Nature 379, 742 - 746 (22 February 1996); doi:10.1038/379742a0

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

Kirk M. Druey, Kendall J. Blumer, Veronica H. Kang & John H. Kehrl^*

Laboratory of Immune-regulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-1876, USA, and Department of Cell Biology and Physiology, Washington University School of Medicine, St Louis, Missouri 63110, USA
^* To whom correspondence should be addressed.

A GENERAL property of signal transduction pathways is that prolonged stimulation decreases responsiveness, a phenomenon termed desensitization. Yeast cells stimulated with mating phero-mone activate a heterotrimeric G-protein-linked, MAP-kinase-dependent signalling pathway that induces Gl-phase cell-cycle arrest and morphological differentiation (reviewed in refs 1, 2). Eventually the cells desensitize to pheromone and resume growth³. Genetic studies have demonstrated the relative importance 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 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.

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