title: The GAPs, GEFs, GDIs and…now, GEMs: New kids on the heterotrimeric G protein signaling block.
abstract: 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.
authors.affiliation: a Departments of Medicine and Cell and Molecular Medicine , University of California at San Diego , La Jolla , CA , USA.
authors.forename: Pradipta
authors.initials: P
authors.lastname: Ghosh
authors.affiliation: b Department of Mechanical and Aerospace Engineering , Jacobs School of Engineering, University of California at San Diego , La Jolla , CA , USA.
authors.forename: Padmini
authors.initials: P
authors.lastname: Rangamani
authors.affiliation: c Skaggs School of Pharmacy and Pharmaceutical Sciences , University of California at San Diego , La Jolla , CA , USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Kufareva
mesh_terms: D000818:Animals; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D020690:GTPase-Activating Proteins; D020730:Guanine Nucleotide Dissociation Inhibitors; D020662:Guanine Nucleotide Exchange Factors; D043562:Receptors, G-Protein-Coupled; D020962:Heterotrimeric GTP-Binding Proteins
keywords: 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