The GAPs, GEFs, and GDIs of heterotrimeric G-protein alpha subunits

lThe heterotrimeric G-protein alpha subunit has long been considered a bimodal, GTP-hydrolyzing switch controlling the duration of signal transduction by seven-transmembrane domain (7TM) cell-surface receptors. In 1996, we and others identified a superfamily of regulator of G-protein signaling (RGS) proteins that accelerate the rate of GTP hydrolysis by G alpha subunits (dubbed GTPase-accelerating protein or GAP activity). This discovery resolved the paradox between the rapid physiological timing seen for 7TM receptor signal transduction in vivo and the slow rates of GTP hydrolysis exhibited by purified G alpha subunits in vitro. Here, we review more recent discoveries that have highlighted newly-appreciated roles for RGS proteins beyond mere negative regulators of 7TM signaling. These new roles include the RGS-box-containing, RhoA-specific guanine nucleotide exchange factors (RGS-RhoGEFs) that serve as G alpha effectors to couple 7TM and semaphorin receptor signaling to RhoA activation, the potential for RGS12 to serve as a nexus for signaling from tyrosine kinases and G-proteins of both the G alpha and Ras-superfamilies, the potential for R7-subfamily RGS proteins to couple G alpha subunits to 7TM receptors in the absence of conventional G beta gamma. dimers, and the potential for the conjoint 7TM/RGS-box Arabidopsis protein AtRGS1 to serve as a ligand-operated GAP for the plant G alpha AtGPA1. Moreover, we review the discovery of novel biochemical activities that also impinge on the guanine nucleotide binding and hydrolysis cycle of G alpha subunits: namely, the guanine nucleotide dissociation inhibitor (GDI) activity of the GoLoco motif-containing proteins and the 7TM receptor-independent guanine nucleotide exchange factor (GEF) activity of Ric-8/synembryn. Discovery of these novel GAP, GDI, and GEF activities have helped to illuminate a new role for Ga subunit GDP/GTP cycling required for microtubule force generation and mitotic spindle function in chromosomal segregation.