Receptor-independent Activators of Heterotrimeric G-protein Signaling Pathways

Heterotrimeric G-protein signaling systems are activated via cell surface receptors possessing the seven-membrane span motif. Several observations suggest the existence of other modes of stimulus input to heterotrimeric G-proteins. As part of an overall effort to identify such proteins we developed...

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Bibliographic Details
Published in:The Journal of biological chemistry Vol. 274; no. 47; pp. 33202 - 33205
Main Authors: Takesono, Aya, Cismowski, Mary J., Ribas, Catalina, Bernard, Michael, Chung, Peter, Hazard, Starr, Duzic, Emir, Lanier, Stephen M.
Format: Journal Article
Language:English
Published: United States Elsevier Inc 19-11-1999
American Society for Biochemistry and Molecular Biology
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Summary:Heterotrimeric G-protein signaling systems are activated via cell surface receptors possessing the seven-membrane span motif. Several observations suggest the existence of other modes of stimulus input to heterotrimeric G-proteins. As part of an overall effort to identify such proteins we developed a functional screen based upon the pheromone response pathway in Saccharomyces cerevisiae. We identified two mammalian proteins, AGS2 and AGS3 (activators of G-proteinsignaling), that activated the pheromone response pathway at the level of heterotrimeric G-proteins in the absence of a typical receptor. β-galactosidase reporter assays in yeast strains expressing different Gα subunits (Gpa1, Gsα, Giα2(Gpa1(1–41)), Giα3(Gpa1(1–41)), Gα16(Gpa1(1–41))) indicated that AGS proteins selectively activated G-protein heterotrimers. AGS3 was only active in the Giα2 and Giα3genetic backgrounds, whereas AGS2 was active in each of the genetic backgrounds except Gpa1. In protein interaction studies, AGS2 selectively associated with Gβγ, whereas AGS3 bound Gα and exhibited a preference for GαGDP versus GαGTPγS. Subsequent studies indicated that the mechanisms of G-protein activation by AGS2 and AGS3 were distinct from that of a typical G-protein-coupled receptor. AGS proteins provide unexpected mechanisms for input to heterotrimeric G-protein signaling pathways. AGS2 and AGS3 may also serve as novel binding partners for Gα and Gβγ that allow the subunits to subserve functions that do not require initial heterotrimer formation.
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ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.274.47.33202