Faculty Opinions recommendation of Regulators of G-protein signaling accelerate GPCR signaling kinetics and govern sensitivity solely by accelerating GTPase activity.

2010 ◽  
Author(s):  
Philip Wedegaertner ◽  
Matthew Martz
Keyword(s):  
G Protein ◽  
G Protein Signaling ◽  
Gtpase Activity ◽  
Protein Signaling ◽  
Gpcr Signaling

scholarly journals Regulators of G-protein Signaling accelerate GPCR signaling kinetics and govern sensitivity solely by accelerating GTPase activity

2010 ◽  
Vol 107 (15) ◽  
pp. 7066-7071 ◽  
Author(s):  
N. A. Lambert ◽  
C. A. Johnston ◽  
S. D. Cappell ◽  
S. Kuravi ◽  
A. J. Kimple ◽  
...  
Keyword(s):  
G Protein ◽  
G Protein Signaling ◽  
Gtpase Activity ◽  
Protein Signaling ◽  
Gpcr Signaling

Modulation of Transducin GTPase Activity by Chimeric RGS16 and RGS9 Regulators of G Protein Signaling and the Effector Molecule†

Biochemistry ◽  
1999 ◽  
Vol 38 (16) ◽  
pp. 4931-4937 ◽  
Author(s):  
Randall L. McEntaffer ◽  
Michael Natochin ◽  
Nikolai O. Artemyev
Keyword(s):  
G Protein ◽  
G Protein Signaling ◽  
Gtpase Activity ◽  
Protein Signaling ◽  
Effector Molecule

scholarly journals Probing the mutational landscape of regulators of G protein signaling proteins in cancer

2020 ◽  
Vol 13 (617) ◽  
pp. eaax8620 ◽  
Author(s):  
Vincent DiGiacomo ◽  
Marcin Maziarz ◽  
Alex Luebbers ◽  
Jillian M. Norris ◽  
Pandu Laksono ◽  
...  
Keyword(s):  
G Protein ◽  
G Proteins ◽  
Mammalian Cells ◽  
G Protein Signaling ◽  
Rgs Proteins ◽  
Protein Signaling ◽  
Loss Of Function ◽  
Gpcr Signaling ◽  
Mutational Landscape ◽  
Binding Interface

The advent of deep-sequencing techniques has revealed that mutations in G protein–coupled receptor (GPCR) signaling pathways in cancer are more prominent than was previously appreciated. An emergent theme is that cancer-associated mutations tend to cause enhanced GPCR pathway activation to favor oncogenicity. Regulators of G protein signaling (RGS) proteins are critical modulators of GPCR signaling that dampen the activity of heterotrimeric G proteins through their GTPase-accelerating protein (GAP) activity, which is conferred by a conserved domain dubbed the “RGS-box.” Here, we developed an experimental pipeline to systematically assess the mutational landscape of RGS GAPs in cancer. A pan-cancer bioinformatics analysis of the 20 RGS domains with GAP activity revealed hundreds of low-frequency mutations spread throughout the conserved RGS domain structure with a slight enrichment at positions that interface with G proteins. We empirically tested multiple mutations representing all RGS GAP subfamilies and sampling both G protein interface and noninterface positions with a scalable, yeast-based assay. Last, a subset of mutants was validated using G protein activity biosensors in mammalian cells. Our findings reveal that a sizable fraction of RGS protein mutations leads to a loss of function through various mechanisms, including disruption of the G protein–binding interface, loss of protein stability, or allosteric effects on G protein coupling. Moreover, our results also validate a scalable pipeline for the rapid characterization of cancer-associated mutations in RGS proteins.

The G protein signaling regulator RGS3 enhances the GTPase activity of KRAS

Science ◽  
2021 ◽  
Vol 374 (6564) ◽  
pp. 197-201 ◽  
Author(s):  
Chuanchuan Li ◽  
Alberto Vides ◽  
Dongsung Kim ◽  
Jenny Y. Xue ◽  
Yulei Zhao ◽  
...  
Keyword(s):  
G Protein ◽  
G Protein Signaling ◽  
Gtpase Activity ◽  
Protein Signaling

scholarly journals GPR158/179 regulate G protein signaling by controlling localization and activity of the RGS7 complexes

2012 ◽  
Vol 197 (6) ◽  
pp. 711-719 ◽  
Author(s):  
Cesare Orlandi ◽  
Ekaterina Posokhova ◽  
Ikuo Masuho ◽  
Thomas A. Ray ◽  
Nazarul Hasan ◽  
...  
Keyword(s):  
G Protein ◽  
Night Vision ◽  
G Protein Signaling ◽  
Rgs Proteins ◽  
Protein Signaling ◽  
Gpcr Signaling ◽  
Signaling Specificity ◽  
Orphan Gpcrs ◽  
G Protein Coupled

The extent and temporal characteristics of G protein–coupled receptor (GPCR) signaling are shaped by the regulator of G protein signaling (RGS) proteins, which promote G protein deactivation. With hundreds of GPCRs and dozens of RGS proteins, compartmentalization plays a key role in establishing signaling specificity. However, the molecular details and mechanisms of this process are poorly understood. In this paper, we report that the R7 group of RGS regulators is controlled by interaction with two previously uncharacterized orphan GPCRs: GPR158 and GPR179. We show that GPR158/179 recruited RGS complexes to the plasma membrane and augmented their ability to regulate GPCR signaling. The loss of GPR179 in a mouse model of night blindness prevented targeting of RGS to the postsynaptic compartment of bipolar neurons in the retina, illuminating the role of GPR179 in night vision. We propose that the interaction of RGS proteins with orphan GPCRs promotes signaling selectivity in G protein pathways.

scholarly journals Distinct G protein–coupled receptor recycling pathways allow spatial control of downstream G protein signaling

2016 ◽  
Vol 214 (7) ◽  
pp. 797-806 ◽  
Author(s):  
Shanna Lynn Bowman ◽  
Daniel John Shiwarski ◽  
Manojkumar A. Puthenveedu
Keyword(s):  
G Protein ◽  
Cell Biology ◽  
G Protein Signaling ◽  
Protein Signaling ◽  
Gpcr Signaling ◽  
Sorting Nexin ◽  
Sequence Dependent ◽  
Physiological Relevance ◽  
G Protein Coupled ◽  
Dependent Pathway

G protein–coupled receptors (GPCRs) are recycled via a sequence-dependent pathway that is spatially and biochemically distinct from bulk recycling. Why there are two distinct recycling pathways from the endosome is a fundamental question in cell biology. In this study, we show that the separation of these two pathways is essential for normal spatial encoding of GPCR signaling. The prototypical β-2 adrenergic receptor (B2AR) activates Gα stimulatory protein (Gαs) on the endosome exclusively in sequence-dependent recycling tubules marked by actin/sorting nexin/retromer tubular (ASRT) microdomains. B2AR was detected in an active conformation in bulk recycling tubules, but was unable to activate Gαs. Protein kinase A phosphorylation of B2AR increases the fraction of receptors localized to ASRT domains and biases the downstream transcriptional effects of B2AR to genes controlled by endosomal signals. Our results identify the physiological relevance of separating GPCR recycling from bulk recycling and suggest a mechanism to tune downstream responses of GPCR signaling by manipulating the spatial origin of G protein signaling.

scholarly journals A Physiologically Required G Protein-coupled Receptor (GPCR)-Regulator of G Protein Signaling (RGS) Interaction That Compartmentalizes RGS Activity

2013 ◽  
Vol 288 (38) ◽  
pp. 27327-27342 ◽  
Author(s):  
Wayne Croft ◽  
Claire Hill ◽  
Eilish McCann ◽  
Michael Bond ◽  
Manuel Esparza-Franco ◽  
...  
Keyword(s):  
G Protein ◽  
G Protein Signaling ◽  
Rgs Proteins ◽  
Protein Signaling ◽  
Gpcr Signaling ◽  
Additional Layer ◽  
Physiological Relevance ◽  
Gtpase Cycle ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) can interact with regulator of G protein signaling (RGS) proteins. However, the effects of such interactions on signal transduction and their physiological relevance have been largely undetermined. Ligand-bound GPCRs initiate by promoting exchange of GDP for GTP on the Gα subunit of heterotrimeric G proteins. Signaling is terminated by hydrolysis of GTP to GDP through intrinsic GTPase activity of the Gα subunit, a reaction catalyzed by RGS proteins. Using yeast as a tool to study GPCR signaling in isolation, we define an interaction between the cognate GPCR (Mam2) and RGS (Rgs1), mapping the interaction domains. This reaction tethers Rgs1 at the plasma membrane and is essential for physiological signaling response. In vivo quantitative data inform the development of a kinetic model of the GTPase cycle, which extends previous attempts by including GPCR-RGS interactions. In vivo and in silico data confirm that GPCR-RGS interactions can impose an additional layer of regulation through mediating RGS subcellular localization to compartmentalize RGS activity within a cell, thus highlighting their importance as potential targets to modulate GPCR signaling pathways.

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