The GAPs, GEFs, and GDIs of heterotrimeric G-protein alpha subunits

Abstract

A Ab bs st tr ra ac ct t The heterotrimeric G-protein alpha subunit has long been considered a bimodal, GTP-hydrolyzing switch controlling the duration of signal transduction by seven-transmembrane domain (7TM) cell-surface receptors.In 1996, we and others identified a superfamily of "regulator of G-protein signaling" (RGS) proteins that accelerate the rate of GTP hydrolysis by Gα subunits (dubbed GTPase-accelerating protein or "GAP" activity). This discovery resolved the paradox between the rapid physiological timing seen for 7TM receptor signal transduction in vivo and the slow rates of GTP hydrolysis exhibited by purified Gα subunits in vitro. Here, we review more recent discoveries that have highlighted newly-appreciated roles for RGS proteins beyond mere negative regulators of 7TM signaling. These new roles include the RGS-box-containing, RhoA-specific guanine nucleotide exchange factors (RGS-RhoGEFs) that serve as Gα effectors to couple 7TM and semaphorin receptor signaling to RhoA activation, the potential for RGS12 to serve as a nexus for signaling from tyrosine kinases and G-proteins of both the Gα and Ras-superfamilies, the potential for R7-subfamily RGS proteins to couple Gα subunits to 7TM receptors in the absence of conventional Gβγ dimers, and the potential for the conjoint 7TM/RGS-box Arabidopsis protein AtRGS1 to serve as a ligand-operated GAP for the plant Gα AtGPA1. Moreover, we review the discovery of novel biochemical activities that also impinge on the guanine nucleotide binding and hydrolysis cycle of Gα subunits: namely, the guanine nucleotide dissociation inhibitor (GDI) activity of the GoLoco motif-containing proteins and the 7TM receptorindependent guanine nucleotide exchange factor (GEF) activity of Ric-8/synembryn. Discovery of these novel GAP, GDI, and GEF activities have helped to illuminate a new role for Gα subunit GDP/GTP cycling required for microtubule force generation and mitotic spindle function in chromosomal segregation.

Therapeutic effects of cell-permeant peptides that activate G proteins downstream of growth factors

“…Second, G proteins are an ideal target for therapeutic intervention because they serve as signal amplification switches, and potent and pathway-selective activators/inhibitors of a G protein can serve multiple purposes ranging from being a research tool to pharmacologic probe for use in experimental and clinical therapeutics (36). The technique we define here allows exogenous manipulation of the RTK-GIV-Gi pathway by enhancing or suppressing the coupling of G protein with RTKs and their subsequent transactivation, in a dose-dependent manner while minimizing the risk of tampering with other physiologic functions/interactions of G proteins/or other components within the network of modulators of G protein signaling (37).…”

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

“…The members of the third group, non-receptor GEFs, are a heterogeneous group of cytosolic proteins that accelerate GDP to GTP exchange, and thereby, cause activation of Ga subunits through a non-canonical mechanism, independently of GPCRs or Gbg dimers. [7][8][9][10][11] These fundamentals have been described in-depth in a widely-cited review by Siderovski and Willard 6 over a decade ago. In the years since, a growing body of work by us and others indicates that genetic or epigenetic factors that deregulate the intricate network of "accessory proteins" in a variety of disease states are just as significant as those that directly affect the G proteins and GPCRs, if not more so.…”

Characterization of the Heterotrimeric G-Protein Complex and Its Regulator from the Green Alga Chara braunii Expands the Evolutionary Breadth of Plant G-Protein Signaling

“…The intrinsic GTPase activity of Ga causes hydrolysis of the bound GTP and regenerates GDP·Gabg, completing one signaling cycle (CabreraVera et al, 2003;Offermanns, 2003;Urano et al, 2013). REGULATOR OF G-PROTEIN SIGNALING (RGS) domain-containing proteins, which enhance the GTPase activity of Ga, accelerate the rate of the G-protein cycle (Siderovski and Willard, 2005).…”