Affinage

RGS2

Regulator of G-protein signaling 2 · UniProt P41220

Length
211 aa
Mass
24.4 kDa
Annotated
2026-04-28
100 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RGS2 is a multifunctional signaling regulator best characterized as a selective GTPase-activating protein (GAP) for Gqα that terminates Gq/11-coupled GPCR signaling, with additional G protein-independent roles in translational control and transcriptional regulation. Its RGS domain accelerates GTP hydrolysis on Gqα with high selectivity determined by specific residues in the switch I binding pocket, while its N-terminal amphipathic helix targets the protein to the plasma membrane via acidic phospholipid binding and mediates direct inhibition of adenylyl cyclases (types V and others) and receptor coupling through interaction with third intracellular loops of specific GPCRs (M1 mAChR, α1A-AR, PAR4), a process scaffolded by spinophilin (PMID:9405622, PMID:19478087, PMID:12604604, PMID:14976183, PMID:15793568, PMID:32517689). Independent of GAP activity, a 37-amino acid segment within the RGS domain binds eIF2Bε to inhibit global mRNA translation initiation and selectively upregulate ATF4/CHOP, sustaining translational arrest in dormant cancer cells and cooperating with the lncRNA HITT to suppress PD-L1 translation (PMID:19736320, PMID:33393490, PMID:37014700). RGS2 protein turnover is controlled by N-end rule-related ubiquitination at K71 and FBXO44–CUL4B–DDB1 E3 ligase-mediated proteasomal degradation, with PKC phosphorylation additionally reducing GAP activity; loss of RGS2 in mice causes hypertension originating primarily from the kidney, enhanced bronchoconstriction, and prolonged vasoconstrictor responses (PMID:25970626, PMID:25187114, PMID:11063746, PMID:12588882, PMID:20847141, PMID:22080612).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1997 High

    Establishing that RGS2 is a selective GAP for Gqα resolved which heterotrimeric G protein it regulates, distinguishing it from other RGS family members that preferentially target Gi.

    Evidence Pulldown from brain membranes and reconstituted PLC-β1 activation in phospholipid vesicles with purified proteins

    PMID:9405622

    Open questions at the time
    • Structural basis of Gq selectivity not yet defined
    • In vivo physiological consequence unknown
    • Whether RGS2 has functions beyond GAP activity unknown
  2. 1999 High

    Mutagenesis mapped the structural determinants of Gq selectivity to the switch I binding pocket and α8-α9 loop, explaining why RGS2 discriminates against Giα while RGS4 does not.

    Evidence Structure-guided mutagenesis with in vivo phosphoinositide hydrolysis assays comparing RGS2 and RGS4

    PMID:10567399

    Open questions at the time
    • No crystal structure of RGS2–Gqα complex
    • How selectivity operates at atomic resolution unclear
  3. 2000 High

    PKC phosphorylation was shown to reduce RGS2 GAP activity, establishing a feedback mechanism whereby Gq-activated PKC can attenuate RGS2 function and prolong signaling.

    Evidence In vitro kinase assay with purified PKC, stoichiometric phosphorylation, GAP activity in reconstituted proteoliposomes

    PMID:11063746

    Open questions at the time
    • Phosphorylation site(s) not mapped
    • In vivo relevance of PKC-mediated regulation not tested
  4. 2001 High

    Identification of the N-terminal amphipathic helix as the plasma membrane targeting element explained how a cytosolic RGS protein accesses its membrane-localized G protein substrates.

    Evidence GFP-tagged RGS2 confocal microscopy, mutational analysis, and biophysical vesicle-binding assays in HEK293 cells

    PMID:11278586

    Open questions at the time
    • Relative contribution of lipid binding vs. G protein binding to steady-state localization unclear
    • Nuclear function of RGS2 undefined
  5. 2002 High

    Discovery that the N-terminal 19 residues of RGS2 directly inhibit adenylyl cyclase (type V, C1 domain) independently of GAP activity revealed a second, non-canonical signaling function.

    Evidence Deletion and alanine-scanning mutagenesis, cAMP accumulation assays, in vitro binding to AC domains

    PMID:12604604

    Open questions at the time
    • Whether AC inhibition occurs in physiological contexts not established
    • Specificity across all AC isoforms incomplete
  6. 2003 High

    RGS2-knockout mice exhibited hypertension and prolonged vasoconstriction, establishing the first in vivo physiological role as a negative regulator of vascular Gq signaling and blood pressure.

    Evidence RGS2−/− mouse, telemetric blood pressure, Ca2+ signaling in vascular smooth muscle cells

    PMID:12588882

    Open questions at the time
    • Tissue(s) responsible for the blood pressure phenotype not dissected
    • Contribution of non-GAP functions to the phenotype unknown
  7. 2004 High

    Demonstrating that RGS2 binds directly to the M1 muscarinic receptor i3 loop via its N-terminus and forms a ternary complex with activated Gqα established a receptor-directed recruitment mechanism for RGS specificity.

    Evidence GST pulldown, fluorescence co-localization, truncation mutants, membrane phosphoinositide hydrolysis assay

    PMID:14976183

    Open questions at the time
    • Generalizability to other Gq-coupled receptors not known
    • Whether the ternary complex operates identically in native tissue unclear
  8. 2005 High

    Spinophilin was identified as a scaffold that bridges RGS2 to GPCRs via their i3 loops, markedly enhancing RGS2-mediated signal termination — expanding the receptor coupling model to include a scaffolding component.

    Evidence Reciprocal co-immunoprecipitation, Xenopus oocyte Ca2+ signaling, spl−/− and rgs2−/− cells, αAR-βAR chimeras

    PMID:15793568

    Open questions at the time
    • Whether spinophilin scaffolding applies to all RGS2-receptor pairs untested
    • Structural basis of the ternary RGS2–spinophilin–receptor complex unknown
  9. 2007 Medium

    N-terminal residues were found to control proteasomal degradation via an N-end rule-like pathway, with a hypertension-associated Q2L variant showing accelerated turnover and reduced Gq inhibition — linking protein stability to disease.

    Evidence Mutagenesis, immunoblotting of protein levels, inositol phosphate accumulation assay in HEK293 cells

    PMID:17220356

    Open questions at the time
    • E3 ligase responsible not identified in this study
    • Whether Q2L is causative for hypertension or merely associated not proven
  10. 2009 High

    The crystal structure of a triple-mutant RGS2 complexed with Giα1 at 2.8 Å revealed that three conserved residues create unfavorable geometry at the switch I interface for Giα, providing the atomic-level explanation for Gq selectivity.

    Evidence X-ray crystallography at 2.8 Å, mutagenesis with GTPase activity assays

    PMID:19478087

    Open questions at the time
    • Structure of wild-type RGS2 with Gqα not obtained
    • Dynamic aspects of selectivity not captured
  11. 2009 High

    Discovery that a 37-residue region within the RGS domain binds eIF2Bε and inhibits translation initiation established a G protein-independent function in global protein synthesis control.

    Evidence Co-immunoprecipitation, in vitro translation assay, domain mapping, eIF2–eIF2B GTPase cycle assay

    PMID:19736320

    Open questions at the time
    • Physiological stimuli that activate this translational function not defined
    • Whether eIF2Bε binding and GAP activity are mutually exclusive unknown
  12. 2010 High

    Kidney cross-transplantation demonstrated that renal RGS2, not peripheral vascular RGS2, is the primary determinant of blood pressure, redefining the tissue site of RGS2's cardiovascular function.

    Evidence Kidney transplantation between RGS2−/− and wild-type mice with telemetric blood pressure monitoring

    PMID:20847141

    Open questions at the time
    • Specific nephron cell type and downstream signaling pathway not fully resolved
    • Interplay between renal and vascular RGS2 under stress conditions unknown
  13. 2015 Medium

    Identification of FBXO44–CUL4B–DDB1 as the E3 ubiquitin ligase complex targeting RGS2, and K71 as a key ubiquitination site stabilized by deubiquitinase MCPIP1, defined the proteolytic turnover machinery controlling RGS2 abundance.

    Evidence Genome-wide siRNA screen, co-immunoprecipitation of CUL4B/DDB1/FBXO44, K71R mutagenesis, MCPIP1 overexpression

    PMID:25187114 PMID:25970626

    Open questions at the time
    • How FBXO44 recognition of RGS2 relates to N-end rule pathway not integrated
    • Whether MCPIP1-RGS2 axis operates in vascular tissue not tested
  14. 2019 Medium

    The eIF2Bε-binding domain of RGS2 was shown to selectively upregulate ATF4 and CHOP translation independently of eIF2α phosphorylation, revealing a non-canonical integrated stress response activation mechanism.

    Evidence RGS2eb domain overexpression, polysome profiling, immunoblot for ATF4/CHOP, eIF2α phosphorylation status

    PMID:30826455

    Open questions at the time
    • Whether endogenous RGS2 levels are sufficient to trigger this pathway unknown
    • Downstream consequences for cell fate decisions not fully explored
  15. 2021 Medium

    In dormant cancer cells, RGS2 was found to maintain translational arrest through persistent eIF2α phosphorylation coupled with proteasomal ATF4 degradation, and pharmacological reversal promoted ER stress-induced apoptosis — establishing a role in tumor dormancy.

    Evidence Slow-cycling cell isolation, RGS2 overexpression/knockdown, eIF2α phosphorylation, xenograft models, PDE5 inhibitor treatment

    PMID:33393490

    Open questions at the time
    • Whether RGS2-mediated dormancy operates in all cancer types unknown
    • Mechanism connecting RGS2 to persistent eIF2α phosphorylation (vs. eIF2Bε inhibition) not reconciled
  16. 2023 Medium

    RGS2 was shown to co-bind PD-L1 mRNA 5ʹ UTR with lncRNA HITT to suppress PD-L1 translation, linking its translational control function to immune evasion, and separately to promote estradiol biosynthesis by targeting HAND1 for degradation via USP14 suppression.

    Evidence RNA immunoprecipitation, PD-L1 translation reporter, T cell cytotoxicity assay, co-IP of RGS2–HAND1/USP14, aromatase reporter

    PMID:36653442 PMID:37014700

    Open questions at the time
    • Whether RGS2 binds PD-L1 mRNA directly or solely via HITT not resolved
    • HAND1 regulation mechanism awaits independent confirmation
    • Integration of GAP and translational functions in the same cell context not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • A unified model explaining how RGS2 partitions between its GAP, adenylyl cyclase inhibitory, translational control, and nuclear transcriptional functions in specific physiological contexts remains unestablished.
  • No structure of RGS2 bound to Gqα or eIF2Bε
  • Signal-dependent switching between membrane vs. nuclear vs. cytosolic functions not defined
  • Relative contributions of GAP vs. translational control functions to disease phenotypes not dissected

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0045182 translation regulator activity 4 GO:0140096 catalytic activity, acting on a protein 3 GO:0003723 RNA binding 1 GO:0140110 transcription regulator activity 1
Localization
GO:0005886 plasma membrane 5 GO:0005634 nucleus 3 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 10 R-HSA-392499 Metabolism of proteins 4 R-HSA-1643685 Disease 3 R-HSA-8953854 Metabolism of RNA 3
Partners
ADCY5EIF2B5FBXO44GNA11GNAQPPP1R9BSTAT3ZC3H12A

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 RGS2 is a selective and potent GTPase-activating protein (GAP) for Gqα, but not Giα, Gsα, or G12/13α. RGS2 selectively binds Gqα in brain membranes and purified recombinant form, and potently inhibits Gq-directed activation of phospholipase Cβ1 in reconstituted phospholipid vesicles, being 10-fold more potent than RGS4. Pulldown from brain membranes, binding to purified recombinant Gqα, GTPase activity assays, reconstituted phospholipid vesicle PLCβ1 activation assay Proceedings of the National Academy of Sciences of the United States of America High 9405622
1998 RGS2 stimulates the GTPase activity of Gqα and Gi1α in biochemical assays; the effect on Gi1α was only observed after reconstitution in phospholipid vesicles containing M2 muscarinic receptors. RGS2 also inhibits both Gq- and Gi-dependent responses in transfected cells. GTPase activity assays, phospholipid vesicle reconstitution, transfected cell signaling assays The Journal of neuroscience : the official journal of the Society for Neuroscience High 9736641
1999 G protein selectivity of RGS2 is determined by specific structural features: RGS2 is 5-fold more potent than RGS4 as an inhibitor of Gq-stimulated phosphoinositide hydrolysis in vivo, while RGS4 is 8-fold more potent for Gi-mediated signaling. Mutations in RGS2 that alter its switch I binding pocket and α8-α9 loop increase potency toward Gi without affecting Gq potency. In vivo phosphoinositide hydrolysis assays, mutagenesis, comparison with RGS4-Giα1 crystal structure The Journal of biological chemistry High 10567399
2000 RGS2 is phosphorylated by PKC in vitro to near-stoichiometric levels, and also in intact COS7 cells in response to PKC activation. PKC phosphorylation decreases RGS2's capacity to attenuate GTP- and GTPγS-stimulated PLCβ activation and reduces its GAP activity in reconstituted proteoliposomes. In vitro kinase assay with purified PKC isoforms, intact cell phosphorylation assay (PMA), PLCβ activity assay, GAP activity in reconstituted proteoliposomes with P2Y1 receptor and Gqαβγ The Journal of biological chemistry High 11063746
2001 RGS2 contains a conserved N-terminal amphipathic α-helix that binds vesicles containing acidic phospholipids and is necessary and sufficient for plasma membrane localization. Expression of activated Gq increases RGS2 association with the plasma membrane and decreases nuclear accumulation. The N-terminus also directs nuclear accumulation of GFP, and RGS2 enters the nucleus by passive diffusion (lacks a nuclear import signal). Confocal microscopy of GFP-tagged RGS2, mutational analysis, biophysical analysis (vesicle binding), HEK293 cell fractionation The Journal of biological chemistry High 11278586
2002 RGS2 directly inhibits adenylyl cyclase activity independently of its GAP activity. The N-terminal 19 amino acids of RGS2 are required for inhibition of cAMP accumulation and binding to adenylyl cyclase. RGS2 interacts directly with the C1 (but not C2) domain of type V adenylyl cyclase. Three specific N-terminal residues identified by alanine scanning are responsible for this inhibitory function. Deletion/alanine scanning mutagenesis, cAMP accumulation assays in HEK293 cells, in vitro binding to adenylyl cyclase domains The Journal of biological chemistry High 12604604
2003 RGS2-deficient mice exhibit hypertension, renovascular abnormalities, persistent resistance vasoconstriction, and prolonged vasoconstrictor responses in vivo. Loss of RGS2 in vascular smooth muscle cells increases agonist potency and efficacy at P2Y receptors and slows Ca2+ signal termination kinetics. RGS2 knockout mouse model, telemetric blood pressure measurement, in vitro Ca2+ signaling in vascular smooth muscle cells The Journal of clinical investigation High 12588882
2003 GFP-RGS2 localizes to the nucleus in HEK293 cells and is selectively recruited to the plasma membrane by co-expression with Gsα, Gqα, or corresponding receptors (β2-adrenergic, AT1A angiotensin II). G protein mutants with reduced RGS affinity fail to recruit RGS2, indicating direct G protein binding mediates membrane recruitment. GFP-tagged RGS2 expression, confocal microscopy, co-expression with G protein mutants in HEK293 cells Molecular pharmacology Medium 12920194
2004 RGS2 binds directly and selectively to the third intracellular (i3) loop of the M1 muscarinic receptor (but not M2 or RGS16). The N-terminal region of RGS2 is necessary and sufficient for M1i3 binding. RGS2 forms a stable heterotrimeric complex with activated Gqα and M1i3. Deletion of the N-terminus abolishes effector antagonist activity but not GAP activity toward G11α. Direct binding assays (GST pulldown), co-localization by fluorescence microscopy, membrane phosphoinositide hydrolysis assay, truncation mutants The Journal of biological chemistry High 14976183
2004 RGS2 functions as a mediator of the NO-cGMP pathway in vascular smooth muscle: cGMP analogs fail to inhibit vasopressin-triggered Ca2+ transients in smooth muscle cells from RGS2−/− resistance arteries despite normal PKG expression and activation, and the blood pressure-lowering effect of nitric oxide donor SNP is impaired in RGS2−/− mice. RGS2 knockout mice, blood pressure telemetry, Ca2+ signaling in freshly isolated resistance artery smooth muscle cells, PKG activity assay Molecular pharmacology High 15563583
2005 Spinophilin (SPL) scaffolds RGS2 to GPCRs by binding the N-terminal domain of RGS2 and the third intracellular loop of GPCRs, markedly increasing RGS2-mediated inhibition of α-adrenergic receptor Ca2+ signaling. The constitutively active αAR(A293E) mutant that cannot bind SPL is resistant to RGS2 inhibition. RGS2-mediated inhibition of αAR Ca2+ signaling is reduced in spl−/− cells. Co-immunoprecipitation, Xenopus oocyte expression system, Ca2+ signaling assays, αAR-βAR chimeras, knockout cell comparison Nature cell biology High 15793568
2005 RGS2 binds directly to the third intracellular loop of the α1A-adrenergic receptor (but not α1B or α1D), is recruited to the plasma membrane by unstimulated α1A-AR, and inhibits receptor and Gq/11 signaling. The N-terminus of RGS2 is required, and residues K219, S220, R238 within the α1A-AR i3 loop are essential for the interaction. GST pulldown (direct binding), fluorescence imaging, mutagenesis of receptor, functional signaling assays in cells The Journal of biological chemistry High 15917235
2005 RGS2 interacts with Gsα and multiple adenylyl cyclase isoforms (ACI, ACII, ACV, ACVI) in living HEK293 cells. BRET signals were detected between RGS2-Rluc and Gsα-GFP, and between GFP-RGS2 and ACII- or ACVI-Rluc. RGS2 also interacts with the β2-adrenergic receptor third intracellular loop (GST pulldown), and the receptor-RGS2 BRET signal is stabilized by co-expressed AC. BRET assay, confocal microscopy, GST pulldown with β2AR i3 loop Cellular signalling Medium 16095880
2007 N-terminal residues of RGS2 control its proteasomal degradation in HEK293 cells. An N-terminal RGS2 variant Q2L (found in hypertensive patients) shows significantly reduced expression and reduced inhibition of AT1 receptor-stimulated inositol phosphate accumulation, consistent with N-end rule-mediated ubiquitylation. Mutagenesis, immunoblotting, inositol phosphate accumulation assay in HEK293 cells Molecular pharmacology Medium 17220356
2007 RGS2 downregulation in dopamine neurons of the ventral tegmental area increases GABAB receptor–GIRK channel coupling efficiency. Repeated GHB exposure downregulates RGS2 and increases this coupling, providing a mechanism for GHB tolerance. Electrophysiology in VTA neurons of wild-type and RGS2-knockout mice, GHB exposure paradigm, molecular analysis Nature neuroscience High 17965710
2007 The unique dileucine motif adjacent to the RGS2 amphipathic helix, and the hydrophobic extension of this helix, mediate constitutive plasma membrane targeting. Disrupting this motif or membrane phospholipid composition reduces plasma membrane association and inhibitory function of RGS2, without affecting its binding to M1 receptor i3 loop or activated Gqα. Mutagenesis, GFP-RGS2 confocal microscopy, prenylation chimeras, phospholipid perturbation, signaling functional assays The Journal of biological chemistry High 17848575
2009 RGS2 binds to eIF2Bε (eukaryotic initiation factor 2B epsilon subunit) and inhibits mRNA translation. This function maps to a 37-amino acid region within the conserved RGS domain, is distinct from GAP activity, and involves interference with the eIF2-eIF2B GTPase cycle required for translation initiation. Co-immunoprecipitation (RGS2–eIF2Bε), in vitro translation assay, domain mapping, eIF2-eIF2B GTPase cycle assay The Journal of cell biology High 19736320
2009 X-ray crystal structure of a triple-mutant RGS2 (with Gαi-directed activity) in complex with transition-state mimetic Gαi at 2.8 Å resolution revealed the structural basis of wild-type RGS2 selectivity for Gqα over Gαi/o. Three evolutionarily conserved residues weaken Gαi association by unfavorable geometry at the switch I binding pocket. X-ray crystallography, mutagenesis, GTPase activity assays The Journal of biological chemistry High 19478087
2008 A hypertension-associated RGS2 missense variant R44H, located within the N-terminal amphipathic α-helix, binds the plasma membrane less efficiently than wild-type RGS2. Tryptophan fluorescence and circular dichroism show that R44H prevents hydrophobic entrenchment into the lipid bilayer without disrupting helix formation, resulting in weaker inhibition of Gq signaling. Confocal microscopy (YFP-R44H), tryptophan fluorescence spectroscopy, circular dichroism, Gq signaling functional assay Molecular pharmacology High 18230714
2010 RGS2 is a primary terminator of β2-adrenergic receptor–Gi signaling in cardiomyocytes. Selective upregulation of RGS2 upon agonist withdrawal impairs β2AR-Gi signaling; adenoviral RGS2 overexpression suppresses agonist-activated β2AR-Gi signaling, while RGS2 ablation sustains this signaling. Adult mouse cardiomyocyte culture, adenoviral RGS2 overexpression, RGS2 knockout, cAMP and contractility measurements Journal of molecular and cellular cardiology Medium 21291891
2011 β2-adrenoceptor agonist and glucocorticoid combinations synergistically induce RGS2 expression in human airway smooth muscle cells, and this induced RGS2 reduces intracellular Ca2+ flux elicited by Gq-coupled spasmogens. Rgs2-deficient mice show enhanced bronchoconstriction and absence of LABA-induced bronchoprotection. Primary human airway smooth muscle cell culture, Ca2+ flux assay, Rgs2-/- mouse model, methacholine challenge Proceedings of the National Academy of Sciences of the United States of America High 22080612
2015 FBXO44, operating within a CUL4B/DDB1 E3 ubiquitin ligase complex (not the canonical CUL1/Skp1 complex), mediates RGS2 proteasomal degradation. This was identified by genomic siRNA screening. Genome-wide siRNA screen, co-immunoprecipitation, ubiquitylation assay, proteasome inhibitor treatment PloS one Medium 25970626
2015 RGS2 protein is degraded via polyubiquitination at K71 residue, and is stabilized by the deubiquitinase MCPIP1; a catalytically dead C157A MCPIP1 mutant does not stabilize RGS2. RGS2 overexpression decreases TSPYL5 protein levels in breast cancer cells. Mutagenesis (K71R), MG-132 treatment, dominant-negative deubiquitinase mutant, immunoblot Journal of cellular biochemistry Medium 25187114
2019 RGS2 translation is controlled by its interaction with eIF2Bε: RGS2 or its eIF2B-interacting domain (RGS2eb) increases levels of ATF4 and CHOP at the translational level, independently of eIF2α phosphorylation, promoting expression of stress-related apoptotic factors. RGS2/RGS2eb overexpression, polysome analysis, immunoblot for ATF4 and CHOP, eIF2α phosphorylation status determination Cellular signalling Medium 30826455
2021 RGS2 causes prolonged translational arrest in slow-cycling/dormant cancer cells through persistent eIF2α phosphorylation, mediated by proteasome-dependent degradation of ATF4 (an eIF2 phosphatase scaffold). RGS2 antagonism or phosphodiesterase 5 inhibitors reverse this translational arrest and promote ER stress-induced apoptosis. Proliferation-sensitive dye labeling, RGS2 overexpression/knockdown, eIF2α phosphorylation assays, ATF4 degradation assay, in vitro and xenograft in vivo models The Journal of clinical investigation Medium 33393490
2020 RGS2 forms a ternary complex with PAR4 and Gαq in live cells (shown by BRET), and co-expression of PAR4 and Gαq shifts RGS2 localization from cytoplasm to plasma membrane. RGS2 abolishes PAR4-activated ERK phosphorylation, calcium mobilization, and RhoA activity. BRET assay in live cells, confocal microscopy, ERK phosphorylation assay, Ca2+ mobilization assay, RhoA activity assay Cell communication and signaling : CCS Medium 32517689
2011 RGS2 directly binds STAT3 in the nucleus and represses STAT3-mediated transcriptional activation of Nox1. GFP-RGS2 concentrates in the nucleus, and TLR2 signaling, through PKC-η/PLD2, reduces RGS2 expression to derepress STAT3-mediated Nox1 induction. Co-immunoprecipitation (RGS2–STAT3), nuclear GFP-RGS2 localization by confocal microscopy, luciferase reporter assay for Nox1 promoter, siRNA knockdown Cellular signalling Medium 22120521
2000 RGS2 and RGS4 bind purified recombinant β'-COP (a COPI subunit) in vitro; endogenous cytosolic RGS2 from HEK293T cells co-fractionates with the COPI complex by gel filtration. RGS4 inhibits COPI association with Golgi membranes and intracellular transport independently of its GAP activity, through dilysine motifs. In vitro binding to recombinant β'-COP, gel filtration co-fractionation, Golgi membrane COPI binding assay Molecular biology of the cell Medium 10982407
2007 RGS2 deficiency leads to increased renal responsiveness to vasopressin: RGS2 is expressed specifically in vasopressin-sensitive nephron segments, vasopressin rapidly upregulates RGS2 expression, and cAMP accumulation in microdissected collecting ducts is significantly higher in RGS2−/− mice. RGS2 knockout mice, microdissected collecting duct cAMP assay, in situ hybridization for localization, water restriction/loading test Journal of the American Society of Nephrology : JASN Medium 17475820
2010 Loss of renal RGS2 (by kidney cross-transplantation) is sufficient to cause hypertension, whereas absence of RGS2 from all extrarenal tissues (including peripheral vasculature) does not significantly alter blood pressure. This establishes that RGS2 acts within the kidney to modulate blood pressure. Kidney cross-transplantation between RGS2-deficient and wild-type mice, telemetric blood pressure measurement Journal of the American Society of Nephrology : JASN High 20847141
2023 RGS2 enhances estradiol biosynthesis in trophoblasts by promoting degradation of the transcription factor HAND1: RGS2 suppresses USP14-mediated deubiquitination of HAND1, leading to its proteasomal degradation and relief of HAND1-induced trans-repression of the aromatase gene. Conversely, aromatase binds RGS2 and represses its GAP activity. Co-immunoprecipitation (RGS2–HAND1, RGS2–aromatase, USP14–HAND1), ubiquitination assays, aromatase promoter reporter assay, E2 measurement, JEG-3 trophoblast cell line Experimental & molecular medicine Medium 36653442
2023 The lncRNA HITT, induced by IFN-γ via E2F1, coordinates with RGS2 by co-binding the 5' UTR of PD-L1 mRNA to reduce PD-L1 translation, thereby enhancing T cell-mediated cytotoxicity in a PD-L1-dependent manner. RNA immunoprecipitation (HITT and RGS2 binding to PD-L1 5'UTR), luciferase reporter (PD-L1 translation), T cell cytotoxicity assay, in vivo tumor models The Journal of clinical investigation Medium 37014700

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 RGS2/G0S8 is a selective inhibitor of Gqalpha function. Proceedings of the National Academy of Sciences of the United States of America 302 9405622
1998 Dynamic regulation of RGS2 suggests a novel mechanism in G-protein signaling and neuronal plasticity. The Journal of neuroscience : the official journal of the Society for Neuroscience 253 9736641
2003 Hypertension and prolonged vasoconstrictor signaling in RGS2-deficient mice. The Journal of clinical investigation 246 12588882
2000 Regulation of T cell activation, anxiety, and male aggression by RGS2. Proceedings of the National Academy of Sciences of the United States of America 232 11027316
2004 Genetic dissection of a behavioral quantitative trait locus shows that Rgs2 modulates anxiety in mice. Nature genetics 222 15489855
2004 RGS2 binds directly and selectively to the M1 muscarinic acetylcholine receptor third intracellular loop to modulate Gq/11alpha signaling. The Journal of biological chemistry 188 14976183
2007 RGS2 modulates coupling between GABAB receptors and GIRK channels in dopamine neurons of the ventral tegmental area. Nature neuroscience 176 17965710
1999 G protein selectivity is a determinant of RGS2 function. The Journal of biological chemistry 152 10567399
2002 RGS2: a multifunctional regulator of G-protein signaling. The international journal of biochemistry & cell biology 129 11906816
2005 Spinophilin regulates Ca2+ signalling by binding the N-terminal domain of RGS2 and the third intracellular loop of G-protein-coupled receptors. Nature cell biology 118 15793568
2003 Recruitment of RGS2 and RGS4 to the plasma membrane by G proteins and receptors reflects functional interactions. Molecular pharmacology 114 12920194
1999 A novel regulator of G protein signalling in yeast, Rgs2, downregulates glucose-activation of the cAMP pathway through direct inhibition of Gpa2. The EMBO journal 114 10523302
2003 Identification of RGS2 and type V adenylyl cyclase interaction sites. The Journal of biological chemistry 111 12604604
2001 Mechanisms governing subcellular localization and function of human RGS2. The Journal of biological chemistry 108 11278586
2005 RGS2 interacts with Gs and adenylyl cyclase in living cells. Cellular signalling 103 16095880
2008 Influence of RGS2 on anxiety-related temperament, personality, and brain function. Archives of general psychiatry 98 18316676
2005 Selective loss of fine tuning of Gq/11 signaling by RGS2 protein exacerbates cardiomyocyte hypertrophy. The Journal of biological chemistry 88 16380388
2005 Selective inhibition of alpha1A-adrenergic receptor signaling by RGS2 association with the receptor third intracellular loop. The Journal of biological chemistry 85 15917235
2000 Protein kinase C phosphorylates RGS2 and modulates its capacity for negative regulation of Galpha 11 signaling. The Journal of biological chemistry 85 11063746
2006 Regulator of G-protein signaling 2 (RGS2) inhibits androgen-independent activation of androgen receptor in prostate cancer cells. Oncogene 81 16449965
2005 Autonomic nervous system and blood pressure regulation in RGS2-deficient mice. American journal of physiology. Regulatory, integrative and comparative physiology 81 15661972
2004 RGS2 is a mediator of nitric oxide action on blood pressure and vasoconstrictor signaling. Molecular pharmacology 81 15563583
2000 Specific regulation of RGS2 messenger RNA by angiotensin II in cultured vascular smooth muscle cells. Molecular pharmacology 81 10692485
2004 Increased expression of regulator of G protein signaling-2 (RGS-2) in Bartter's/Gitelman's syndrome. A role in the control of vascular tone and implication for hypertension. The Journal of clinical endocrinology and metabolism 78 15292363
2007 N-terminal residues control proteasomal degradation of RGS2, RGS4, and RGS5 in human embryonic kidney 293 cells. Molecular pharmacology 75 17220356
2008 Variant in RGS2 moderates posttraumatic stress symptoms following potentially traumatic event exposure. Journal of anxiety disorders 73 19162436
2011 β2-Adrenoceptor agonist-induced RGS2 expression is a genomic mechanism of bronchoprotection that is enhanced by glucocorticoids. Proceedings of the National Academy of Sciences of the United States of America 67 22080612
2009 Structural determinants of G-protein alpha subunit selectivity by regulator of G-protein signaling 2 (RGS2). The Journal of biological chemistry 66 19478087
1997 Comparison of mRNA expression of two regulators of G-protein signaling, RGS1/BL34/1R20 and RGS2/G0S8, in cultured human blood mononuclear cells. DNA and cell biology 61 9174164
2004 Dopamine receptor-mediated regulation of RGS2 and RGS4 mRNA differentially depends on ascending dopamine projections and time. The European journal of neuroscience 56 15090051
2000 Dynamic regulation of RGS2 in bone: potential new insights into parathyroid hormone signaling mechanisms. Endocrinology 55 10614620
2010 RGS2 inhibits beta-adrenergic receptor-induced cardiomyocyte hypertrophy. Cellular signalling 52 20362664
2015 RGS2 suppresses breast cancer cell growth via a MCPIP1-dependent pathway. Journal of cellular biochemistry 51 25187114
2006 Up-regulation of endogenous RGS2 mediates cross-desensitization between Gs and Gq signaling in osteoblasts. The Journal of biological chemistry 51 16950788
2009 Translational control by RGS2. The Journal of cell biology 49 19736320
2011 Identification of a cAMP-response element in the regulator of G-protein signaling-2 (RGS2) promoter as a key cis-regulatory element for RGS2 transcriptional regulation by angiotensin II in cultured vascular smooth muscles. The Journal of biological chemistry 48 22057271
2002 Expression of RGS2, RGS4 and RGS7 in the developing postnatal brain. The European journal of neuroscience 48 11906535
2009 Evidence for enhanced M3 muscarinic receptor function and sensitivity to atrial arrhythmia in the RGS2-deficient mouse. American journal of physiology. Heart and circulatory physiology 47 19966055
2006 RGS2 is upregulated by and attenuates the hypertrophic effect of alpha1-adrenergic activation in cultured ventricular myocytes. Cellular signalling 47 16517124
2021 RGS2-mediated translational control mediates cancer cell dormancy and tumor relapse. The Journal of clinical investigation 46 33393490
2001 RGS2 promotes adipocyte differentiation in the presence of ligand for peroxisome proliferator-activated receptor gamma. The Journal of biological chemistry 46 11418611
1999 New roles for RGS2, 5 and 8 on the ratio-dependent modulation of recombinant GIRK channels expressed in Xenopus oocytes. The Journal of physiology 45 10332086
2022 Fatty acid metabolism is related to the immune microenvironment changes of gastric cancer and RGS2 is a new tumor biomarker. Frontiers in immunology 42 36591293
2001 Oxidative stress and heat shock stimulate RGS2 expression in 1321N1 astrocytoma cells. Archives of biochemistry and biophysics 42 11488592
2000 Muscarinic stimulation of alpha1E Ca channels is selectively blocked by the effector antagonist function of RGS2 and phospholipase C-beta1. The Journal of neuroscience : the official journal of the Society for Neuroscience 41 11007872
1995 Differential expression of a basic helix-loop-helix phosphoprotein gene, G0S8, in acute leukemia and localization to human chromosome 1q31. Leukemia 39 7643615
2017 Epigenetic regulation of RGS2 (Regulator of G-protein signaling 2) in chemoresistant ovarian cancer cells. Journal of chemotherapy (Florence, Italy) 37 28102109
2008 Silencing regulator of G protein signaling-2 (RGS-2) increases angiotensin II signaling: insights into hypertension from findings in Bartter's/Gitelman's syndromes. Journal of hypertension 37 18398336
2010 Deregulation of RGS2 in cardiovascular diseases. Frontiers in bioscience (Scholar edition) 36 20036967
2007 Association of RGS2 gene polymorphisms with suicide and increased RGS2 immunoreactivity in the postmortem brain of suicide victims. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 34 17728697
2007 RGS5, RGS4, and RGS2 expression and aortic contractibility are dynamically co-regulated during aortic banding-induced hypertrophy. Journal of molecular and cellular cardiology 34 18207159
2006 RGS2 is regulated by angiotensin II and functions as a negative feedback of aldosterone production in H295R human adrenocortical cells. Endocrinology 34 16627589
2002 Analysis of regulator of G-protein signaling-2 (RGS-2) expression and function in osteoblastic cells. Journal of cellular biochemistry 34 11968023
2011 RGS2 is a primary terminator of β₂-adrenergic receptor-mediated G(i) signaling. Journal of molecular and cellular cardiology 33 21291891
2007 Association of the RGS2 gene with extrapyramidal symptoms induced by treatment with antipsychotic medication. Pharmacogenetics and genomics 32 17558307
2005 Angiotensin II-evoked enhanced expression of RGS2 attenuates Gi-mediated adenylyl cyclase signaling in A10 cells. Cardiovascular research 32 15914115
2004 RGS2-mediated regulation of Gqalpha. Methods in enzymology 32 15488171
2002 Parathyroid hormone induces RGS-2 expression by a cyclic adenosine 3',5'-monophosphate-mediated pathway in primary neonatal murine osteoblasts. Bone 32 11996904
2016 Upregulation of RGS2: a new mechanism for pirfenidone amelioration of pulmonary fibrosis. Respiratory research 31 27549302
2008 Further evidence for association of the RGS2 gene with antipsychotic-induced parkinsonism: protective role of a functional polymorphism in the 3'-untranslated region. The pharmacogenomics journal 31 18347610
2004 Role of regulator of G protein signaling 2 (RGS2) in Ca(2+) oscillations and adaptation of Ca(2+) signaling to reduce excitability of RGS2-/- cells. The Journal of biological chemistry 31 15292238
2007 Unique hydrophobic extension of the RGS2 amphipathic helix domain imparts increased plasma membrane binding and function relative to other RGS R4/B subfamily members. The Journal of biological chemistry 30 17848575
2005 NO-dependent blood pressure regulation in RGS2-deficient mice. American journal of physiology. Regulatory, integrative and comparative physiology 30 16269576
2007 Vascular microarray profiling in two models of hypertension identifies caveolin-1, Rgs2 and Rgs5 as antihypertensive targets. BMC genomics 29 17986358
2021 ZHX3 promotes the progression of urothelial carcinoma of the bladder via repressing of RGS2 and is a novel substrate of TRIM21. Cancer science 28 33440047
2019 Reduced mRNA Expression of RGS2 (Regulator of G Protein Signaling-2) in the Placenta Is Associated With Human Preeclampsia and Sufficient to Cause Features of the Disorder in Mice. Hypertension (Dallas, Tex. : 1979) 27 31865781
2015 FBXO44-Mediated Degradation of RGS2 Protein Uniquely Depends on a Cullin 4B/DDB1 Complex. PloS one 27 25970626
2008 Association of RGS2 and RGS5 variants with schizophrenia symptom severity. Schizophrenia research 27 18262772
2023 Long noncoding RNA HITT coordinates with RGS2 to inhibit PD-L1 translation in T cell immunity. The Journal of clinical investigation 26 37014700
2016 RGS2 expression predicts amyloid-β sensitivity, MCI and Alzheimer's disease: genome-wide transcriptomic profiling and bioinformatics data mining. Translational psychiatry 26 27701409
2015 RGS2 ggenetic variation: association analysis with panic disorder and dimensional as well as intermediate phenotypes of anxiety. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 26 25740197
2013 Influence of RGS2 on sertraline treatment for social anxiety disorder. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 26 24154666
2007 Increased renal responsiveness to vasopressin and enhanced V2 receptor signaling in RGS2-/- mice. Journal of the American Society of Nephrology : JASN 26 17475820
2018 Analysis of regulator of G-protein signalling 2 (RGS2) expression and function during prostate cancer progression. Scientific reports 25 30467386
2011 Resistance to age-related, normal body weight gain in RGS2 deficient mice. Cellular signalling 25 21447383
2001 RGS2: regulation of expression and nuclear localization. Biochemical and biophysical research communications 24 11322774
2000 RGS4 and RGS2 bind coatomer and inhibit COPI association with Golgi membranes and intracellular transport. Molecular biology of the cell 24 10982407
2001 Second messengers regulate RGS2 expression which is targeted to the nucleus. Biochimica et biophysica acta 23 11755214
2020 Regulators of G-protein signaling, RGS2 and RGS4, inhibit protease-activated receptor 4-mediated signaling by forming a complex with the receptor and Gα in live cells. Cell communication and signaling : CCS 22 32517689
2014 RGS2 regulates urotensin II-induced intracellular Ca2+ elevation and contraction in glomerular mesangial cells. Journal of cellular physiology 22 24105430
2009 Ischemia induces regulator of G protein signaling 2 (RGS2) protein upregulation and enhances apoptosis in astrocytes. American journal of physiology. Cell physiology 22 20032508
2008 The RGS2 gene product from a candidate hypertension allele shows decreased plasma membrane association and inhibition of Gq. Molecular pharmacology 22 18230714
2001 RGS2 blocks slow muscarinic inhibition of N-type Ca(2+) channels reconstituted in a human cell line. The Journal of physiology 22 11306654
2018 A bronchoprotective role for Rgs2 in a murine model of lipopolysaccharide-induced airways inflammation. Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology 21 30305828
2017 Protective Roles for RGS2 in a Mouse Model of House Dust Mite-Induced Airway Inflammation. PloS one 21 28107494
2016 Digoxin-Mediated Upregulation of RGS2 Protein Protects against Cardiac Injury. The Journal of pharmacology and experimental therapeutics 21 26941169
2015 MicroRNA hsa-miR-4717-5p regulates RGS2 and may be a risk factor for anxiety-related traits. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 21 25847876
2014 Hypertension after preeclampsia and relation to the C1114G polymorphism (rs4606) in RGS2: data from the Norwegian HUNT2 study. BMC medical genetics 21 24593135
2014 Regulator of G protein signaling 2 (RGS2) deficiency accelerates the progression of kidney fibrosis. Biochimica et biophysica acta 21 24973550
2011 RGS2 is a negative regulator of STAT3-mediated Nox1 expression. Cellular signalling 21 22120521
2010 Renal actions of RGS2 control blood pressure. Journal of the American Society of Nephrology : JASN 21 20847141
2002 Oxytocin stimulation of RGS2 mRNA expression in cultured human myometrial cells. American journal of physiology. Endocrinology and metabolism 21 11832360
2014 Expression and regulation of regulator of G-protein signaling protein-2 (RGS2) in equine and bovine follicles prior to ovulation: molecular characterization of RGS2 transactivation in bovine granulosa cells. Biology of reproduction 20 25339105
2011 Association of RGS2 variants with panic disorder in a Japanese population. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 20 21438143
2006 Cellular stress increases RGS2 mRNA and decreases RGS4 mRNA levels in SH-SY5Y cells. Neuroscience letters 20 16733081
2017 Increased fear learning, spatial learning as well as neophobia in Rgs2-/- mice. Genes, brain, and behavior 19 28846187
2023 RGS2 promotes estradiol biosynthesis by trophoblasts during human pregnancy. Experimental & molecular medicine 18 36653442
2012 RGS2 is a component of the cellular stress response. Biochemical and biophysical research communications 18 22922103
2019 RGS2 promotes the translation of stress-associated proteins ATF4 and CHOP via its eIF2B-inhibitory domain. Cellular signalling 17 30826455
2013 Valproic acid substantially downregulated genes folr1, IGF2R, RGS2, COL6A3, EDNRB, KLF6, and pax-3, N-acetylcysteine alleviated most of the induced gene alterations in chicken embryo model. Romanian journal of morphology and embryology = Revue roumaine de morphologie et embryologie 17 24398995