Inhibition of G-protein-mediated MAP kinase activation by a new mammalian gene family.
A general property of signal transduction pathways is that prolonged stimulation decreases responsiveness, a phenomenon termed desensitization. Yeast cells stimulated with mating pheromone activate a heterotrimeric G-protein-linked, MAP-kinase-dependent signalling pathway that induces G1-phase cell-cycle arrest and morphological differentiation (reviewed in refs 1, 2). Eventually the cells desensitize to pheromone and resume growth. Genetic studies have demonstrated the relative importance of a desensitization mechanism that uses the SST2 gene product, Sst2p. Here we identify a mammalian gene family termed RGS (for regulator of G-protein signalling) that encodes structural and functional homologues of Sst2p. Introduction of RGS family members into yeast blunts signal transduction through the pheromone-response pathway. Like 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 also markedly impair MAP kinase activation by mammalian G-protein-linked receptors, indicating the existence and importance of an SST2-like desensitization mechanism in mammalian cells.
Druey
K M
KM
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-1876, USA.
Blumer
K J
KJ
Kang
V H
VH
Kehrl
J H
JH
D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001483:Base Sequence; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002460:Cell Line; D015342:DNA Probes; D004789:Enzyme Activation; D005656:Fungal Proteins / Q000235:genetics; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020690:GTPase-Activating Proteins; D006801:Humans; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D008969:Molecular Sequence Data; D005810:Multigene Family; D010675:Pheromones / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D020710:RGS Proteins; D051381:Rats; D018123:Receptors, Interleukin / Q000378:metabolism; D023062:Receptors, Interleukin-8A; D011994:Recombinant Proteins / Q000378:metabolism; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D016415:Sequence Alignment; D015398:Signal Transduction
D015703:Antigens, CD; D015342:DNA Probes; D005656:Fungal Proteins; D020690:GTPase-Activating Proteins; D010675:Pheromones; D011506:Proteins; D020710:RGS Proteins; C485898:RGS3 protein, human; D018123:Receptors, Interleukin; D023062:Receptors, Interleukin-8A; D011994:Recombinant Proteins; D012097:Repressor Proteins; C415085:Rgs3 protein, mouse; C437714:Rgs3 protein, rat; C094301:SST2 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C098799:RGS4 protein; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins