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

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