RGS-containing RhoGEFs: the missing link between transforming G proteins and Rho?

Abstract

Many mitogens promote cell proliferation by acting on cell surface receptors that either possess an intrinsic protein-tyrosine kinase activity (Yarden et al., 1986) or interact with heterotrimeric GTPbinding proteins (G proteins). The latter are collectively known as G protein-coupled receptors (GPCRs) and comprise the largest group of cell surface molecules involved in signal transmission. With more than 1000 members, they are encoded by the biggest gene family in the human genome (Flower, 1999), and the importance and diversity of their physiological roles are directly supported by their link to a number of hereditary and acquired diseases (Spiegel, 1996; Stadel et al., 1997). Furthermore, these receptors and their ligands are the target of over 50% of all current therapeutic agents (Flower, 1999). GPCRs exhibit a common structural motif consisting of seven membrane-spanning regions (Dohlman et al., 1987), and can be activated by a diverse array of external stimuli, including growth factors, vasoactive polypeptides, chemoattractants, neurotransmitters, hormones, phospholipids, photons, odorants, and taste ligands. In general, agonist binding provokes rapid conformational changes in the transmembrane a helices, which result in the exposure of previously masked G protein binding sites in the intracellular loops (Altenbach et al., 1996; Bourne, 1997; Wess, 1997). This causes the exchange of GDP for GTP 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 e€ector molecules. To date, sixteen distinct mammalian G protein a subunits have been identi®ed and divided into four families based on their sequence similarity: as, ai, aq, and a12 (Wilkie et al., 1992). The aq family of heterotrimeric G protein a subunits is coupled to phospholipase-C b to induce the hydrolysis of phosphatidylinositol bis phosphate, the consequent rise in the intracellular concentration of Ca, and the activation of protein kinase C, whereas the as and ai families are known to activate and inhibit adenylyl cyclase to increase and decrease the level of cyclic AMP, respectively. ai proteins also regulate ion channels, certain phospholipases and phosphodiesterases (Hamm, 1998). The targets for both members of the a12 family, a12 and a13, were unknown until recently. In addition, eleven-G protein g subunits and ®ve G protein b subunits have been cloned so far and they regulate certain ion channels, phospholipase-C, and phosphatidylinositol-3 kinases (Clapham and Neer, 1997). Through these G proteins subunits, GPCRs regulate a diverse array of physiological functions such as neurotransmission, chemoreception, photoreception, metabolism, growth, and di€erentiation. In addition to these physiological responses, there is also emerging evidence of the involvement of aberrant GPCR function in cellular transformation and oncogenesis (see Gutkind, 1998 for a recent review). In this regard, recent work suggests that the Rho family of small GTP-binding proteins plays a central role in the regulation of cell proliferation by GPCRs, and that the persistent activation of Rhomediated pathways by heterotrimeric G proteins can lead to cellular transformation. In this review, we will focus on recent e€orts addressing the molecular mechanisms by which GPCRs and G protein a subunits activate Rho, with emphasis on their contribution to the understanding on how this signal transducing system regulates normal and aberrant cell growth.