Inhibition of G-protein-mediated MAP kinase activation by a new mammalian gene family

Nature. 1996 Feb 22;379(6567):742-6. doi: 10.1038/379742a0.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antigens, CD / metabolism
  • Base Sequence
  • Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors*
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Cell Line
  • DNA Probes
  • Enzyme Activation
  • Fungal Proteins / genetics
  • GTP-Binding Proteins / antagonists & inhibitors
  • GTP-Binding Proteins / metabolism*
  • GTPase-Activating Proteins*
  • Humans
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases*
  • Molecular Sequence Data
  • Multigene Family*
  • Pheromones / metabolism
  • Proteins / genetics
  • Proteins / metabolism*
  • RGS Proteins*
  • Rats
  • Receptors, Interleukin / metabolism
  • Receptors, Interleukin-8A
  • Recombinant Proteins / metabolism
  • Repressor Proteins*
  • Saccharomyces cerevisiae Proteins*
  • Sequence Alignment
  • Signal Transduction


  • Antigens, CD
  • DNA Probes
  • Fungal Proteins
  • GTPase-Activating Proteins
  • Pheromones
  • Proteins
  • RGS Proteins
  • RGS3 protein, human
  • Receptors, Interleukin
  • Receptors, Interleukin-8A
  • Recombinant Proteins
  • Repressor Proteins
  • Rgs3 protein, mouse
  • Rgs3 protein, rat
  • SST2 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • RGS4 protein
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • GTP-Binding Proteins

Associated data

  • GENBANK/U27655
  • GENBANK/U27767
  • GENBANK/U27768