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J Biol Chem, Vol. 274, Issue 47, 33202-33205, November 19, 1999
From the Department of Pharmacology, Medical University of
South Carolina, Charleston, South Carolina 29425 and
§ Cadus Pharmaceutical Corporation,
Tarrytown, New York 10591
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-protein
signaling), that activated the pheromone response pathway
at the level of heterotrimeric G-proteins in the absence of a typical
receptor. 
-galactosidase reporter assays in yeast strains expressing
different G
subunits (Gpa1, Gs,
Gi2(Gpa1(1-41)), Gi3(Gpa1(1-41)),
G16(Gpa1(1-41))) indicated that AGS proteins
selectively activated G-protein heterotrimers. AGS3 was only active in
the Gi2 and Gi3
genetic backgrounds, whereas AGS2 was active in each of the genetic
backgrounds except Gpa1. In protein interaction studies, AGS2
selectively associated with G
, whereas AGS3 bound G and
exhibited a preference for GGDP versus GGTPS.
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 G and G that
allow the subunits to subserve functions that do not require initial
heterotrimer formation.
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