Regulation of G protein-mediated signal transduction by RGS proteins

RGS proteins form a new family of regulatory proteins of G protein signalin g. They contain homologous core domains (RGS domains) of about 120 amino ac ids. RGS domains interact with activated G alpha subunits. Several RGS prot eins have been shown biochemically to act as GTPase activating proteins (GA Ps) for their interacting G alpha subunits. Other than RGS domains, RCS pro teins differ significantly in size, amino acid sequences, and tissue distri bution. In addition, many RGS proteins have other protein-protein interacti on motifs involved in cell signaling. We have shown that p115RhoGEF, a newl y identified GEF(guanine nucleotide exchange factor) for RhoGTPase, has a R GS domain at its N-terminal region and this domain acts as a specific GAP f or G alpha 12 and G alpha 13. Furthermore, binding of activated G alpha 13 to this RGS domain stimulated GEF activity of p1 15RhoGEF. Activated G alph a 12 inhibited G alpha 13-stimulated GEF activity. Thus p115RhoGEF is a dir ect link between heterotrimeric G protein and RhoGTPase and it functions as an effector for G alpha 12 and G alpha 13 in addition to acting as their G AP. We also found that RGS domain at N-terminal regions of G protein recept or kinase 2 (GRK2) specifically interacts with G alphaq/11 and inhibits G a lphaq-mediated activation of PLC-beta, apparently through sequestration of activated G alphaq. However, unlike other RGS proteins, this RGS domain did not show significant GAP activity to G alphaq. These results indicate that RGS proteins have far more diverse functions than acting simply as GAPs an d the characterization of function of each RGS protein is crucial to unders tand the G protein signaling network in cells. (C) 2001 Elsevier Science In c. All rights reserved.