Receptor-independent activators of heterotrimeric G-proteins

Heterotrimeric G-protein signalling systems are primarily activated via cel l surface receptors possessing the seven membrane span motif. Several obser vations suggest the existence of other modes of input to such signalling sy stems either downstream of effecters or at the level of G-proteins themselv es. Using a functional screen based upon the pheromone response pathway in Saccharomyces cerevisiae, we identified three proteins, AGS1-3 (for Activat ors of G-protein Signalling), that activated heterotrimeric G-protein signa lling pathways in the absence of a typical receptor. AGS1 defines a distinc t member of the super family of ras related proteins. AGS2 is identical to mouse Tctex1, a protein that exists as a light chain component of the cytop lasmic motor protein dynein and subserves as yet undefined functions in cel l signalling pathways. AGS3 possesses a series of tetratrico repeat motifs and a series of four amino acid repeats termed G-protein regulatory motifs. The GPR motifs are found in a number of proteins that interact with and re gulate G alpha. Although each AGS protein activates G-protein signaling, th ey do so by different mechanisms within the context of the G-protein activa tion/deactivation cycle. AGS proteins provide unexpected mechanisms for inp ut to heterotrimeric G-protein signalling pathways. (C) 2001 Elsevier Scien ce Inc. All rights reserved.