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Cell Cycle. 2017 Apr 3;16(7):607-612. doi: 10.1080/15384101.2017.1282584. Epub 2017 Mar 13.

The GAPs, GEFs, GDIs and…now, GEMs: New kids on the heterotrimeric G protein signaling block.

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a Departments of Medicine and Cell and Molecular Medicine , University of California at San Diego , La Jolla , CA , USA.
b Department of Mechanical and Aerospace Engineering , Jacobs School of Engineering, University of California at San Diego , La Jolla , CA , USA.
c Skaggs School of Pharmacy and Pharmaceutical Sciences , University of California at San Diego , La Jolla , CA , USA.


The canonical process of activation of heterotrimeric G proteins by G protein coupled receptors (GPCRs) is well studied. Recently, a rapidly emerging paradigm has revealed the existence of a new, non-canonical set of cytosolic G protein modulators, guanine exchange modulators (GEMs). Among G proteins regulators, GEMs are uniquely capable of initiating pleiotropic signals: these bifunctional modulators can activate cAMP inhibitory (Gi) proteins and inhibit cAMP-stimulatory (Gs) proteins through a single short evolutionarily conserved module. A prototypical member of the GEM family, GIV/Girdin, integrates signals downstream of a myriad of cell surface receptors, e.g., growth factor RTKs, integrins, cytokine, GPCRs, etc., and translates these signals into G protein activation or inhibition. By their pleiotropic action, GIV and other GEMs modulate several key pathways within downstream signaling network. Unlike canonical G protein signaling that is finite and is triggered directly and exclusively by GPCRs, the temporal and spatial features of non-canonical activation of G protein via GIV-family of cytosolic GEMs are unusually relaxed. GIV uses this relaxed circuitry to integrate, reinforce and compartmentalize signals downstream of both growth factors and G proteins in a way that enables it to orchestrate cellular phenotypes in a sustained manner. Mounting evidence suggests the importance of GIV and other GEMs as disease modulators and their potential to serve as therapeutic targets; however, a lot remains unknown within the layers of the proverbial onion that must be systematically peeled. This perspective summarizes the key concepts of the GEM-dependent G protein signaling paradigm and discusses the multidisciplinary approaches that are likely to revolutionize our understanding of this paradigm from the atomic level to systems biology.


G protein -coupled receptors; GIV/Girdin; growth factor receptor tyrosine kinases; guanine nucleotide dissociation inhibitor (GDI); guanine nucleotide exchange factor (GEF); guanine nucleotide exchange modulator (GEM); heterotrimeric G proteins

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