INHIBITION OF C-PROTEIN-MEDIATED MAP KINASE ACTIVATION BY A NEW MAMMALIAN GENE FAMILY

A GENERAL property of signal transduction pathways is that prolonged s timulation decreases responsiveness, a phenomenon termed desensitizati on. Yeast cells stimulated with mating pheromone activate a heterotrim eric G-protein-linked, MAP-kinase-dependent signalling pathway that in duces G1-phase cell-cycle arrest and morphological differentiation (re viewed in refs 1, 2). Eventually the cells desensitize to pheromone an d resume growth(3). Genetic studies have demonstrated the relative imp ortance of a desensitization mechanism that uses the SST2 gene product , Sst2p(4-7). Here we identify a mammalian gene family termed RGS (for regulator of G-protein signalling) that encodes structural and functi onal homologues of Sst2p. Introduction of RGS family members into yeas t blunts signal transduction through the pheromone-response pathway. L ike SST2 (refs 8-10), they negatively regulate this pathway at a point upstream or at the level of the G protein. The RGS family members als o markedly impair MAP kinase activation by mammalian G-protein-linked receptors, indicating the existence and importance of an SST2-like des ensitization mechanism in mammalian cells.