Affinage

RGS5

Regulator of G-protein signaling 5 · UniProt O15539

Length
181 aa
Mass
20.9 kDa
Annotated
2026-06-10
77 papers in source corpus 30 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RGS5 is a GTPase-activating protein (GAP) that accelerates GTP hydrolysis by Gαi and Gαq subunits and thereby acts as a negative regulator of G-protein-coupled receptor signaling, with a predominant role in vascular smooth muscle and pericyte biology (PMID:11253162, PMID:12514120). Through GAP activity on Gαq/11 it dampens angiotensin II- and endothelin-1-evoked intracellular Ca2+ transients and downstream MAPK signaling in vascular smooth muscle cells (PMID:11253162, PMID:12006602, PMID:12514120), and upon receptor activation or mechanical stimulation it traffics to the plasma membrane to co-localize with the activated AT1 receptor (PMID:29061726). In vivo, RGS5 sets vascular tone and blood pressure: Rgs5-null mice are hypotensive with dilated aortas and show exaggerated vasodilatory ERK/VASP signaling (PMID:18268011), while in resistance arteries RGS5 (a transcriptional target of PPARγ/δ) blunts angiotensin II-driven PKC activation and preserves BKCa channel activity to control myogenic tone (PMID:22962432). By simultaneously suppressing Gαq/11-Ca2+ signaling and licensing Gα12/13-RhoA signaling, RGS5 drives the phenotypic switch of smooth muscle cells required for arteriogenesis and hypertensive remodeling (PMID:24972930, PMID:29208700). In pericytes RGS5 governs tumor vessel morphology—its loss promotes pericyte maturation, vascular normalization, and enhanced anti-tumor immune infiltration (PMID:18418378)—and it controls pericyte survival and cardiac homeostasis, where TGFβ-driven pSmad2 binding redirects RGS5 to the nucleus to rescue PI3K-AKT survival signaling, and where pericyte RGS5 loss elicits a TGFβ2-dependent profibrotic program (PMID:34012071, PMID:38563133). RGS5 protein abundance is tightly governed by the N-end rule pathway: ATE1 arginylates oxidized N-terminal Cys-2 to generate an N-degron recognized by the UBR1/UBR2 ubiquitin ligases for proteasomal degradation, and a stabilizing Cys-2 mutation increases RGS5 expression and function (PMID:16217033, PMID:17220356). GAP activity is further switched off by PKC phosphorylation at Ser166, which abolishes Gα binding (PMID:17540411). Beyond the vasculature, RGS5 represses Hedgehog/Gαi signaling in association with Smoothened at the primary cilium (PMID:23637832), and in astrocytes it binds TNFR1 and TNFR2 directly to augment TNF receptor signaling and promote neuroinflammation (PMID:37674228).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2001 High

    Established RGS5's core biochemical identity by showing it is a GAP selective for Gαi and Gαq subunits that dampens receptor-evoked calcium signaling, defining the molecular activity all later vascular roles build on.

    Evidence In vitro GTP hydrolysis and Gα-binding assays plus Ca2+ signaling and fractionation in 293T cells

    PMID:11253162

    Open questions at the time
    • Did not establish the physiological receptor/tissue context
    • Membrane-targeting role of N-terminus separated from GAP catalysis but not structurally resolved
  2. 2002 Medium

    Showed endogenous RGS5 selectively constrains AT1 receptor-Gq/11 signaling in vascular smooth muscle, moving from biochemistry to a defined endogenous receptor target.

    Evidence Ribozyme knockdown with MAPK and inositol phosphate readouts in rat aortic smooth muscle cells

    PMID:12006602

    Open questions at the time
    • Single loss-of-function approach
    • In vivo relevance not yet tested
  3. 2003 Medium

    Defined RGS5 as a pericyte-specific gene downstream of PDGF-B/PDGFRβ-driven pericyte recruitment, localizing its biology to the pericyte/VSMC compartment.

    Evidence ERK assays, in situ hybridization, and PDGFRβ/PDGF-B knockout mice

    PMID:12514120

    Open questions at the time
    • Mechanism coupling pericyte identity to RGS5 transcription unresolved
  4. 2005 High

    Revealed that RGS5 abundance is controlled post-translationally by the N-end rule pathway via ATE1 arginylation of oxidized Cys-2 and UBR1/UBR2-dependent ubiquitination, explaining its normally low cellular levels and oxygen sensitivity.

    Evidence In vivo degradation assays in ATE1-/- and UBR1/UBR2-null cells with Cys-2 mutagenesis

    PMID:16217033

    Open questions at the time
    • How physiological hypoxia tunes RGS5 stability in vascular cells not directly measured
    • Did not link degradation rate to a specific GAP-dependent phenotype
  5. 2005 Medium

    Identified a human-specific cytosolic splice variant lacking the N-terminal 108 residues that selectively inhibits Gαi signaling and can competitively block full-length RGS5, introducing isoform-level regulation of GAP specificity.

    Evidence RT-PCR cloning, fractionation, and co-transfection Ca2+ assays in HEK293 cells

    PMID:15670159

    Open questions at the time
    • Endogenous abundance and in vivo role of the variant unknown
    • Dominant-negative mechanism inferred from overexpression
  6. 2007 High

    Showed PKC phosphorylation at Ser166 abolishes Gα binding and GAP activity, providing an acute signaling switch that inactivates RGS5 independent of its degradation.

    Evidence In vitro PKC kinase assay, mass spectrometry, S166D mutant, and Ca2+ signaling readouts

    PMID:17540411

    Open questions at the time
    • Which receptors/PKC isoforms drive Ser166 phosphorylation in vivo not defined
  7. 2008 High

    Demonstrated in vivo that RGS5 sets blood pressure and vascular tone, with knockout causing hypotension, aortic dilation, and exaggerated vasodilatory signaling.

    Evidence Rgs5 knockout mice with telemetry, morphometry, and ex vivo pVASP/pERK signaling

    PMID:18268011

    Open questions at the time
    • Receptor coupling underlying enhanced NO/S1P responses not pinpointed
  8. 2008 High

    Established RGS5 as a master regulator of abnormal tumor vasculature, where its loss normalizes vessels and improves immune infiltration and survival.

    Evidence Rgs5 knockout tumor models with vascular imaging, immune infiltration, and survival analysis

    PMID:18418378

    Open questions at the time
    • Cell-autonomous pericyte signaling driving normalization not dissected in this study
  9. 2012 High

    Placed RGS5 in transcriptional and electrophysiological control of myogenic tone as a PPARγ/δ target that preserves BKCa channel activity by limiting angiotensin II-PKC signaling.

    Evidence PPRE reporter, siRNA, BKCa patch-clamp, myogenic tone, and dominant-negative PPARγ mice

    PMID:22962432

    Open questions at the time
    • Direct link from RGS5 GAP activity to BKCa modulation mechanistically incomplete
  10. 2014 High

    Resolved the dual G-protein logic of RGS5 in arteriogenesis: it suppresses Gαq/11-Ca2+ while facilitating Gα12/13-RhoA signaling to drive the activated, proliferative SMC phenotype.

    Evidence Gain/loss-of-function in VSMCs with Ca2+ and RhoA assays plus a femoral ligation arteriogenesis model

    PMID:24972930

    Open questions at the time
    • How a GAP promotes rather than inhibits Gα12/13-RhoA signaling not mechanistically explained
  11. 2018 High

    Extended the RhoA-licensing role to hypertensive remodeling, showing RGS5 is required for stress-fiber formation and synthetic phenotype switching under pressure.

    Evidence RGS5-deficient mice with angiotensin II infusion, stretch assays, RhoA activity, and PKC inhibition

    PMID:29208700

    Open questions at the time
    • Whether nuclear or membrane RGS5 mediates the remodeling phenotype unresolved
  12. 2017 Medium

    Linked RGS5 function to receptor-triggered subcellular trafficking, showing it moves to the activated AT1R at the membrane and that this trafficking is impaired in hypertensive vessels.

    Evidence Proximity ligation assay and siRNA knockdown with myogenic constriction in arteriolar VSMCs

    PMID:29061726

    Open questions at the time
    • Molecular driver of RGS5 translocation not identified
    • Correlative link to hypertension
  13. 2015 Medium

    Identified GPSM3 as a selective RGS5-binding partner that maintains or enhances RGS5 GAP activity, distinguishing RGS5 regulation from other RGS proteins.

    Evidence Co-IP/pulldown and solution/membrane GTP hydrolysis assays

    PMID:25842189

    Open questions at the time
    • No independent replication
    • Physiological consequence of GPSM3-RGS5 complex not tested
  14. 2021 Medium

    Defined a tumor-microenvironment switch in which TGFβ-driven pSmad2 binds RGS5 and translocates it to the nucleus, releasing Gαi/q to rescue PI3K-AKT survival signaling in pericytes.

    Evidence Co-IP of RGS5 with Gαi/q and pSmad2, nuclear fractionation, and apoptosis/PI3K-AKT readouts in pericytes

    PMID:34012071

    Open questions at the time
    • Direct demonstration that nuclear sequestration causes the survival phenotype is indirect
    • Single lab
  15. 2023 High

    Connected pericyte RGS5 loss to cardiac dysfunction and fibrosis via a TGFβ2-dependent paracrine profibrotic program, extending its pericyte role to organ homeostasis.

    Evidence Pericyte-specific RGS5 deletion, snRNA-seq, and pericyte-fibroblast co-culture/conditioned medium experiments

    PMID:38563133

    Open questions at the time
    • How RGS5 GAP activity represses the profibrotic transcriptional program not resolved
  16. 2013 Medium

    Placed RGS5 outside the vasculature as an endogenous Hedgehog repressor acting as a Gαi GAP in complex with Smoothened at the primary cilium.

    Evidence Overexpression/siRNA, Co-IP with Smo, and ciliary co-localization in C3H10T1/2 cells

    PMID:23637832

    Open questions at the time
    • Direct GAP action on Smo-coupled Gαi at the cilium inferred, not biochemically reconstituted
  17. 2023 High

    Revealed a non-GAP signaling role in astrocytes where RGS5 binds TNFR1/TNFR2 directly to augment TNF signaling and drive neuroinflammation, identifying a druggable protein-protein interaction.

    Evidence Astrocyte-specific knockout, reciprocal Co-IP with TNFRs, PD models, and peptide/small-molecule disruption

    PMID:37674228

    Open questions at the time
    • Structural basis of RGS5-TNFR binding undefined
    • Relationship between TNFR binding and canonical GAP activity unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RGS5 reconciles its dual roles as a GAP that both inhibits (Gαq/11, Gαi) and enables (Gα12/13-RhoA) signaling, and how its trafficking, dimerization, and non-GAP TNFR/Smo binding are integrated at the structural level, remains unresolved.
  • No full atomic-resolution RGS5-Gα structure analyzed beyond preliminary crystallization
  • Functional significance of RGS5 homodimerization unestablished
  • Mechanism by which a GAP facilitates Gα12/13-RhoA signaling unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0098772 molecular function regulator activity 4 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005886 plasma membrane 3 GO:0005829 cytosol 2 GO:0005634 nucleus 1 GO:0005929 cilium 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-397014 Muscle contraction 3 R-HSA-168256 Immune System 2 R-HSA-392499 Metabolism of proteins 2
Partners
GNAI1GNAI3GNAQGPSM3SMAD2SMOTNFRSF1ATNFRSF1B

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 RGS5 binds Gαi1, Gαi2, Gαi3, Gαo, and Gαq (but not Gαs or Gα13) in the presence of GDP/AlF4-, and accelerates GTP hydrolysis by Gαi3, functioning as a GAP for these G-protein subunits. RGS5 suppresses angiotensin II- and endothelin-1-induced intracellular Ca2+ transients in AT1a-expressing cells. The N-terminal region (aa 1-33) targets RGS5 to membranes but is not essential for GAP activity. In vitro GTP hydrolysis assay, Gα-binding assay with GDP/AlF4-, Ca2+ signaling assay in 293T cells, subcellular fractionation Life sciences High 11253162
2002 Endogenous RGS5 is a selective negative modulator of angiotensin AT1a receptor signaling through Gq/11 in rat vascular smooth muscle cells; RGS5 ribozyme knockdown specifically enhanced angiotensin II-induced MAP kinase activation and inositol phosphate release (pertussis toxin-insensitive), whereas RGS3 selectively modulated muscarinic m3 receptor signaling. Synthetic ribozyme-mediated knockdown, MAP kinase assay, inositol phosphate release assay in rat aortic smooth muscle cells The Journal of biological chemistry Medium 12006602
2003 RGS5 acts as a potent GAP for Gαi and Gαq and attenuates angiotensin II-, endothelin-1-, sphingosine-1-phosphate-, and PDGF-induced ERK-2 phosphorylation in pericytes/VSMCs. RGS5 expression is pericyte-specific and depends on PDGF-B/PDGFRβ signaling for pericyte recruitment but is expressed independently of this pathway once pericytes are present. ERK-2 phosphorylation assay, in situ hybridization, mouse genetic models (PDGFR-β and PDGF-B knockout) FASEB journal Medium 12514120
2005 RGS5 is degraded in vivo through the N-end rule ubiquitin-proteasome pathway: ATE1 Arg-transferase arginylates oxidized N-terminal Cys-2 of RGS5, generating an N-degron recognized by ubiquitin ligases UBR1 and UBR2. Mutation of Cys-2 prevents this modification and stabilizes RGS5. Hypoxia or loss of UBR1/UBR2 perturbs this degradation. In vivo degradation assay in ATE1-/- and UBR1/UBR2-null cells, Cys-2 mutant analysis, protein stability assays Proceedings of the National Academy of Sciences of the United States of America High 16217033
2005 A human-specific alternatively spliced variant of RGS5 (RGS5s) lacks the N-terminal 108 amino acids, localizes almost exclusively to the cytosol (unlike full-length RGS5 which is in both membrane and cytosolic fractions), inhibits Gαi-coupled receptor (CB1) signaling but not Gαq-coupled AT1 or FP receptor Ca2+ signaling. Co-expression of RGS5s with RGS5 blocks RGS5-mediated inhibition of AT1 and FP receptor signaling, suggesting a dominant-negative or competitive mechanism. RT-PCR cloning, subcellular fractionation, Ca2+ signaling assay, co-transfection in HEK293 cells The FEBS journal Medium 15670159
2007 PKC phosphorylates RGS5 at Ser166 (identified by mass spectrometry), and this phosphorylation abolishes Gα-subunit binding and GAP activity. Substitution of Ser166 with aspartate (phospho-mimetic) markedly reduced inhibition of ET-1-induced Ca2+ responses; PKC inhibitors enhanced RGS5 inhibitory function. In vitro PKC phosphorylation assay, mass spectrometry, site-directed mutagenesis (S166D), Gα binding assay, Ca2+ signaling assay Life sciences High 17540411
2007 N-terminal residues control proteasomal degradation of RGS5 in HEK293 cells; a stabilizing C2S mutation enhances RGS5 expression and function, whereas wild-type RGS5 has minimal cellular expression due to rapid N-end rule-mediated degradation. Mutagenesis, proteasome inhibitor treatment, expression/functional assays in HEK293 cells Molecular pharmacology Medium 17220356
1999 The N-terminal amphipathic alpha-helix (aa 12-30) of RGS16 is required for plasma membrane association, and the hydrophobic residues on the nonpolar face plus positively charged residues at the polar/nonpolar interface are critical; RGS5 contains a homologous domain predicted to mediate membrane association by the same mechanism. RGS16 (and by homology RGS5) is a peripheral membrane protein not requiring palmitoylation. Site-directed mutagenesis, subcellular fractionation, differential centrifugation, alkaline wash (peripheral membrane protein characterization) The Journal of biological chemistry Medium 10391923
2008 Rgs5-deficient mice have persistently low blood pressure and dilated aortas. Isolated aortic smooth muscle cells from Rgs5-/- mice show exaggerated ERK phosphorylation and VASP phosphorylation in response to nitric oxide donor (sodium nitroprusside) or sphingosine-1-phosphate, indicating RGS5 attenuates vasodilatory signaling in vivo. Rgs5 knockout mouse, blood pressure telemetry, aortic morphometry, ex vivo smooth muscle cell signaling assays (western blot for pVASP, pERK) Molecular and cellular biology High 18268011
2008 Loss of Rgs5 in tumors results in pericyte maturation and vascular normalization (reduced vessel leakiness, reduced hypoxia), enhancing immune effector cell influx into tumors and prolonging survival of tumor-bearing mice, establishing RGS5 as a master regulator of abnormal tumor vascular morphology. Rgs5 knockout mouse in tumor models, MRI/histological vascular analysis, immune cell infiltration assay, survival analysis Nature High 18418378
2009 Under hypoxia, RGS5 expression in endothelial cells is induced via HIF-1α-dependent transcription (RGS5 promoter activity is absent in HIF-1β-/- cells). RGS5 overexpression induces endothelial apoptosis via caspase-3 activation and increased Bax/Bcl-2 ratio. RGS5 augments VEGF-mediated p38 (but not ERK1/2) activation and impairs VEGF-induced angiogenesis in Matrigel assay. HIF-1β-/- cell promoter assay, RGS5 overexpression/siRNA knockdown in HUVEC, Annexin V apoptosis assay, caspase-3 activity assay, p38/ERK western blot, Matrigel angiogenesis assay The Journal of biological chemistry Medium 19564336
2011 Beta-agonist treatment of human airway smooth muscle cells decreases RGS5 expression. RGS5 knockdown increases agonist-evoked intracellular calcium flux and myosin light chain phosphorylation. Airway smooth muscle from Rgs5-/- mice contracts more to carbachol than WT, establishing RGS5 as a negative regulator of bronchial smooth muscle contraction. siRNA knockdown in human airway smooth muscle cells, Ca2+ flux assay, MLC phosphorylation assay, precision-cut lung slice contraction in Rgs5-/- mice The Journal of biological chemistry High 21278382
2012 PPARγ and PPARδ each bind a PPAR response element near the RGS5 promoter and transcriptionally regulate RGS5 expression in vascular smooth muscle cells. RGS5, as a PPARγ/δ target, blunts angiotensin II-mediated PKC activation and preserves large-conductance Ca2+-activated K+ (BKCa) channel activity, controlling myogenic tone in resistance arteries. Chromatin reporter assay (PPRE), siRNA knockdown of RGS5, patch-clamp of BKCa current, myogenic tone measurement, transgenic dominant-negative PPARγ SMC mice, gene expression profiling Circulation research High 22962432
2012 Rgs5-/- mice show prolonged cardiac repolarization (prolonged QT interval and action potential duration) and increased susceptibility to ventricular tachyarrhythmia. This correlates with reduced outward K+ currents (Ito, IKur, Iss, Ipeak) and downregulated expression of Kv4.2, Kv4.3, Kv1.5, and Kv2.1 channels in ventricular myocytes. Rgs5 knockout mouse, in vivo/ex vivo electrocardiography, whole-cell patch clamp in ventricular myocytes, protein/mRNA expression analysis Journal of molecular and cellular cardiology High 23079193
2013 RGS5 is an endogenous repressor of Hedgehog signaling: RGS5 overexpression inhibits Shh-mediated signaling and osteogenesis, while siRNA knockdown of RGS5 (but not RGS4) potentiates Shh signaling. RGS5 co-localizes with Smoothened in primary cilia and co-immunoprecipitates with Smo, placing RGS5 downstream of Smo as a GAP for Gαi in the Hh pathway. RGS5 overexpression and siRNA knockdown in C3H10T1/2 cells, co-immunoprecipitation, immunohistochemistry of primary cilia, osteogenesis assay PloS one Medium 23637832
2014 RGS5 is upregulated in vascular SMCs of remodeling collateral arterioles during arteriogenesis. RGS5 overexpression blunts Gαq/11-mediated Ca2+ mobilization and facilitates Gα12/13-mediated RhoA signaling, promoting SMC proliferation and acquisition of the activated phenotype required for collateral growth. RGS5 knockdown blocks RhoA activation, SMC proliferation, and collateral arteriole growth. RGS5 overexpression/knockdown in VSMCs, intracellular Ca2+ assay, RhoA activity assay (G-LISA/pull-down), mouse arteriogenesis model (femoral artery ligation), RGS5-deficient mice EMBO molecular medicine High 24972930
2015 GPSM3 selectively binds RGS5 (not RGS4 or other RGS proteins tested) and enhances RGS5's ability to accelerate GTP hydrolysis by Gαi1 in solution-based assays. In membrane-based assays with M2 receptor-activated Gαi1, GPSM3 does not inhibit RGS5 GAP activity (unlike its effect on RGS4), suggesting binding of GPSM3 to RGS5 maintains or enhances GAP activity. Co-immunoprecipitation/pulldown, in vitro GTP hydrolysis assay (solution-based and membrane-based), primary rat aortic smooth muscle cell expression analysis Molecular and cellular biochemistry Medium 25842189
2017 In vascular smooth muscle cells, AT1R activation by angiotensin II or mechanical stimulation (hypotonic solution) induces translocation/trafficking of RGS5 toward the plasma membrane to co-localize with the activated AT1R (demonstrated by proximity ligation assay). RGS5 knockdown enhances constriction to angiotensin II and augments myogenic responses. This trafficking is impaired in VSMCs from spontaneously hypertensive rats. In situ proximity ligation assay, siRNA knockdown of RGS5 in arteriolar VSMCs, myogenic constriction measurement, intact arteriole contractility Hypertension Medium 29061726
2017 RGS5 inhibits Shh function in cortical neurons: RGS5 overexpression via adenovirus reduces neurite outgrowth and FM4-64 uptake (presynaptic terminal maturation marker), and affects cAMP-PKA signaling in cortical neurons, suggesting RGS5 acts as a Gαi GAP downstream of Smoothened in neuronal hedgehog signaling. Adenoviral RGS5 overexpression in primary cortical neurons, neurite outgrowth measurement, FM4-64 uptake assay, cAMP assay Molecular and cellular neurosciences Medium 28684360
2018 Hypertensive pressure levels or biomechanical stretch increase RGS5 expression in VSMCs. RGS5 is required for hypertension-induced RhoA activation and stress fiber formation; RGS5-deficient VSMCs fail to acquire a synthetic phenotype (cannot downregulate α-SMA, smooth muscle-MHC, or proliferate) under hypertensive conditions. PKC inhibition mimics the downstream effect of RGS5-mediated Gαq/11 inhibition, amplifying RhoA activity. RGS5-deficient mice with experimental hypertension (angiotensin II infusion), mechanical stretch assay in VSMCs, RhoA activity assay, contractile marker western blot, PKC inhibitor experiments FASEB journal High 29208700
2021 RGS5 binds Gαi/q and promotes pericyte apoptosis in vitro by blocking PI3K-AKT signaling, leading to Bcl2 downregulation and PUMA-p53-Bax-mediated mitochondrial damage. Within the tumor microenvironment, TGFβ causes pSmad2 to bind RGS5 and translocate it to the nucleus, suppressing both RGS5-Gαi/q interaction and pSmad2/3-Smad4 pairing, thereby rescuing PI3K-AKT survival signaling and preventing apoptosis in tumor pericytes. Co-immunoprecipitation of RGS5 with Gαi/q and pSmad2, nuclear fractionation, PI3K-AKT/Bcl2/Bax western blot, caspase assay, siRNA/overexpression in pericytes, TGFβ treatment Cell death and differentiation Medium 34012071
2021 ATE1-mediated arginylation controls RGS5 protein turnover and thereby regulates Wnt/β-catenin signaling in liver cancer cells: ATE1 overexpression accelerates β-catenin degradation through RGS5-dependent regulation of GSK3-β activity; RGS5 knockdown reverses ATE1-mediated suppression of Wnt signaling. Co-immunoprecipitation confirms RGS5 interaction with components of this pathway. ATE1/RGS5 loss- and gain-of-function in HCC cells, β-catenin western blot, GSK3-β activity assay, GSK inhibitor rescue experiment, co-immunoprecipitation Molecular cancer research Medium 34158395
2021 RGS5 overexpression in proliferating VSMCs attenuates ERK1/2 and Akt signaling, reduces proliferation and migration; this effect is mimicked by selective Gαi/o inhibition but not by Gαq/11 inhibition, indicating RGS5 maintains VSMC resting state principally by suppressing Gαi/o-mediated ERK1/2 activation. RGS5 overexpression in 2D-cultured VSMCs, Gαi/o- and Gαq/11-selective inhibitors, ERK1/2/Akt phosphorylation western blot, proliferation and migration assays, microarray expression profiling Cells Medium 34359918
2021 RGS5 deletion in neutrophils impairs their migration toward chemokines despite preserved Ca2+ signaling; ERK dephosphorylation is implicated in reduced neutrophil migration. In vivo, RGS5-/- mice fail to recruit neutrophils to the lung after bleomycin or LPS injury, preserving lung function. RGS5-/- mouse lung injury models (bleomycin, LPS), in vitro neutrophil migration assay, Ca2+ signaling measurement, ERK phosphorylation western blot, myeloperoxidase measurement International journal of molecular sciences Medium 34502263
2023 In astrocytes, RGS5 promotes neuroinflammation by binding directly to TNFR1 and TNFR2 (shown by Co-IP), augmenting TNF receptor signaling and switching astrocytes from neuroprotective to pro-inflammatory. Selective ablation of Rgs5 in astrocytes inhibits cytokine production and is neuroprotective in PD models; the RGS5 aa 1-108 fragment or small molecules (feshurin, butein) that disrupt RGS5/TNFR interaction suppress astrocytic cytokine production. Conditional astrocyte-specific Rgs5 knockout, RGS5 overexpression, Co-IP of RGS5 with TNFR1/TNFR2, cytokine ELISA, PD mouse models, competitive peptide/small molecule inhibition Journal of neuroinflammation High 37674228
2023 RGS5 in cardiac pericytes is reduced with aging. Deletion of RGS5 causes cardiac dysfunction and myocardial fibrosis by inducing a profibrotic gene signature in pericytes (upregulating TGFB2, PDGFB, ECM components). Conditioned medium from RGS5-deficient pericytes activates adjacent fibroblasts (increased αSMA) via a TGFβ2-dependent mechanism. Pericyte-specific RGS5 deletion in mice, single-nucleus RNA sequencing, pericyte-fibroblast co-culture, conditioned medium experiments, αSMA/TGFβ2 western blot, cardiac function echocardiography, fibrosis histology Circulation research High 38563133
2019 RGS5 overexpression in parathyroid cells inhibits calcium-sensing receptor (CASR) signaling and impairs negative feedback on PTH secretion. Transgenic mice overexpressing RGS5 specifically in parathyroid glands develop hyperparathyroidism, bone changes, and parathyroid neoplasia, establishing RGS5 as an inhibitor of CASR-mediated signaling in parathyroid physiology. Parathyroid-specific RGS5 transgenic mouse, PTH measurement, bone analysis, parathyroid histology, CASR signaling assay in normal human parathyroid cells expressing RGS5 Journal of bone and mineral research High 30690792
2006 The complex of human Gαi3 and RGS5 was crystallized with GDP/Mg2+/AlF4- at 3.0 Å resolution (space group P4(1)2(1)2 or P4(3)2(1)2), providing preliminary structural data for the RGS5-Gα interaction. Recombinant protein expression in E. coli, protein purification, X-ray crystallography (synchrotron, 3.0 Å) Protein and peptide letters Low 17100651
2007 RGS5 forms homodimers detectable by western blot (~42 kDa band) and confirmed by yeast two-hybrid and GFP-tagged RGS5 analysis in HEK293A cells. The dimer is longer-lived than the monomer, suggesting a regulatory function. Western blot of overexpressed RGS5, yeast two-hybrid assay, GFP-RGS5 fusion analysis in yeast and HEK293A cells Cellular physiology and biochemistry Low 17762159
2011 Rgs5 expression shows vascular bed-specific differences in adult mice driven by an origin-specific epigenetic program: the Rgs5 promoter is more heavily methylated at CpG dinucleotides in carotid artery (neural crest-derived) VSMCs compared to descending aorta VSMCs in adults but not neonates. In vitro methylation of the Rgs5 promoter confirmed transcriptional repression by CpG methylation. Rgs5-LacZ reporter mouse (lineage mapping), bisulfite sequencing of Rgs5 promoter, in vitro methylation reporter assay, primary VSMC culture FASEB journal Medium 21965603

Source papers

Stage 0 corpus · 77 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Vascular normalization in Rgs5-deficient tumours promotes immune destruction. Nature 455 18418378
2005 RGS4 and RGS5 are in vivo substrates of the N-end rule pathway. Proceedings of the National Academy of Sciences of the United States of America 230 16217033
2003 Transcription profiling of platelet-derived growth factor-B-deficient mouse embryos identifies RGS5 as a novel marker for pericytes and vascular smooth muscle cells. The American journal of pathology 192 12598306
2003 Pericyte-specific expression of Rgs5: implications for PDGF and EDG receptor signaling during vascular maturation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 161 12514120
2002 Receptor-selective effects of endogenous RGS3 and RGS5 to regulate mitogen-activated protein kinase activation in rat vascular smooth muscle cells. The Journal of biological chemistry 99 12006602
1999 The membrane association domain of RGS16 contains unique amphipathic features that are conserved in RGS4 and RGS5. The Journal of biological chemistry 89 10391923
2008 Rgs5 targeting leads to chronic low blood pressure and a lean body habitus. Molecular and cellular biology 77 18268011
2007 N-terminal residues control proteasomal degradation of RGS2, RGS4, and RGS5 in human embryonic kidney 293 cells. Molecular pharmacology 76 17220356
2007 RGS5 expression is a quantitative measure of pericyte coverage of blood vessels. Angiogenesis 72 18038251
2001 Characterization of RGS5 in regulation of G protein-coupled receptor signaling. Life sciences 70 11253162
2008 Generation and characterization of rgs5 mutant mice. Molecular and cellular biology 68 18212066
2009 RGS5, a hypoxia-inducible apoptotic stimulator in endothelial cells. The Journal of biological chemistry 62 19564336
2004 Expression of regulator of G protein signalling protein 5 (RGS5) in the tumour vasculature of human renal cell carcinoma. The Journal of pathology 61 15095478
2012 PPARγ regulates resistance vessel tone through a mechanism involving RGS5-mediated control of protein kinase C and BKCa channel activity. Circulation research 55 22962432
2007 Coexpression of Notch3 and Rgs5 in the pericyte-vascular smooth muscle cell axis in response to pulp injury. The International journal of developmental biology 53 17939118
2023 Resmetirom Ameliorates NASH-Model Mice by Suppressing STAT3 and NF-κB Signaling Pathways in an RGS5-Dependent Manner. International journal of molecular sciences 52 36982915
1998 Isolation, tissue expression, and chromosomal assignment of human RGS5, a novel G-protein signaling regulator gene. Journal of human genetics 49 9747037
2011 Regulator of G-protein signaling 5 (RGS5) protein: a novel marker of cancer vasculature elicited and sustained by the tumor's proangiogenic microenvironment. Cellular and molecular life sciences : CMLS 42 22130514
2007 Identification and characterization of T-cell epitopes deduced from RGS5, a novel broadly expressed tumor antigen. Clinical cancer research : an official journal of the American Association for Cancer Research 39 17545542
2005 Expression profiling identifies smooth muscle cell diversity within human intima and plaque fibrous cap: loss of RGS5 distinguishes the cap. Arteriosclerosis, thrombosis, and vascular biology 39 16293795
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
2021 RGS5-TGFβ-Smad2/3 axis switches pro- to anti-apoptotic signaling in tumor-residing pericytes, assisting tumor growth. Cell death and differentiation 32 34012071
2014 RGS5 promotes arterial growth during arteriogenesis. EMBO molecular medicine 31 24972930
2024 RGS5+ lymphatic endothelial cells facilitate metastasis and acquired drug resistance of breast cancer through oxidative stress-sensing mechanism. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy 30 39306871
2011 The relationship between RGS5 expression and cancer differentiation and metastasis in non-small cell lung cancer. Journal of surgical oncology 29 21780128
2011 Association of ATP1B1, RGS5 and SELE polymorphisms with hypertension and blood pressure in African-Americans. Journal of hypertension 29 21881522
2011 Origin-specific epigenetic program correlates with vascular bed-specific differences in Rgs5 expression. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 29 21965603
2007 Vascular microarray profiling in two models of hypertension identifies caveolin-1, Rgs2 and Rgs5 as antihypertensive targets. BMC genomics 29 17986358
2011 Beta-agonist-associated reduction in RGS5 expression promotes airway smooth muscle hyper-responsiveness. The Journal of biological chemistry 27 21278382
2008 Association of RGS2 and RGS5 variants with schizophrenia symptom severity. Schizophrenia research 27 18262772
2024 Age-Dependent RGS5 Loss in Pericytes Induces Cardiac Dysfunction and Fibrosis. Circulation research 26 38563133
2012 Absence of Rgs5 prolongs cardiac repolarization and predisposes to ventricular tachyarrhythmia in mice. Journal of molecular and cellular cardiology 26 23079193
2010 Relationship between RGS5 expression and differentiation and angiogenesis of gastric carcinoma. World journal of gastroenterology 26 21105200
2005 Identification of a novel alternative splicing variant of RGS5 mRNA in human ocular tissues. The FEBS journal 25 15670159
2018 Hypertension-evoked RhoA activity in vascular smooth muscle cells requires RGS5. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 24 29208700
2017 Angiotensin II Type 1 Receptor Mechanoactivation Involves RGS5 (Regulator of G Protein Signaling 5) in Skeletal Muscle Arteries: Impaired Trafficking of RGS5 in Hypertension. Hypertension (Dallas, Tex. : 1979) 23 29061726
2015 The pericyte antigen RGS5 in perivascular soft tissue tumors. Human pathology 22 26558691
2011 Combinational therapy of interferon-α and chemotherapy normalizes tumor vasculature by regulating pericytes including the novel marker RGS5 in melanoma. Journal of immunotherapy (Hagerstown, Md. : 1997) 20 21389866
2021 ATE1 Inhibits Liver Cancer Progression through RGS5-Mediated Suppression of Wnt/β-Catenin Signaling. Molecular cancer research : MCR 19 34158395
2018 RGS5 decreases the proliferation of human ovarian carcinoma‑derived primary endothelial cells through the MAPK/ERK signaling pathway in hypoxia. Oncology reports 19 30365142
2023 RGS5 augments astrocyte activation and facilitates neuroinflammation via TNF signaling. Journal of neuroinflammation 17 37674228
2021 Down-regulated RGS5 by genetic variants impairs endothelial cell function and contributes to coronary artery disease. Cardiovascular research 17 31605122
2016 Vascular and Central Activation of Peroxisome Proliferator-Activated Receptor-β Attenuates Angiotensin II-Induced Hypertension: Role of RGS-5. The Journal of pharmacology and experimental therapeutics 17 27189971
2004 Beta adrenergic receptor-mediated atrial specific up-regulation of RGS5. Life sciences 17 15680317
2023 RGS5 maintaining vascular homeostasis is altered by the tumor microenvironment. Biology direct 16 37986113
2020 RGS5 plays a significant role in renal cell carcinoma. Royal Society open science 15 32431860
2023 Listeria-based vaccination against the pericyte antigen RGS5 elicits anti-vascular effects and colon cancer protection. Oncoimmunology 14 37781234
2022 RGS5: a novel role as a hypoxia-responsive protein that suppresses chemokinetic and chemotactic migration in brain pericytes. Biology open 14 36111549
2014 Dlx1 and Rgs5 in the ductus arteriosus: vessel-specific genes identified by transcriptional profiling of laser-capture microdissected endothelial and smooth muscle cells. PloS one 14 24489801
2012 Atrial tachyarrhythmia in Rgs5-null mice. PloS one 14 23144791
2023 RGS5 as a Biomarker of Pericytes, Involvement in Vascular Remodeling and Pulmonary Arterial Hypertension. Vascular health and risk management 13 37881333
2003 A culture device demonstrates that hydrostatic pressure increases mRNA of RGS5 in neuroblastoma and CHC1-L in lymphocytic cells. Cells, tissues, organs 13 14504426
2007 Phosphorylation of Ser166 in RGS5 by protein kinase C causes loss of RGS function. Life sciences 12 17540411
2017 Regulator of G protein signaling 5 (RGS5) inhibits sonic hedgehog function in mouse cortical neurons. Molecular and cellular neurosciences 10 28684360
2015 MicroRNAs that target RGS5. Iranian journal of basic medical sciences 10 25810883
2021 RGS5 Attenuates Baseline Activity of ERK1/2 and Promotes Growth Arrest of Vascular Smooth Muscle Cells. Cells 9 34359918
2016 Ruminal expression of the NQO1, RGS5, and ACAT1 genes may be indicators of feed efficiency in beef steers. Animal genetics 9 27611366
2013 Regulator of G-protein signaling - 5 (RGS5) is a novel repressor of hedgehog signaling. PloS one 9 23637832
2019 Parathyroid-Targeted Overexpression of Regulator of G-Protein Signaling 5 (RGS5) Causes Hyperparathyroidism in Transgenic Mice. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 8 30690792
2023 Lnc‑RGS5 sponges miR‑542‑5p to promote FoxM1/VEGFA signaling and breast cancer cell proliferation. International journal of oncology 7 37594134
2022 NLGP regulates RGS5-TGFβ axis to promote pericyte-dependent vascular normalization during restricted tumor growth. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 7 35363396
2022 miR-320a Targeting RGS5 Aggravates Atherosclerosis by Promoting Migration and Proliferation of ox-LDL-Stimulated Vascular Smooth Muscle Cells. Journal of cardiovascular pharmacology 6 35522176
2015 Association of regulator of G protein signaling (RGS5) gene variants and essential hypertension in Mongolian and Han populations. Genetics and molecular research : GMR 6 26782409
2023 Lineage Tracing of RGS5-CreER-Labeled Cells in Long Bones During Homeostasis and Injury. Stem cells (Dayton, Ohio) 4 36888549
2000 Molecular cloning and characterization of Xenopus RGS5. Biochemical and biophysical research communications 4 10733901
2024 The mechanism of RGS5 regulating gastric cancer mismatch repair protein. Molecular carcinogenesis 3 38860604
2021 RGS5 Determines Neutrophil Migration in the Acute Inflammatory Phase of Bleomycin-Induced Lung Injury. International journal of molecular sciences 3 34502263
2015 Regulation of RGS5 GAP activity by GPSM3. Molecular and cellular biochemistry 3 25842189
2012 RGS5 gene and therapeutic response to short acting bronchodilators in paediatric asthma patients. Pediatric pulmonology 3 23193110
2025 Germline deletion of Rgs2 and/or Rgs5 in male mice does not exacerbate left ventricular remodeling induced by subchronic isoproterenol infusion. Physiological reports 2 39746869
2021 Absence of Rgs5 Influences the Spatial and Temporal Fluctuation of Cardiac Repolarization in Mice. Frontiers in physiology 2 33815137
2007 Evidence for the dimerization of human regulator of G-protein signalling 5 (RGS5). Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 2 17762159
2025 A pan-cancer analysis of the oncogenic and immunological roles of RGS5 in clear cell renal cell carcinomas based on in vitro experiment validation. Human genomics 1 39985100
2022 Hypoxia-induced miR-182-5p regulates vascular smooth muscle cell phenotypic switch by targeting RGS5. Cell biology international 1 35946384
2020 RGS5 rs4657251 polymorphism is associated with small vessel occlusion stroke in Taiwan Han Chinese. Journal of the Chinese Medical Association : JCMA 1 32080025
2025 Overexpression of MEOX2 inhibits breast cancer cell metastasis by targeting oxidative stress-induced RGS5. In vitro cellular & developmental biology. Animal 0 40603753
2006 Expression, purification, and preliminary X-ray crystallographic analysis of the complex of G(alphai3)-RGS5 from human with GDP/Mg2+)/AlF4-. Protein and peptide letters 0 17100651

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