activity and the accumulating evidence supporting an active role for the Gbeta gamma dimers in signal transmission (37) prompted exploration of the role of beta gamma complexes in signaling to the MAPK pathway. This led to the observation that membrane-bound forms of beta gamma heterodimers can directly elicit signaling pathways leading to MAPK activation (35) and prompted the search for molecules acting downstream of Gbeta gamma in this biochemical route. In a variety of experimental conditions, it was shown that MAPK activation by beta gamma subunits required neither PLC-beta nor PKC activation but was blocked by dominant interfering mutants of the GTP-binding protein Ras (34, 35) and that beta gamma subunits can induce the accumulation of Ras in the GTP-bound, active form (34). Taken together, these findings indicated that signaling from GPCRs to MAPK involves beta gamma subunits of heterotrimeric G proteins acting on a Ras-dependent pathway and provided strong evidence that the GPCR signaling pathway converges at the level of Ras with that emerging from receptors of the tyrosine kinase class.

    The Pathway Linking GPCRs and Gbeta gamma to Ras: Tyrosine Kinases, Adaptor Molecules, Phosphoinositide 3-Kinases, PKC, and Novel Molecular Mediators

The inhibitory effect of genistein on lysophosphatidic acid-induced MAPK activation provided the first indirect indication that tyrosine kinases might mediate the activation of MAPK by GPCRs (38). Furthermore, several groups observed that activation of GPCRs in a variety of cellular systems leads to the rapid phosphorylation of the adaptor protein Shc on tyrosine residues and the consequent formation of Shc-GRB2 complexes (39, 40). Searching for candidate tyrosine kinases, Luttrell et al. (41) have recently obtained evidence that Src, or a Src-like kinase, links beta gamma to activation of the Ras-MAPK pathway through phosphorylation of Shc and the recruitment of GRB2 and SOS. That report was soon followed by several studies describing the implication of other non-receptor tyrosine kinases linking GPCRs to MAPK. These include Src-like kinases such as Fyn, Lyn, and Yes and the more distantly related Syk (42, 43) and a novel Ca2+ and PKC-dependent protein tyrosine kinase, Pyk2 (44-46). The latter is closely related to focal adhesion kinase, which is involved in the formation of focal complexes containing Src, paxillin, dynamin, and Grb2 after integrin binding. Focal adhesion kinase can also be activated by GPCRs (47, 48) and may possibly be involved in GPCR signaling to MAPK. Tyrosine kinases of the receptor class have also been implicated in GPCR signaling; both PDGF and epidermal growth factor receptors were recently shown to become phosphorylated in response to GPCR agonists (49, 50) and to play a role in MAPK activation by GPCRs by recruiting signaling complexes containing Shc and GRB2. In short, it is becoming increasingly clear that a number of non-receptor tyrosine kinases and tyrosine kinase receptors can link GPCRs to the Ras-MAPK pathway. However, the relative contribution of each of these kinases in GPCR signaling to MAPK is still unclear and under current investigation.

Additional potential links between Gbeta gamma and the Ras-MAPK pathway have been recently identified. They include the protein tyrosine phosphatase SH-PTP1 (51) and Ras-GRF, a distinct Ras guanine nucleotide exchange factor expressed in neuronal cells, which can be activated in response to GPCR stimulation or upon coexpression of Gbeta gamma (52). In addition, several groups observed that wortmannin, a phosphatidylinositol 3-kinase (PI3K) inhibitor, can diminish MAPK activation by GPCRs (see Ref. 53), and a novel PI3K isotype, termed PI3Kgamma , that is activated by Gbeta gamma complexes (54) was found to play a critical role in linking Gi-coupled receptors and Gbeta gamma to the MAPK signaling pathway (55). In this case, PI3Kgamma was found to act downstream from Gbeta gamma and upstream of Src-like kinases, thus suggesting a potential mechanism whereby heterotrimeric G proteins can regulate non-receptor tyrosine kinases.

Ras-independent activation of MAPK by GPCRs has also been reported (56, 57), although it was defined as such primarily based on the failure to observe accumulation of Ras in the GTP-bound form in response to GPCR stimulation. However, as dominant interfering mutants of Ras can diminish MAPK activation, even in systems where GTP-bound Ras was not readily demonstrable (56), it is still possible that undetected amounts of Ras in the GTP-bound form might be sufficient to cooperate with other pathways to induce MAPK activation. Alternatively, in certain cellular backgrounds, GPCRs might be able to utilize pathways bypassing the requirement for Ras activation. One such potential Ras-independent pathway might help explain the activation of MAPK by constitutively active Galpha i2, the gip2 oncogene, which can be observed in only a limited number of cell types (58). Another putative Ras-independent pathway might involve PKC, as direct activation of PKC by phorbol esters can induce MAPK in a Ras-dependent or Ras-independent fashion (59, 60). Consequently, in cells where PKC can directly activate signaling pathways leading to MAPK activation, it is expected that MAPK activation by Gq-coupled receptors would not strictly require Ras. In this line, Gq-coupled receptor activation of MAPK has been shown to be PKC-dependent (60), fully PKC-independent (61), or partially PKC-dependent (62).

We can conclude that multiple molecules may mediate MAPK activation by GPCRs and Gbeta gamma . The expression of some of these molecules follows a restricted tissue distribution (44, 52, 54), which might help explain the seemingly conflicting results obtained by different groups analyzing the relative contribution of each pathway in different cell lines and tissue culture systems. The nature of the biochemical routes utilized to communicate GPCRs to the MAPK pathway would then be expected to depend heavily on the repertoire of signaling molecules available in each particular tissue and cell type.

    G Protein-coupled Receptors Activate the Jun Kinase (JNK) Pathway by a Novel Biochemical Route

The studies described above strongly suggest that both GPCRs and tyrosine kinase receptors can activate Ras, thereby initiating a cascade of events leading to MAPK activation and transcriptional regulation. However, activation of GPCRs was found to induce a clearly distinct pattern of expression of immediate early genes, including those of the jun and fos family (64). In particular, activation of GPCRs but not tyrosine kinase receptors for PDGF led, in NIH 3T3 cells, to a remarkable expression of c-jun (64). This response did not correlate with MAPK activation (64), thus suggesting that GPCRs control a distinct biochemical route regulating gene expression. Furthermore, recent work demonstrated that a novel family of enzymes closely related to MAPK, named Jun kinases (JNKs) (65) or stress-activated protein kinases (SAPKs) (66), selectively phosphorylates and regulates the activity of the c-Jun protein. Based on those findings, the ability to signal to JNK by cell surface receptors was further investigated. Interestingly, in NIH 3T3 cells, GPCRs but not PDGF receptors were found potently to activate JNK (64), thus establishing that the GPCR signaling pathways diverge at the level of JNK from those utilized by tyrosine kinase receptors.

Although it was initially thought that JNKs were located downstream from Ras, this hypothesis was in conflict with the lack of activation of JNK by PDGF or by other agonists acting on receptors that are known to couple to the Ras pathway (64, 66). Soon, it was found that the Ras-related small GTP-binding proteins Rac1 and Cdc42 initiate an independent kinase cascade regulating JNK activity (67) and that Rac and Cdc42 are an integral part of the signaling route linking many cell surface receptors, including GPCRs, to JNK (68). More recent work has identified many components of this pathway and has shown that JNK is potently activated by several naturally occurring human oncogenes (reviewed in Ref. 69). Further examination of the G protein subunits linking GPCRs to JNK provided evidence that free beta gamma dimers (68) and, in some cellular systems, Galpha 12 (70) transfer signals from this class of receptors to JNK.

The pathway(s) connecting GPCRs to other, recently discovered members of the MAPK superfamily, such as ERK6, ERK5, and SAPK4, have not yet been defined. However, GPCRs have recently been shown to activate a novel pathway that involves the transcriptional regulation of the serum response factor by the small GTP-binding protein Rho (71), and a recent study suggests that both G12 and Gbeta gamma might connect GPCRs to Rho and to serum response factor (72). Those molecules linking GPCRs and heterotrimeric G proteins to Rho remain undefined.

    Conclusion

The emerging picture from recent reports is that in mammalian cells, beta gamma subunits of heterotrimeric G proteins communicate GPCRs with the MAPK and JNK pathways acting, respectively, on a Ras and Rac1/Cdc42-dependent biochemical route. These findings together strongly suggest that beta gamma complexes provide a molecular bridge between heterotrimeric G proteins and small GTP-binding proteins. This connection is strikingly similar to the pathway linking G protein-coupled pheromone receptors to MAPK-related enzymes in the budding yeast Saccharomyces cerevisiae. In yeast, the G protein beta  subunit can initiate activity of a MAPK cascade by binding an exchange factor for the small GTP-binding protein Cdc42, and then this GTP-binding protein physically interacts with the most upstream kinase, Ste20, causing its activation (73). An additional scaffolding protein, Ste5, binds yeast beta gamma and several components of this MAPK cascade. In mammalian cells a number of sequentially acting molecules are required instead to connect GPCRs and Gbeta gamma to Ras, including tyrosine kinases, lipid kinases, adapter molecules, PKC, and certain Ras guanine nucleotide exchange factors. However, it is still possible that heterotrimeric G proteins might directly regulate the activity of yet to be identified guanine nucleotide exchange factors for Rho-related GTPases, similar to those shown in yeast. In this line, no mammalian homologue for Ste5 has been described so far. Surprisingly, however, a very recent report suggests that a PDZ-containing protein acts as a scaffold, linking several signaling molecules to Galpha q in the visual system of the fruit fly (63). Thus, it is conceivable that still unidentified scaffolding proteins might also participate in the mammalian pathway connecting heterotrimeric G proteins to MAPK cascades.

We can conclude that the molecular complexity of the signaling pathways connecting GPCRs to the nucleus has just begun to be appreciated. These pathways involve an unsuspected number of biochemical routes, including those connecting heterotrimeric G proteins to small GTP-binding proteins of the Ras and Rho family, their regulated kinases, and their nuclear targets (Fig. 2). Further work in this area is expected to help identify the nature of all contributing molecules, as well as to elucidate fully their functional relationships. Emerging areas of interest also include exploring how all these signaling events that are initiated upon agonist binding to GPCRs, including second messenger generating systems, cytoskeletal changes, and physical interaction of heterotrimeric G protein subunits with molecules regulating kinase cascades, are integrated in space and time to elicit biologically relevant responses, including normal and aberrant cell growth.


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Fig. 2.   Divergent protein kinase cascades link G protein-coupled receptors to the nucleus. Accumulating evidence suggests that parallel kinase cascades control the activity of members of the MAP kinase family of serine-threonine kinases. (see text for details). The pathway connecting G protein-coupled receptors to low molecular weight GTP-binding proteins and to additional members of the MAP kinase superfamily as well as the identity of biologically relevant targets for these kinase cascades is yet to be fully elucidated.

    FOOTNOTES

* This minireview will be reprinted in the 1997 Minireview Compendium, which will be available in December, 1997. This is the third article of three in the "Signaling by Heterotrimeric G Proteins Minireview Series."

Dagger To whom correspondence should be addressed: Cell Growth Control Section, Oral and Pharyngeal Cancer Branch, NIDR, National Institutes of Health, Bldg. 30, Rm. 212, 9000 Rockville Pike, Bethesda, MD 20892-4330. Tel.: 301-496-6259; Fax: 301-402-0823.

1 The abbreviations used are: GPCR, G protein-coupled receptor; PIP2, phosphatidylinositol bisphosphate; MAP, mitogen-activated protein; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; MEK, MAP or ERK kinase; PLC, phospholipase C; PKC, protein kinase C; PDGF, platelet-derived growth factor; PI3K, phosphatidylinositol 3-kinase; JNK, Jun kinase; SAPK, stress-activated protein kinase.

    REFERENCES
Top
Introduction
References

  1. Dohlman, H. G., Caron, M. G., and Lefkowitz, R. J. (1987) Biochemistry 26, 2657-2664[Medline] [Order article via Infotrieve]
  2. Yarden, Y., Escobedo, J. A., Kuang, W. J., Yang-Feng, T. L., Daniel, T. O., Tremble, P. M., Chen, E. Y., Ando, M. E., Harkins, R. N., Francke, U., Fried, V. A., Ullrich, A., Williams, L. T. (1986) Nature 323, 226-232[Medline] [Order article via Infotrieve]
  3. Sherr, C. J., Rettenmier, C. W., Sacca, R., Roussel, M. F., Look, A. T., Stanley, E. R. (1985) Cell 41, 665-676[Medline] [Order article via Infotrieve]
  4. Doolittle, R. F., Hunkapiller, M. W., Hood, L. E., Devare, S. G., Robbins, K. C., Aaronson, S. A., Antoniades, H. N. (1983) Science 221, 275-277[Medline] [Order article via Infotrieve]
  5. Ullrich, A., and Schlessinger, J. (1990) Cell 61, 203-212[Medline] [Order article via Infotrieve]
  6. Rozengurt, E. (1986) Science 234, 161-166[Medline] [Order article via Infotrieve]
  7. van Biesen, T., Luttrell, L. M., Hawes, B. E., Lefkowitz, R. J. (1996) Endocr. Rev. 17, 698-714[Medline] [Order article via Infotrieve]
  8. Nagata, A., Ito, M., Iwata, N., Kuno, J., Takano, H., Minowa, O., Chihara, K., Matsui, T., and Noda, T. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 11825-11830[Abstract/Free Full Text]
  9. Young, D., Waitches, G., Birchmeier, C., Fasano, O., and Wigler, M. (1986) Cell 45, 711-719[Medline] [Order article via Infotrieve]
  10. Julius, D., Livelli, T. J., Jessell, T. M., Axel, R. (1989) Science 244, 1057-1062[Medline] [Order article via Infotrieve]
  11. Gutkind, J. S., Novotny, E. A., Brann, M. R., Robbins, K. C. (1991) Proc. Natl. Acad. Sci. U. S. A. 88, 4703-4707[Abstract]
  12. Allen, L. F., Lefkowitz, R. J., Caron, M. G., Cotecchia, S. (1991) Proc. Natl. Acad. Sci. U. S. A. 88, 11354-11358[Abstract]
  13. Dhanasekaran, N., Heasley, L. E., and Johnson, G. L. (1995) Endocr. Rev. 16, 259-270[Medline] [Order article via Infotrieve]
  14. Weinstein, L. S., Shenker, A., Gejman, P. V., Merino, M. J., Friedman, E., Spiegel, A. M. (1991) N. Engl. J. Med. 325, 1688-1695[Abstract]
  15. Landis, C. A., Masters, S. B., Spada, A., Pace, A. M., Bourne, H. R., Vallar, L. (1989) Nature 340, 692-696[CrossRef][Medline] [Order article via Infotrieve]
  16. Lyons, J., Landis, C. A., Harsh, G., Vallar, L., Grunewald, K., Feichtinger, H., Duh, Q. Y., Clark, O. H., Kawasaki, E., Bourne, H. R., McCormick, F. (1990) Science 249, 655-659[Medline] [Order article via Infotrieve]
  17. Xu, N., Voyno-Yasenetskaya, T., and Gutkind, J. S. (1994) Biochem. Biophys. Res. Commun. 201, 603-609[CrossRef][Medline] [Order article via Infotrieve]
  18. Xu, N., Bradley, L., Ambdukar, I., and Gutkind, J. S. (1993) Proc. Natl. Acad. Sci. U. S. A. 90, 6741-6745[Abstract]
  19. Chan, A. M., Fleming, T. P., McGovern, E. S., Chedid, M., Miki, T., Aaronson, S. A. (1993) Mol. Cell. Biol. 13, 762-768[Abstract]
  20. Parma, J., Duprez, L., Van Sande, J., Cochaux, P., Gervy, C., Mockel, J., Dumont, J., Vassart, G. (1993) Nature 365, 649-651[CrossRef][Medline] [Order article via Infotrieve]
  21. Shenker, A., Laue, L., Kosugi, S., Merendino, J. J., Jr., Minegishi, T., Cutler, G. B., Jr. (1993) Nature 365, 652-654[CrossRef][Medline] [Order article via Infotrieve]
  22. Cuttitta, F., Carney, D. N., Mulshine, J., Moody, T. W., Fedorko, J., Fischler, A., Minna, J. D. (1985) Nature 316, 823-826[Medline] [Order article via Infotrieve]
  23. Hoosein, N. M., Kiener, P. A., Curry, R. C., Rovati, L. C., McGilbra, D. K., Brattain, M. G. (1988) Cancer Res. 48, 7179-7183[Abstract]
  24. Tahara, E. (1990) J. Cancer Res. Clin. Oncol. 116, 121-131[Medline] [Order article via Infotrieve]
  25. Nicholas, J., Cameron, K. R., and Honess, R. W. (1992) Nature 355, 362-365[CrossRef][Medline] [Order article via Infotrieve]
  26. Arvanitakis, L., Geras-Raaka, E., Varma, A., Gershengorn, M. C., Cesarman, E. (1997) Nature 385, 347-350[CrossRef][Medline] [Order article via Infotrieve]
  27. Mohammadi, M., Dionne, C. A., Li, W., Li, N., Spivak, T., Honegger, A. M., Jaye, M., Schlessinger, J. (1992) Nature 358, 681-684[CrossRef][Medline] [Order article via Infotrieve]
  28. Coughlin, S. R., Escobedo, J. A., and Williams, L. T. (1989) Science 243, 1191-1194[Medline] [Order article via Infotrieve]
  29. Moolenaar, W. H. (1991) Cell Growth Differ. 2, 359-364[Medline] [Order article via Infotrieve]
  30. Pages, G., Lenormand, P., L'Allemain, G., Chambard, J. C., Meloche, S., Pouyssegur, J. (1993) Proc. Natl. Acad. Sci. U. S. A. 90, 8319-8323[Abstract/Free Full Text]
  31. Mansour, S. J., Matten, W. T., Hermann, A. S., Candia, J. M., Rong, S., Fukasawa, K., Vande Woude, G. F., Ahn, N. G. (1994) Science 265, 966-970[Medline] [Order article via Infotrieve]
  32. Schlessinger, J. (1993) Trends Biochem. Sci. 18, 273-275[CrossRef][Medline] [Order article via Infotrieve]
  33. Davis, R. J. (1993) J. Biol. Chem. 268, 14553-14556[Free Full Text]
  34. Koch, W. J., Hawes, B. E., Allen, L. F., Lefkowitz, R. J. (1994) Proc. Natl. Acad. Sci. U. S. A. 91, 12706-12710[Abstract/Free Full Text]
  35. Crespo, P., Xu, N., Simonds, W. F., Gutkind, J. S. (1994) Nature 369, 418-420[CrossRef][Medline] [Order article via Infotrieve]
  36. Faure, M., Voyno-Yasenetskaya, T. A., Bourne, H. R. (1994) J. Biol. Chem. 269, 7851-7854[Abstract/Free Full Text]
  37. Clapham, D. E., and Neer, E. J. (1997) Annu. Rev. Pharmacol. Toxicol. 37, 167-203[CrossRef][Medline] [Order article via Infotrieve]
  38. Hordijk, P. L., Verlaan, I., van Corven, E. J., Moolenaar, W. H. (1994) J. Biol. Chem. 269, 645-651[Abstract/Free Full Text]
  39. van Biesen, T., Hawes, B. E., Luttrell, D. K., Krueger, K. M., Touhara, K., Porfiri, E., Sakaue, M., Luttrell, L. M., Lefkowitz, R. J. (1995) Nature 376, 781-784[CrossRef][Medline] [Order article via Infotrieve]
  40. Chen, Y., Grall, D., Salcini, A. E., Pelicci, P. G., Pouyssegur, J., Van Obberghen-Schilling, E. (1996) EMBO J. 15, 1037-1044[Abstract]
  41. Luttrell, L. M., Hawes, B. E., van Biesen, T., Luttrell, D. K., Lansing, T. J., Lefkowitz, R. J. (1996) J. Biol. Chem. 271, 19443-19450[Abstract/Free Full Text]
  42. Ptasznik, A., Traynor-Kaplan, A., and Bokoch, G. M. (1995) J. Biol. Chem. 270, 19969-19973[Abstract/Free Full Text]
  43. Wan, Y., Kurosaki, T., and Huang, X. Y. (1996) Nature 380, 541-544[CrossRef][Medline] [Order article via Infotrieve]
  44. Lev, S., Moreno, H., Martinez, R., Canoll, P., Peles, E., Musacchio, J. M., Plowman, G. D., Rudy, B., Schlessinger, J. (1995) Nature 376, 737-745[CrossRef][Medline] [Order article via Infotrieve]
  45. Dikic, I., Tokiwa, G., Lev, S., Courtneidge, S. A., Schlessinger, J. (1996) Nature 383, 547-550[CrossRef][Medline] [Order article via Infotrieve]
  46. Della Rocca, G. J., van Biesen, T., Daaka, Y., Luttrell, D. K., Luttrell, L. M., Lefkowitz, R. J. (1997) J. Biol. Chem. 272, 19125-19132[Abstract/Free Full Text]
  47. Gutkind, J. S., and Robbins, K. C. (1992) Biochem. Biophys. Res. Commun. 188, 155-161[Medline] [Order article via Infotrieve]
  48. Rankin, S., Morii, N., Narumiya, S., and Rozengurt, E. (1994) FEBS Lett. 354, 315-319[CrossRef][Medline] [Order article via Infotrieve]
  49. Linseman, D. A., Benjamin, C. W., and Jones, D. A. (1995) J. Biol. Chem. 270, 12563-12568[Abstract/Free Full Text]
  50. Daub, H., Weiss, F. U., Wallasch, C., and Ullrich, A. (1996) Nature 379, 557-560[CrossRef][Medline] [Order article via Infotrieve]
  51. Gaits, F., Li, R. Y., Bigay, J., Ragab, A., Ragab-Thomas, M. F., Chap, H. (1996) J. Biol. Chem. 271, 20151-20155[Abstract/Free Full Text]
  52. Mattingly, R. R., and Macara, I. G. (1996) Nature 382, 268-272[CrossRef][Medline] [Order article via Infotrieve]
  53. Hawes, B. E., Luttrell, L. M., van Biesen, T., Lefkowitz, R. J. (1996) J. Biol. Chem. 271, 12133-12136[Abstract/Free Full Text]
  54. Stoyanov, B., Volinia, S., Hanck, T., Rubio, I., Loubtchenkov, M., Malek, D., Stoyanova, S., Vanhaesebroeck, B., Dhand, R., Nurnberg, B., et al.. (1995) Science 269, 690-693[Medline] [Order article via Infotrieve]
  55. Lopez-Ilasaca, M., Crespo, P., Pelicci, P. G., Gutkind, J. S., Wetzker, R. (1997) Science 275, 394-397[Abstract/Free Full Text]
  56. Pace, A. M., Faure, M., and Bourne, H. R. (1995) Mol. Biol. Cell 6, 1685-1695[Abstract]
  57. Takahashi, T., Kawahara, Y., Okuda, M., Ueno, H., Takeshita, A., and Yokoyama, M. (1997) J. Biol. Chem. 272, 16018-16022[Abstract/Free Full Text]
  58. Gupta, S. K., Gallego, C., Johnson, G. L., Heasley, L. E. (1992) J. Biol. Chem. 267, 7987-7990[Abstract/Free Full Text]
  59. Thomas, S. M., DeMarco, M., D'Arcangelo, G., Halegoua, S., and Brugge, J. S. (1992) Cell 68, 1031-1040[Medline] [Order article via Infotrieve]
  60. Hawes, B. E., van Biesen, T., Koch, W. J., Luttrell, L. M., Lefkowitz, R. J. (1995) J. Biol. Chem. 270, 17148-17153[Abstract/Free Full Text]
  61. Charlesworth, A., and Rozengurt, E. (1997) Oncogene 14, 2323-2329[CrossRef][Medline] [Order article via Infotrieve]
  62. Crespo, P., Xu, N., Daniotti, J. L., Troppmair, J., Rapp, U. R., Gutkind, J. S. (1994) J. Biol. Chem. 269, 21103-21109[Abstract/Free Full Text]
  63. Tsunoda, S., Sierralta, J., Sun, Y., Bodner, R., Suzuki, E., Becker, A., Socolich, M., and Zuker, C. S. (1997) Nature 388, 243-249[CrossRef][Medline] [Order article via Infotrieve]
  64. Coso, O. A., Chiariello, M., Kalinec, G., Kyriakis, J. M., Woodgett, J., Gutkind, J. S. (1995) J. Biol. Chem. 270, 5620-5624[Abstract/Free Full Text]
  65. Derijard, B., Hibi, M., Wu, I. H., Barrett, T., Su, B., Deng, T., Karin, M., Davis, R. J. (1994) Cell 76, 1025-1037[Medline] [Order article via Infotrieve]
  66. Kyriakis, J. M., Banerjee, P., Nikolakaki, E., Dai, T., Rubie, E. A., Ahmad, M. F., Avruch, J., Woodgett, J. R. (1994) Nature 369, 156-160[CrossRef][Medline] [Order article via Infotrieve]
  67. Coso, O. A., Chiariello, M., Yu, J. C., Teramoto, H., Crespo, P., Xu, N., Miki, T., Gutkind, J. S. (1995) Cell 81, 1137-1146[Medline] [Order article via Infotrieve]
  68. Coso, O. A., Teramoto, H., Simonds, W. F., Gutkind, J. S. (1996) J. Biol. Chem. 271, 3963-3966[Abstract/Free Full Text]
  69. Fanger, G. R., Gerwins, P., Widmann, C., Jarpe, M. B., Johnson, G. L. (1997) Curr. Opin. Genet. Dev. 7, 67-74[CrossRef][Medline] [Order article via Infotrieve]
  70. Prasad, M. V., Dermott, J. M., Heasley, L. E., Johnson, G. L., Dhanasekaran, N. (1995) J. Biol. Chem. 270, 18655-18659[Abstract/Free Full Text]
  71. Hill, C. S., Wynne, J., and Treisman, R. (1995) Cell 81, 1159-1170[Medline] [Order article via Infotrieve]
  72. Fromm, C., Coso, O., Montaner, S., Xu, N., and Gutkind, J. S. (1997) Proc. Natl. Acad. Sci. U. S. A. 94, 10098-10103[Abstract/Free Full Text]
  73. Herskowitz, I. (1995) Cell 80, 187-197[Medline] [Order article via Infotrieve]


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