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The Missing Link Between Transforming G Proteins and Rho?

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The Missing Link Between Transforming G Proteins and Rho? Oncogene (2001) 20, 1661 ± 1668 ã 2001 Nature Publishing Group All rights reserved 0950 ± 9232/01 $15.00 www.nature.com/onc RGS-containing RhoGEFs: the missing link between transforming G proteins and Rho? Shigetomo Fukuhara1,2, Hiroki Chikumi1 and J Silvio Gutkind*,1 1Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland MD 20892-4340, USA Oncogene (2001) 20, 1661 ± 1668. aq, and a12 (Wilkie et al., 1992). The aq family of heterotrimeric G protein a subunits is coupled to Keywords: Rho; G proteins; Ras; signal transduction; phospholipase-C b to induce the hydrolysis of G protein-coupled receptors phosphatidylinositol bis phosphate, the consequent rise in the intracellular concentration of Ca2+, and the activation of protein kinase C, whereas the as and ai Introduction families are known to activate and inhibit adenylyl cyclase to increase and decrease the level of cyclic Many mitogens promote cell proliferation by acting AMP, respectively. ai proteins also regulate ion on cell surface receptors that either possess an channels, certain phospholipases and phosphodies- intrinsic protein-tyrosine kinase activity (Yarden et terases (Hamm, 1998). The targets for both members al., 1986) or interact with heterotrimeric GTP- of the a12 family, a12 and a13, were unknown until binding proteins (G proteins). The latter are recently. In addition, eleven-G protein g subunits and collectively known as G protein-coupled receptors ®ve G protein b subunits have been cloned so far and (GPCRs) and comprise the largest group of cell they regulate certain ion channels, phospholipase-C, surface molecules involved in signal transmission. and phosphatidylinositol-3 kinases (Clapham and With more than 1000 members, they are encoded by Neer, 1997). the biggest gene family in the human genome Through these G proteins subunits, GPCRs (Flower, 1999), and the importance and diversity regulate a diverse array of physiological functions of their physiological roles are directly supported by such as neurotransmission, chemoreception, photo- their link to a number of hereditary and acquired reception, metabolism, growth, and dierentiation. In diseases (Spiegel, 1996; Stadel et al., 1997). Further- addition to these physiological responses, there is more, these receptors and their ligands are the target also emerging evidence of the involvement of of over 50% of all current therapeutic agents aberrant GPCR function in cellular transformation (Flower, 1999). and oncogenesis (see Gutkind, 1998 for a recent GPCRs exhibit a common structural motif consisting review). In this regard, recent work suggests that the of seven membrane-spanning regions (Dohlman et al., Rho family of small GTP-binding proteins plays a 1987), and can be activated by a diverse array of central role in the regulation of cell proliferation by external stimuli, including growth factors, vasoactive GPCRs, and that the persistent activation of Rho- polypeptides, chemoattractants, neurotransmitters, hor- mediated pathways by heterotrimeric G proteins can mones, phospholipids, photons, odorants, and taste lead to cellular transformation. In this review, we ligands. In general, agonist binding provokes rapid will focus on recent eorts addressing the molecular conformational changes in the transmembrane a mechanisms by which GPCRs and G protein a helices, which result in the exposure of previously subunits activate Rho, with emphasis on their masked G protein binding sites in the intracellular contribution to the understanding on how this signal loops (Altenbach et al., 1996; Bourne, 1997; Wess, transducing system regulates normal and aberrant 1997). This causes the exchange of GDP for GTP cell growth. bound to the G protein a subunit, and GTP-bound a subunits or bg complexes then initiate intracellular signaling responses by acting on a variety of eector Transforming G protein coupled receptors molecules. To date, sixteen distinct mammalian G protein a subunits have been identi®ed and divided into Most oncogenes were discovered by virtue of their four families based on their sequence similarity: as, ai, ability to transform cells in culture or to induce tumorigenesis in experimental animals (Weinberg, 1985). They include activated tyrosine kinase growth factor receptors, their ligands, and aberrant versions of *Correspondence: JS Gutkind, molecules thought to participate in their growth- 2Current address: Division of Integrative Cell Biology, Department of Embryogenesis, Institute of Molecular Embryology and Genetics, promoting pathways (Aaronson, 1991). On the other Kumamoto University, Kumamoto 860-0811, Japan hand, the discovery of the mas oncogene provided the RGS-containing RhoGEFs S Fukuhara et al 1662 ®rst evidence that GPCRs can harbor transforming but behaves as a constitutively active Gq-coupled potential (Young et al., 1986). The natural agonist for receptor and, as predicted, is sucient to subvert the mas oncogene product is still unknown, but is likely normal growth control when expressed in cultured to be a serum component. Similarly, serotonin 1C ®broblasts (Arvanitakis et al., 1997). The KSHV ± receptors were shown to be oncogenic if ectopically GPCR can eectively activate signaling pathways expressed in NIH3T3 cells and activated by the typical of transforming receptors, and may represent serotonin present in the culture medium (Julius et al., a key molecule in the pathogenesis of Kaposi's 1989). Using a more de®ned experimental system, Sarcoma because of its central role in the promotion certain muscarinic receptor subtype were shown to of VEGF-driven angiogenesis and spindle cell prolif- transform NIH3T3 cells in a strictly agonist-dependent eration (Bais et al., 1998; Sodhi et al., 2000). As manner (Gutkind et al., 1991). Since neurotransmitter described in the accompanying review by Heasley acetylcholine, the natural agonist for these receptors, is (2001), there is also compelling evidence for a role of not present in serum, it was possible to correlate GPCRs in many human neoplasias, including small cell biochemical responses with the biological eects lung carcinoma, colon adenomas and carcinomas, elicited by an exogenously added agonist. This gastric hyperplasia and cancer, prostate cancer, and approach established that while Gq-coupled receptors pancreatic carcinoma, which express wild-type GPCRs (m1, m3, and m5), were highly transforming, Gi- that are persistently stimulated by tumor-released coupled receptors (m2 and m4), were without focus- agonists in an autocrine or paracrine fashion. Indeed, forming activity. Together, these ®ndings demonstrated the use of blocking antibodies and receptor antagonists that certain GPCRs could behave as potent agonist- has been shown to be eective in a variety of in vitro dependent oncogenes, and raised the possibility that and in vivo tumor models, which lends support to the activating mutations in GPCRs may render them potential causative role of GPCRs in these diseases transforming. Indeed, this was subsequently shown (Langdon et al., 1992; Sethi et al., 1992; Thomas et al., for the a1b G protein-linked receptor to noradrenaline 1992). It also provides the rationale for the develop- (Allen et al., 1991). In this case, speci®c point ment of novel treatment modalities in cancer therapy. mutations in the C-terminal juxtamembrane region of the third intracellular loop of the a1b receptor relieved the requirement of ligand activation for its transform- Transforming G proteins ing ability. Several GPCRs have now been cloned using The potent transforming potential of certain GPCRs standard transfection and tumorigenesis assays. and their likely contribution to human neoplasias Furthermore, the discovery of activated mutants of prompted many laboratories to explore the biological GPCRs in a variety of neoplastic diseases and consequences of expressing constitutively activate oncogenic viruses provided direct evidence of a role mutants of heterotrimeric G protein a subunits. These of these cell surface receptors and their coupled G experiments were possible due to the observation that proteins in cancerous growth. For example, activating all G protein a subunits exhibit a highly conserved mutations in TSH receptors were found in 30% of region, designated G-3 (Bourne et al., 1991), which is thyroid adenomas (Parma et al., 1993), and mutation- involved in binding and hydrolysis of GTP. This region ally activated LH receptors have been identi®ed in a includes a consensus sequence DVGGQ. Replacement form of familial male precocious puberty that results of the glutamine residue (Q) for leucine (L) in the from hyperplastic growth of Leydig cells (Shenker et corresponding sequence of the ras gene (codon 61) al., 1993). Reports are also available indicating that increases the steady-state levels of GTP-bound p21ras active mutants of FSH receptors are expressed in and unmasks its oncogenic potential (Barbacid, 1987). ovarian sex cord tumors and ovarian small cell Accordingly, constitutively activated Ga subunits (QL carcinoma (Kotlar et al., 1997), CCK-B receptors in mutants) were generated and tested for their ability to colorectal cancer (Hellmich et al., 2000), and Ca2+- transform rodent ®broblasts. In these initial studies, sensing receptors in a form of autosomal-dominant activated mutants of members of the Gas,Gai and Gaq hypocalcemia that is concomitant with a variety of family were found to provoke alterations in cell growth neoplasms (Ho et al., 1999).
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