Affinage

GNAQ

Guanine nucleotide-binding protein G(q) subunit alpha · UniProt P50148

Length
359 aa
Mass
42.1 kDa
Annotated
2026-06-10
100 papers in source corpus 31 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GNAQ encodes the Gαq subunit of a heterotrimeric G protein that couples agonist-activated GPCRs to phospholipase C, transducing receptor signals into intracellular calcium, DAG, and PKC activation; it does so selectively, coupling defined receptors such as the PTH/PTHrP, calcitonin, and gastrin-releasing peptide receptors to PLC in a manner that requires agonist and Gβγ and cannot be substituted by Gαi or βγ (PMID:8732687, PMID:9012857, PMID:9296496). Gαq engages PLCβ1 as a stable pre-associated complex that permits rapid, localized signaling upon activation (PMID:16754659), and it recruits additional effectors including the RhoGEF LARG to activate RhoA (PMID:12024019); conversely, constitutively active Gαq directly binds and inhibits the p110α–p85α PI3K heterodimer independently of PLC (PMID:12704201). Its signaling output is constrained by GRK2, which binds active Gαq through its RGS domain in an activation-dependent manner via the Gαq C-terminus and acts as a bona fide effector, together with the Gβ5·RGS7 dimer and RGS2/RGS4, which form ternary complexes and allosterically modulate Gαq engagement of effectors (PMID:12885252, PMID:12670932, PMID:18936096). Through these cascades Gαq is essential for platelet activation by physiological agonists, for cardiac development, for mGluR-dependent hippocampal long-term depression, and for chemokine-driven calcium responses and chemotaxis in dendritic cells and granulocytes (PMID:9296496, PMID:9687499, PMID:11438569, PMID:17938235), and sustained Gαq activation drives cardiac hypertrophy and heart failure through DAG/PKC-dependent signaling that diacylglycerol kinase ζ can reverse (PMID:9576430, PMID:18219172). Somatic activating mutations at codon Q209 turn GNAQ into a dominant oncogene in blue naevi and uveal melanoma, while the weaker R183Q mutation causes Sturge-Weber syndrome and capillary malformations; both activate downstream PKC–MAPK signaling via RasGRP3 and PKCδ/ε, RhoA–PKN/ROCK–FAK, and in endothelial cells PLCβ3-driven calcium influx through CRAC channels and ANGPT2 induction (PMID:19078957, PMID:23656586, PMID:24141786, PMID:28486107, PMID:34670408, PMID:37858338, PMID:37802293). In a contrasting context, the GNAQ T96S mutation acts dominant-negatively to relieve Gαq-mediated suppression of AKT/MAPK, identifying Gαq as a tumor suppressor in NK/T cell lymphoma (PMID:31527657).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 1996 High

    Established that Gαq is a functional PLC-coupling transducer for specific peptide-hormone GPCRs, defining its core molecular role of linking receptors to inositol phosphate generation.

    Evidence Receptor/Gα cotransfection reconstitution in COS-7/HEK293 with inositol phosphate accumulation assays

    PMID:8732687

    Open questions at the time
    • Did not establish endogenous receptor pairings in native cells
    • Did not resolve selectivity among Gαq family members in vivo
  2. 1997 High

    Resolved which receptors selectively recruit Gαq and showed agonist- and Gβγ-dependence of receptor-catalyzed nucleotide exchange, defining the biochemical activation step.

    Evidence In situ reconstitution with purified Gα subunits and GTP-γS binding for the GRP receptor

    PMID:9012857

    Open questions at the time
    • Limited to a single receptor in reconstituted membranes
    • Did not link to downstream effector engagement
  3. 1997 High

    Demonstrated a non-redundant physiological requirement for Gαq in platelet activation, showing Gαi and βγ cannot substitute, and connecting Gαq to hemostasis.

    Evidence Germline Gαq-knockout mice with platelet aggregation, bleeding time, and thromboembolism assays

    PMID:9296496

    Open questions at the time
    • Did not map the receptors/effectors mediating the platelet defect
    • Whole-body KO confounds cell-autonomy
  4. 1998 High

    Defined Gq-class requirement and redundancy in cardiac development and showed that excess Gαq activity is pathogenic, framing the dosage-sensitive role of Gαq in the heart.

    Evidence Gαq/Gα11 double-KO embryonic lethality and cardiac-specific Gαq overexpression transgenics with pressure overload

    PMID:9576430 PMID:9687499

    Open questions at the time
    • Did not isolate the effector branch responsible for hypertrophy
    • Redundancy with Gα11 obscures Gαq-specific contributions
  5. 1999 High

    Linked Gαq to PI3K-dependent metabolic signaling, showing constitutively active Gαq drives GLUT4 translocation via p110α.

    Evidence Antibody microinjection, Q209L overexpression, PI3K immunoprecipitation, and wortmannin inhibition in adipocytes

    PMID:10490615

    Open questions at the time
    • Apparent positive PI3K link contrasts with later direct-inhibition finding
    • Did not establish endogenous receptor input
  6. 2001 High

    Established a required role for Gαq in synaptic plasticity, specifically mGluR-dependent hippocampal LTD but not LTP.

    Evidence Hippocampal slice electrophysiology in Gαq-KO mice with pharmacological and stimulation-based LTD/LTP induction

    PMID:11438569

    Open questions at the time
    • Did not define the downstream effector chain for LTD
    • Constitutive KO precludes acute/developmental separation
  7. 2002 Medium

    Identified LARG as an effector coupling Gαq to RhoA, extending Gαq output beyond PLCβ to cytoskeletal/Rho signaling.

    Evidence Reciprocal co-IP with transition-state-mimetic Gα and RhoA activation/transformation assays

    PMID:12024019

    Open questions at the time
    • Single-lab co-IP without structural mapping of the interaction
    • Physiological relevance in tissue not established
  8. 2003 Medium

    Clarified signal termination/effector machinery by showing GRK2 binds active Gαq via its RGS domain and Gβ5·RGS7 directly engages and inhibits Gαq.

    Evidence Pull-downs, chimeric Gαq mapping, FRET in live cells, and signaling assays

    PMID:12670932 PMID:12885252

    Open questions at the time
    • Gβ5·RGS7 interaction requires unidentified cellular cofactors
    • GRK2's dual effector/regulator roles not fully reconciled
  9. 2003 High

    Demonstrated a PLC-independent branch in which active Gαq directly inhibits p110α PI3K, defining a distinct biochemical effector relationship.

    Evidence In vitro kinase assays with purified p110α-p85α plus cellular co-IP using inducible Q209L-Gαq

    PMID:12704201

    Open questions at the time
    • Reconciliation with the adipocyte GLUT4/PI3K activation finding unresolved
    • Structural basis of inhibition not determined
  10. 2006 Medium

    Showed Gαq and PLCβ1 exist as a stable pre-formed complex, explaining the rapid, localized kinetics of Gq signaling.

    Evidence Live-cell and in vitro FRET at near-endogenous expression in PC12/HEK293 cells

    PMID:16754659

    Open questions at the time
    • Single-lab FRET without orthogonal structural confirmation
    • Stoichiometry and membrane microdomain context not defined
  11. 2007 High

    Extended Gαq's physiological roles to immune cell migration, cytoskeletal control, and tissue-specific differentiation, showing context-dependent effector use (PKC, calcineurin).

    Evidence Gαq-KO mice (DC/neutrophil chemotaxis), inhibitor/siRNA/Q209L approaches in keratinocytes, and transgenic/pharmacology in osteoblasts and adipocytes

    PMID:16888802 PMID:17609252 PMID:17823129 PMID:17938235

    Open questions at the time
    • Receptor inputs vary by tissue and were not uniformly mapped
    • Downstream effector convergence across cell types not unified
  12. 2008 High

    Identified GNAQ Q209 mutations as constitutively activating oncogenic drivers in melanocytic neoplasia, establishing GNAQ as a dominant oncogene.

    Evidence Tumor sequencing of blue naevi/uveal melanoma with cell-based transformation/activation assays

    PMID:19078957

    Open questions at the time
    • Did not delineate the full downstream effector requirements for transformation
    • Cell-of-origin specificity not addressed
  13. 2008 Medium

    Refined Gαq's regulatory network and cardiac pathology mechanism: RGS2/RGS4–GRK2 ternary complexes allosterically modulate Gαq, and DAG kinase ζ rescues Gαq-driven heart failure.

    Evidence FCPIA/GAP assays for allosteric modulation and Gαq×DGKζ double-transgenic mouse rescue with PKC/MAPK readouts

    PMID:18219172 PMID:18936096

    Open questions at the time
    • Single-lab biochemistry for ternary complexes
    • DGKζ rescue does not prove DAG is the sole pathogenic node
  14. 2010 High

    Defined a mechanotransduction circuit in which Gαq–AT1R–PKCα phosphorylates GRK2 at Ser29 to activate it, mechanistically linking Gαq signaling to GRK2 regulation.

    Evidence Cardiomyocyte stretch model with mini-gene Gαq inhibition, PKCα shRNA, GRK2-S29A mutant, and transgenic mice

    PMID:20194499

    Open questions at the time
    • Specific to cardiac stretch context
    • Did not address feedback on Gαq signaling output
  15. 2011 High

    Established that Gαq/11 signaling antagonizes PTH anabolic action in bone via PKCδ translocation, demonstrating bidirectional control by gain- and loss-of-function in vivo.

    Evidence Osteoblast-specific Gαq/Gα11 double-KO and Q209L transgenic mice with PTH challenge, histomorphometry, and PKCδ assays

    PMID:21345793

    Open questions at the time
    • Receptor coupling to the inhibitory output not fully mapped
    • Cross-talk with Gs/cAMP arm not resolved
  16. 2013 High

    Identified the weaker R183Q activating mutation as the cause of Sturge-Weber syndrome and port-wine stains, expanding GNAQ disease beyond melanoma and linking mutation strength to phenotype.

    Evidence Whole-genome and amplicon sequencing of affected tissue with ERK phosphorylation and luciferase reporter validation

    PMID:23656586

    Open questions at the time
    • Endothelial mechanism not yet defined at this stage
    • Quantitative relationship of activation strength to phenotype unresolved
  17. 2013 High

    Defined PKC as the obligatory intermediary between mutant Gαq and MAPK in uveal melanoma, establishing a therapeutically actionable signaling axis.

    Evidence Pharmacological epistasis with PKC and MEK inhibitors plus in vitro/in vivo melanoma models

    PMID:24141786

    Open questions at the time
    • Did not identify the specific Ras pathway link (addressed later)
    • PKC isoform specificity unresolved at this stage
  18. 2016 Medium

    Pinpointed the endothelial cell as the cell type harboring GNAQ R183Q in capillary malformations, identifying the source of aberrant Gαq signaling.

    Evidence FACS fractionation of human malformation tissue with droplet digital PCR for R183Q

    PMID:26368330

    Open questions at the time
    • Small specimen number
    • Did not establish the downstream endothelial mechanism
  19. 2017 High

    Resolved the Ras-dependent route to MAPK in GNAQ-mutant melanoma, showing RasGRP3 (induced by mutant Gαq) is activated by PKCδ/ε phosphorylation and DAG-mediated recruitment.

    Evidence shRNA knockdown, PKC isoform analysis, DAG recruitment, and MAPK readouts in uveal melanoma cells

    PMID:28486107

    Open questions at the time
    • Single-lab; relative contribution of PKC-dependent vs DAG-dependent recruitment not quantified
    • Generality across other Gαq-mutant tissues untested
  20. 2019 Medium

    Revealed a context-dependent tumor-suppressor role for Gαq, where the dominant-negative T96S mutation relieves Gαq-mediated inhibition of AKT/MAPK to promote NK/T lymphoma.

    Evidence Sequencing, conditional Ncr1-Cre Gαq KO mice, and NK cell survival/pathway assays

    PMID:31527657

    Open questions at the time
    • Dominant-negative mechanism inferred from pathway data, not structurally proven
    • Single-lab; reconciliation with oncogenic Gαq roles incomplete
  21. 2022 Medium

    Quantified the activation hierarchy of GNAQ variants, showing R183 and Q209 mutations differ mainly in activation magnitude while producing similar downstream transcriptomes.

    Evidence GNAQ-responsive luciferase reporter and RNA-seq across variant panel in microvascular endothelial cells

    PMID:35635655

    Open questions at the time
    • Reporter readout may not capture all effector branches
    • Phenotypic divergence despite similar transcriptomes unexplained
  22. 2023 Medium

    Defined effector mechanisms and therapeutic vulnerabilities of mutant Gαq across vascular and melanoma contexts: endothelial PLCβ3→ANGPT2 and CRAC-mediated calcium influx in malformations, RhoA→PKN/ROCK→FAK in melanoma, and MAPK-driven vascular tumor growth.

    Evidence Endothelial R183Q/knock-in models, RNA-seq, allele-selective siRNA, CRAC/PKC/MEK/PKN/FAK inhibitors, ANGPT2 knockdown, and in vivo rescue

    PMID:34670408 PMID:37024491 PMID:37802293 PMID:37858338

    Open questions at the time
    • Each mechanism shown largely single-lab
    • Relative dominance of parallel effector branches per tissue not integrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple parallel Gαq effector branches (PLCβ/PKC-MAPK, RhoA-FAK, direct PI3K inhibition, CRAC-calcium) are differentially weighted to produce distinct cell-type- and mutation-specific phenotypes remains unresolved.
  • No unified model linking effector usage to tissue-specific outcome
  • Structural basis distinguishing R183Q vs Q209 signaling magnitude not defined
  • Reconciliation of Gαq's oncogenic vs tumor-suppressor roles across cell types incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0003924 GTPase activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-1643685 Disease 4 R-HSA-162582 Signal Transduction 3 R-HSA-109582 Hemostasis 1
Partners
ARHGEF12GNB5GRK2PIK3CAPLCB1PLCB3RGS2RGS4
Complex memberships
Gq heterotrimeric G protein

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 Gαq (GNAQ protein) is essential for platelet activation by physiological platelet activators (thrombin, collagen, ADP, etc.). Mice deficient in Gαq have platelets that are completely unresponsive to these activators, resulting in increased bleeding times and protection from thromboembolism. Gαq cannot be functionally replaced by Gαi or βγ subunits in this context. Germline knockout mice (Gαq-deficient), platelet aggregation assays, bleeding time measurements, thromboembolism model Nature High 9296496
1998 Gαq (and the closely related Gα11) are required for cardiac development: double-knockout mice (Gαq−/−;Gα11−/−) die at embryonic day 11 due to cardiomyocyte hypoplasia, demonstrating an essential and partially redundant role of the Gq class in cardiac growth. Double-knockout mouse genetics, embryonic lethal phenotype analysis, histology The EMBO journal High 9687499
1998 Cardiac-specific overexpression of Gαq in transgenic mice stimulates fetal gene expression, depresses cardiomyocyte contractility, and upon pressure overload leads to decompensated eccentric hypertrophy and heart failure, demonstrating that intrinsic Gαq activation is deleterious to cardiac adaptation. Cardiac-specific transgenic mice overexpressing Gαq (G alpha q-25), transverse aortic coarctation, echocardiography, gene expression analysis Circulation High 9576430
1996 Gαq (and other Gαq family members: Gα11, Gα14, Gα15, Gα16) couples PTH/PTHrP receptor and calcitonin receptor to phospholipase C activation in COS-7 and HEK293 cells, demonstrating that dual signaling of these receptors involves distinct G proteins (Gs for adenylyl cyclase; Gq family for PLC). Reconstitution in COS-7/HEK293 cells, cotransfection of receptor with Gαq family α-subunit cDNAs, inositol phosphate accumulation assay Molecular endocrinology High 8732687
1997 The gastrin-releasing peptide receptor (GRPr) selectively couples to Gαq (and not to Gαi/o or Gαt) to catalyze GTP-γS binding. Receptor-catalyzed exchange requires agonist (GRP) and Gβγ subunits; EC50 for GRP was 3.5 nM, consistent with known receptor affinity. In situ reconstitution assay in chaotrope-extracted fibroblast membranes expressing GRPr; GTP-γS binding with purified Gα subunits; radioligand binding Proceedings of the National Academy of Sciences of the United States of America High 9012857
1999 Gαq plays a required role in insulin-stimulated GLUT4 translocation and glucose transport in adipocytes. Constitutively active Q209L-Gαq stimulates GLUT4 translocation in a wortmannin-sensitive (PI3K-dependent) manner and activates PI3Kα (p110α), and anti-p110α (not anti-p110γ) antibody blocks both insulin- and Q209L-Gαq-induced GLUT4 translocation. Microinjection of anti-Gαq/11 antibody or RGS2, adenoviral overexpression of WT or Q209L-Gαq, 2-deoxyglucose uptake, immunoprecipitation of PI3K, wortmannin inhibition Molecular and cellular biology High 10490615
2001 Gαq is required for metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD) in hippocampal CA1, but not for LTP. LTD induced by group I mGluR agonist or by paired-pulse low-frequency stimulation is absent in Gαq-knockout mice; instead, PP-LFS causes potentiation. Gαq−/− knockout mice, hippocampal slice electrophysiology, LTP/LTD induction protocols, pharmacological receptor agonists The Journal of neuroscience High 11438569
2002 LARG (leukemia-associated RhoGEF), unlike p115-RhoGEF, interacts with Gαq (as well as Gα12 and Gα13) via its RGS box in co-immunoprecipitation. Activated Gαq cooperates with LARG to cause synergistic activation of RhoA, identifying LARG as an effector linking Gαq-coupled receptors to RhoA signaling. Cellular co-immunoprecipitation with transition-state mimetic Gα subunits, RhoA activation assays, transforming activity assays, expression of LARG RGS box Molecular and cellular biology Medium 12024019
2003 GRK2 binds to the active form of Gαq (but not Gα16) via its RGS domain in an activation-dependent manner. The C-terminus of Gαq mediates binding to GRK2. GRK2 is the first RGS protein identified that discriminates between members of the Gαq family. Immunoprecipitation, GST-GRK2 pull-down, inositol phosphate signaling assay, plasma membrane recruitment assay with GRK2-GFP, chimeric Gαq/16 subunits Biochemistry Medium 12885252
2003 Constitutively active Gαq (Q209L) inhibits PI3K activity specifically in p110α (not p110β) immunoprecipitates and co-immunoprecipitates with p110α-p85α heterodimer. In vitro incubation of immunoprecipitated Gαq(Q209L) with purified recombinant p110α-p85α decreases PI3K activity. This inhibition is independent of PLC activation. Inducible expression of Gαq(Q209L), PI3K activity assay from immunoprecipitates, co-immunoprecipitation, in vitro kinase assay with purified p110α-p85α, PLC inhibitor pretreatment The Journal of biological chemistry High 12704201
2003 The Gbeta5·RGS7 dimer directly interacts with Gαq as shown by FRET between fluorescently tagged proteins in live mammalian cells, and inhibits Gαq/11-mediated signaling. This interaction requires additional cellular factors not present in purified systems. FRET spectroscopy on cell suspensions and single-cell microscopy, co-immunoprecipitation, functional signaling assays The Journal of biological chemistry Medium 12670932
2006 Gαq and PLCβ1 form a stable pre-associated complex in both unstimulated PC12 and HEK293 cells, as demonstrated by FRET. PLCβ1 binds to both Gαq(GTPγS) and Gαq(GDP) in vitro, but with different protein-protein orientations. Pre-formed complexes give rise to rapid, localized signals upon activation. FRET in live cells (single-cell imaging and cell suspension), in vitro FRET measurements, quantification of protein levels in transfected cells The Journal of biological chemistry Medium 16754659
2007 Gαq is required for the alternative chemokine receptor signaling pathway in dendritic cells and granulocytes. Gαq-deficient neutrophils and DCs show defective calcium responses and chemotaxis to specific chemokines (CCL3 for neutrophils; CCL2, CCL19, CCL21, CXCL12 for DCs), and Gαq-deficient mice show impaired DC migration from skin to lymph nodes. Gαq-deficient mice, calcium flux assays, transwell chemotaxis assays, in vivo skin sensitization model, bone marrow transplantation The Journal of experimental medicine High 17938235
2007 Gαq activation (via P2Y2 receptor stimulation) inhibits keratinocyte spreading and migration by dismantling the actin network, reducing α3 integrin at the cell periphery, dissolving focal contacts, and blocking growth factor-induced ERK and Akt phosphorylation. These effects were confirmed by YM-254890 (Gαq antagonist), Gαq/11 siRNA knockdown, and constitutively active Q209L-Gαq expression. Pharmacological inhibition (YM-254890), siRNA knockdown, constitutively active Gαq overexpression, live-cell kymography, immunofluorescence, wound-healing assay FASEB journal High 17609252
2007 Continuous activation of Gαq in osteoblasts (via Q209L transgene) impairs osteoblast differentiation and causes osteopenia. This effect is mediated via the protein kinase C pathway, as a PKC inhibitor (GF109203X) prevents the impairment of differentiation. Osteoblast-specific transgenic mice expressing constitutively active Gαq(Q209L), histomorphometry, MC3T3-E1 cell culture, PKC inhibitor rescue The Journal of biological chemistry Medium 17823129
2007 Prostaglandin F2α inhibits adipocyte differentiation via a Gαq–Ca2+–calcineurin signaling pathway that blocks expression of pro-adipogenic transcription factors PPARγ and C/EBPα. This mechanism involves an HDAC-sensitive step and does not interfere with mitotic clonal expansion or C/EBPβ. Gαq/11 functional assays, anti-Gαq/11 antibody, calcineurin inhibitor, HDAC inhibitor (TSA), gene expression analysis, adipogenesis assays Journal of cellular biochemistry Medium 16888802
2008 Gαq mutations at codon 209 (in the Ras-like domain) are constitutively activating and turn GNAQ into a dominant oncogene. These somatic mutations occur in 83% of blue naevi and 46% of uveal melanoma, providing an alternative route to MAP kinase activation in melanocytic neoplasia. Tumor sequencing, cell-based transformation assays with mutant GNAQ constructs demonstrating constitutive activation Nature High 19078957
2008 RGS2 and RGS4 form ternary complexes with Gαq and GRK2 (or p63RhoGEF). RGS2 acts as a negative allosteric modulator of Gαq binding to either p63RhoGEF or GRK2. Conversely, GRK2 enhances the GAP activity of RGS4. These findings support GRK2 as a bona fide Gαq effector. Flow cytometry protein interaction assay (FCPIA), GAP assays, allosteric modulation measurements The Journal of biological chemistry Medium 18936096
2008 Diacylglycerol kinase zeta (DGKζ), which degrades DAG downstream of Gαq-PLCβ signaling, rescues Gαq transgenic mice from heart failure. DGKζ prevents cardiac dysfunction, attenuates PKC isoform translocation, and reduces JNK and p38 MAPK phosphorylation caused by activated Gαq. Double-transgenic mice (Gαq × DGKζ), echocardiography, PKC translocation assay, kinase phosphorylation assays, survival analysis Circulation journal Medium 18219172
2010 Mechanical stretch activates GRK2 in cardiac myocytes via a Gαq–angiotensin II AT1 receptor–PKCα pathway. PKCα phosphorylates GRK2 at Ser29, activating it. A GRK2(S29A) mutant abolishes stretch-induced GRK2 activation and restores adenylyl cyclase activity, defining the phosphorylation mechanism. Neonatal rat cardiomyocyte stretch model, mini-gene inhibition of Gαq coupling, shRNA knockdown of PKCα, GRK2(S29A) overexpression, cardiac-specific PKCα transgenic mice, adenylyl cyclase activity assay The Journal of biological chemistry High 20194499
2011 The Gαq signal (constituted by Gαq and Gα11 in osteoblasts) is inhibitory to the anabolic action of PTH on bone. Osteoblast-specific Gαq/Gα11 double-knockout mice show enhanced PTH-induced bone formation, while constitutively active Gαq transgenic mice do not respond to PTH. The inhibitory mechanism involves membrane translocation of PKCδ. Osteoblast-specific Gαq/Gα11 double-KO mice, constitutively active Gαq transgenic mice, PTH injection experiments, bone histomorphometry, primary osteoblast cultures, PKCδ translocation assay, RGS2 overexpression The Journal of biological chemistry High 21345793
2013 A somatic activating mutation in GNAQ (c.548G→A, p.R183Q) causes Sturge-Weber syndrome and port-wine stains. The R183Q mutation leads to constitutive activation of Gαq, modestly increasing ERK activity as shown by phosphorylation-specific antibodies and luciferase reporter assay upon transgenic expression of mutant Gαq. Whole-genome sequencing of paired affected/normal tissue, amplicon sequencing and SNaPshot assays in 97 samples, phosphorylation-specific antibodies for ERK, luciferase reporter assay The New England journal of medicine High 23656586
2013 Mutant GNAQ/GNA11 (Q209 mutations) consistently activates both the PKC and MAPK pathways in uveal melanoma cells. PKC inhibition selectively suppresses MAPK signaling in GNAQ/GNA11-mutant (but not wild-type) melanoma, demonstrating that PKC is an intermediary between mutant Gαq and MAPK activation. PKC inhibitors (AEB071, AHT956), MEK inhibitors (PD0325901, MEK162), cell proliferation and apoptosis assays, western blotting for pathway activation, allograft and xenograft mouse models Oncogene High 24141786
2017 In GNAQ-mutant uveal melanoma, MAPK activation depends on Ras and is mediated by RasGRP3, which is overexpressed selectively in response to GNAQ/11 mutation. RasGRP3 activation requires PKCδ- and PKCε-dependent phosphorylation as well as PKC-independent, DAG-mediated membrane recruitment. PKCδ and PKCε are required and sufficient for MAPK activation downstream of mutant Gαq. shRNA knockdown, PKC isoform-specific analysis, RasGRP3 expression analysis, phosphorylation assays, DAG membrane recruitment assays, MAPK activation readouts Cancer cell High 28486107
2021 Endothelial GNAQ p.R183Q constitutively activates PLCβ3 (a direct downstream effector of Gαq), leading to activation of PKC, NF-κB, and calcineurin signaling. This increases ANGPT2 and DSCR1.4 expression. EC-R183Q cells form enlarged blood vessels in mice, and ANGPT2 knockdown normalizes vessel size, identifying PLCβ3→ANGPT2 as a key mechanism for capillary malformation. Lentiviral expression of R183Q or WT GNAQ in endothelial colony-forming cells, bulk RNA-seq, quantitative PCR, immunostaining of human tissue, YM-254890 inhibitor, PLCβ3 siRNA, PKC inhibitor (AEB071), shRNA knockdown of ANGPT2, in vivo vessel formation assay in mice Arteriosclerosis, thrombosis, and vascular biology High 34670408
2023 Downstream of GNAQ-mutant Gαq, the RhoA signaling axis activates PKN (PRK, an AGC kinase), which converges with ROCK to control FAK (focal adhesion kinase) as a mediator of non-canonical Gαq-driven signaling. PKN inhibition by darovasertib synergizes with FAK inhibitors to halt uveal melanoma growth. High-throughput chemogenetic drug screen, kinase inhibitor profiling (darovasertib), PKN/ROCK/FAK pathway analysis, cell viability assays, in vitro and in vivo (mouse metastatic model) combination studies Cell reports. Medicine Medium 37858338
2023 GNAQ/11 mosaic variants (including R183Q and Q209L) hyperactivate constitutive and ligand-induced intracellular calcium signaling in endothelial cells. The aberrant ligand-activated calcium signal is fueled by extracellular calcium influx through calcium-release-activated channels (CRAC). Allele-selective siRNA targeting the variant allele corrects both constitutive and ligand-activated calcium signaling, and a CRAC inhibitor rescues the ligand-activated signal. Two cellular models expressing GNAQ/11 variants, intracellular calcium imaging, allele-selective siRNA, CRAC channel inhibitor The Journal of investigative dermatology Medium 37802293
2022 Reporter assays comparing GNAQ variants (WT, R183Q, Q209L, Q209R, null) show Q209L has highest activation, while R183Q and Q209R show significantly lower but still activating levels. RNA-seq of microvascular endothelial cells shows all missense variants cause extensive transcriptomic dysregulation compared to WT or null, but R183 and Q209 variants show very few differentially expressed genes when compared to each other — differing in activation magnitude but having similar downstream effects. GNAQ-responsive luciferase reporter assay, RNA-seq in HMEC-1 cells electroporated with GNAQ variants Angiogenesis Medium 35635655
2016 The endothelial cell is the specific cell type enriched for the GNAQ p.R183Q mutation in skin capillary malformations (mutant allelic frequency 3–43% in CD31+ endothelial cells versus lower in other fractions), identifying endothelial cells as the source of aberrant Gαq signaling in capillary malformation. FACS fractionation of human capillary malformation tissue into endothelial, hematopoietic, perivascular, and stromal populations; droplet digital PCR for GNAQ p.R183Q Plastic and reconstructive surgery Medium 26368330
2019 GNAQ T96S mutation (found in 8.7% of NK/T cell lymphoma) acts in a dominant-negative manner to promote tumor growth by suppressing Gαq-mediated inhibition of AKT and MAPK signaling. Conditional Gαq knockout in NK cells (Ncr1-Cre) demonstrates that Gαq deficiency enhances NK cell survival, identifying Gαq as a tumor suppressor in this context. Whole-exome/targeted deep sequencing, conditional KO mice (Ncr1-Cre-Gnaqfl/fl), NK cell survival assays, AKT and MAPK pathway activation assays Nature communications Medium 31527657
2023 Hyperactive GNAQ mutation in endothelial cells (mouse model) drives vascular tumor growth with increased MAPK signaling. Trametinib (MEK inhibitor) suppresses tumor growth by reducing vascular cell proliferation and permeability and prevents coagulopathy. Endothelial-specific hyperactive GNAQ knock-in mouse model, transcriptomic analysis, Trametinib treatment, vascular phenotype and coagulopathy measurement Nature communications Medium 37024491

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature 1232 19078957
2013 Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ. The New England journal of medicine 737 23656586
1997 Defective platelet activation in G alpha(q)-deficient mice. Nature 452 9296496
2008 Oncogenic mutations in GNAQ occur early in uveal melanoma. Investigative ophthalmology & visual science 270 18719078
1998 Embryonic cardiomyocyte hypoplasia and craniofacial defects in G alpha q/G alpha 11-mutant mice. The EMBO journal 205 9687499
2013 Combined PKC and MEK inhibition in uveal melanoma with GNAQ and GNA11 mutations. Oncogene 162 24141786
1998 Decompensation of pressure-overload hypertrophy in G alpha q-overexpressing mice. Circulation 161 9576430
1999 G alpha-q/11 protein plays a key role in insulin-induced glucose transport in 3T3-L1 adipocytes. Molecular and cellular biology 145 10490615
2002 Leukemia-associated Rho guanine nucleotide exchange factor promotes G alpha q-coupled activation of RhoA. Molecular and cellular biology 136 12024019
2017 RasGRP3 Mediates MAPK Pathway Activation in GNAQ Mutant Uveal Melanoma. Cancer cell 131 28486107
2016 Mosaic Activating Mutations in GNA11 and GNAQ Are Associated with Phakomatosis Pigmentovascularis and Extensive Dermal Melanocytosis. The Journal of investigative dermatology 130 26778290
2016 Somatic Activating Mutations in GNAQ and GNA11 Are Associated with Congenital Hemangioma. American journal of human genetics 127 27058448
2002 Interaction of G alpha(12) with G alpha(13) and G alpha(q) signaling pathways. Proceedings of the National Academy of Sciences of the United States of America 102 12077299
2016 Endothelial Cells from Capillary Malformations Are Enriched for Somatic GNAQ Mutations. Plastic and reconstructive surgery 98 26368330
2014 GNAQ and GNA11 mutations in uveal melanoma. Melanoma research 97 25304237
2014 The somatic GNAQ mutation c.548G>A (p.R183Q) is consistently found in Sturge-Weber syndrome. Journal of human genetics 93 25374402
2015 Oncogenic G Protein GNAQ Induces Uveal Melanoma and Intravasation in Mice. Cancer research 81 26113083
2012 Protein kinase C inhibitor AEB071 targets ocular melanoma harboring GNAQ mutations via effects on the PKC/Erk1/2 and PKC/NF-κB pathways. Molecular cancer therapeutics 81 22653968
1996 G alpha q family members couple parathyroid hormone (PTH)/PTH-related peptide and calcitonin receptors to phospholipase C in COS-7 cells. Molecular endocrinology (Baltimore, Md.) 79 8732687
2017 GNAQ and GNA11 mutations and downstream YAP activation in choroidal nevi. British journal of cancer 76 28809862
2017 Recurrent GNAQ mutations in anastomosing hemangiomas. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 73 28084343
2007 Prostaglandin F2alpha inhibits adipocyte differentiation via a G alpha q-calcium-calcineurin-dependent signaling pathway. Journal of cellular biochemistry 73 16888802
2021 Somatic mutations of GNA11 and GNAQ in CTNNB1-mutant aldosterone-producing adenomas presenting in puberty, pregnancy or menopause. Nature genetics 69 34385710
2019 Exosomal long noncoding RNA lnc-GNAQ-6:1 may serve as a diagnostic marker for gastric cancer. Clinica chimica acta; international journal of clinical chemistry 66 31730812
2007 Identification of an alternative G{alpha}q-dependent chemokine receptor signal transduction pathway in dendritic cells and granulocytes. The Journal of experimental medicine 65 17938235
2006 Stable association between G alpha(q) and phospholipase C beta 1 in living cells. The Journal of biological chemistry 65 16754659
1997 Selective reconstitution of gastrin-releasing peptide receptor with G alpha q. Proceedings of the National Academy of Sciences of the United States of America 61 9012857
2018 Frequent GNAQ and GNA14 Mutations in Hepatic Small Vessel Neoplasm. The American journal of surgical pathology 60 29975248
2016 Somatic GNAQ Mutation is Enriched in Brain Endothelial Cells in Sturge-Weber Syndrome. Pediatric neurology 60 27919468
2003 Differential interaction of GRK2 with members of the G alpha q family. Biochemistry 58 12885252
2003 Activated G alpha q inhibits p110 alpha phosphatidylinositol 3-kinase and Akt. The Journal of biological chemistry 56 12704201
2001 G(alpha)q-deficient mice lack metabotropic glutamate receptor-dependent long-term depression but show normal long-term potentiation in the hippocampal CA1 region. The Journal of neuroscience : the official journal of the Society for Neuroscience 56 11438569
2000 Alterations in Ca2+ cycling proteins and G alpha q signaling after left ventricular assist device support in failing human hearts. Cardiovascular research 55 10728414
2007 G(alpha)q-mediated regulation of TASK3 two-pore domain potassium channels: the role of protein kinase C. Molecular pharmacology 54 17374744
2015 Mutation scanning of BRAF, NRAS, KIT, and GNAQ/GNA11 in oral mucosal melanoma: a study of 57 cases. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 53 26399561
2022 Copper ionophore elesclomol selectively targets GNAQ/11-mutant uveal melanoma. Oncogene 51 35697803
2015 BRD4-targeted therapy induces Myc-independent cytotoxicity in Gnaq/11-mutatant uveal melanoma cells. Oncotarget 51 26397223
2001 Coupling of endothelin receptors to the ERK/MAP kinase pathway. Roles of palmitoylation and G(alpha)q. European journal of biochemistry 51 11606208
2021 Endothelial GNAQ p.R183Q Increases ANGPT2 (Angiopoietin-2) and Drives Formation of Enlarged Blood Vessels. Arteriosclerosis, thrombosis, and vascular biology 50 34670408
2016 Gaq proteins: molecular pharmacology and therapeutic potential. Cellular and molecular life sciences : CMLS 50 27815595
1997 Increased G alpha q/11 immunoreactivity in postmortem occipital cortex from patients with bipolar affective disorder. Biological psychiatry 44 9066988
2020 Chloroquine Sensitizes GNAQ/11-mutated Melanoma to MEK1/2 Inhibition. Clinical cancer research : an official journal of the American Association for Cancer Research 43 32933997
2018 GNAS, GNAQ, and GNA11 alterations in patients with diverse cancers. Cancer 43 30204251
2013 Ultradeep sequencing detects GNAQ and GNA11 mutations in cell-free DNA from plasma of patients with uveal melanoma. Cancer medicine 43 23634288
2007 G alpha(q/11)-coupled P2Y2 nucleotide receptor inhibits human keratinocyte spreading and migration. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 42 17609252
2007 G alpha(q)-coupled muscarinic acetylcholine receptors enhance nicotinic acetylcholine receptor signaling in Caenorhabditis elegans mating behavior. The Journal of neuroscience : the official journal of the Society for Neuroscience 41 17287516
1995 G alpha q and G alpha 13 regulate NHE-1 and intracellular calcium in epithelial cells. The American journal of physiology 40 7840138
2019 High frequency of GNA14, GNAQ, and GNA11 mutations in cherry hemangioma: a histopathological and molecular study of 85 cases indicating GNA14 as the most commonly mutated gene in vascular neoplasms. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 39 31189994
2010 Analysis of GNAQ mutations, proliferation and MAPK pathway activation in uveal melanomas. The British journal of ophthalmology 38 20805136
2008 Assembly of high order G alpha q-effector complexes with RGS proteins. The Journal of biological chemistry 38 18936096
2012 Gallium compound GaQ(3) -induced Ca(2+) signalling triggers p53-dependent and -independent apoptosis in cancer cells. British journal of pharmacology 37 22074401
2017 Computational analysis for GNAQ mutations: New insights on the molecular etiology of Sturge-Weber syndrome. Journal of molecular graphics & modelling 36 28779688
2017 Frequent GNAQ, GNA11, and EIF1AX Mutations in Iris Melanoma. Investigative ophthalmology & visual science 35 28700778
2003 G beta 5.RGS7 inhibits G alpha q-mediated signaling via a direct protein-protein interaction. The Journal of biological chemistry 35 12670932
1996 G alpha q/11 mediates neurotensin excitation of substantia nigra dopaminergic neurons. Brain research. Molecular brain research 35 9011762
2019 Association of Somatic GNAQ Mutation With Capillary Malformations in a Case of Choroidal Hemangioma. JAMA ophthalmology 34 30422215
2015 Distribution of GNAQ and GNA11 Mutation Signatures in Uveal Melanoma Points to a Light Dependent Mutation Mechanism. PloS one 33 26368812
2020 GNAQ and GNA11 mutant nonuveal melanoma: a subtype distinct from both cutaneous and uveal melanoma. The British journal of dermatology 32 32064597
2013 Identification of HRAS mutations and absence of GNAQ or GNA11 mutations in deep penetrating nevi. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 32 23599145
2001 G alpha(q/11) coupled to mammalian phospholipase C beta 3-like enzyme mediates the ginsenoside effect on Ca(2+)-activated Cl(-) current in the Xenopus oocyte. The Journal of biological chemistry 31 11673455
2022 A novel somatic mutation in GNAQ in a capillary malformation provides insight into molecular pathogenesis. Angiogenesis 29 35635655
2019 Recurrent GNAQ mutation encoding T96S in natural killer/T cell lymphoma. Nature communications 29 31527657
2018 Somatic GNAQ mutation in the forme fruste of Sturge-Weber syndrome. Neurology. Genetics 29 29725622
2016 Gnaq and Gna11 in the Endothelin Signaling Pathway and Melanoma. Frontiers in genetics 29 27148356
2019 GNA11 joins GNAQ and GNA14 as a recurrently mutated gene in anastomosing hemangioma. Virchows Archiv : an international journal of pathology 28 31707589
2010 G alpha(q)-mediated activation of GRK2 by mechanical stretch in cardiac myocytes: the role of protein kinase C. The Journal of biological chemistry 28 20194499
2010 Somatic mutations in GNAQ in amelanotic/hypomelanotic blue nevi. Human pathology 28 21056896
2008 Diacylglycerol kinase zeta inhibits G(alpha)q-induced atrial remodeling in transgenic mice. Heart rhythm 27 19121805
2007 Tumor necrosis factor receptor-1 can function through a G alpha q/11-beta-arrestin-1 signaling complex. The Journal of biological chemistry 27 17664271
2007 Continuous activation of G alpha q in osteoblasts results in osteopenia through impaired osteoblast differentiation. The Journal of biological chemistry 27 17823129
2023 MEK inhibition reduced vascular tumor growth and coagulopathy in a mouse model with hyperactive GNAQ. Nature communications 26 37024491
2019 A somatic missense mutation in GNAQ causes capillary malformation. Current opinion in hematology 26 30870248
2018 BRAF, NRAS, and GNAQ Mutations in Conjunctival Melanocytic Nevi. Investigative ophthalmology & visual science 26 29332123
2018 Uveal melanoma driver mutations in GNAQ/11 yield numerous changes in melanocyte biology. Pigment cell & melanoma research 25 29570931
2010 Hypothalamic paraventricular nucleus G alpha q subunit protein pathways mediate vasopressin dysregulation and fluid retention in salt-sensitive rats. Endocrinology 25 20861238
2022 In uveal melanoma Gα-protein GNA11 mutations convey a shorter disease-specific survival and are more strongly associated with loss of BAP1 and chromosomal alterations than Gα-protein GNAQ mutations. European journal of cancer (Oxford, England : 1990) 24 35580369
2018 GNAQ Mutations in Diffuse and Solitary Choroidal Hemangiomas. Ophthalmology 24 30537484
2017 GNAQ Mutation in the Venous Vascular Malformation and Underlying Brain Tissue in Sturge-Weber Syndrome. Neuropediatrics 24 28571101
2021 GNA14, GNA11, and GNAQ Mutations Are Frequent in Benign but Not Malignant Cutaneous Vascular Tumors. Frontiers in genetics 23 34040639
2019 GNAQ Q209R Mutations Are Highly Specific for Circumscribed Choroidal Hemangioma. Cancers 23 31336681
2014 Oncogenic GNAQ and GNA11 mutations in uveal melanoma in Chinese. PloS one 23 25280020
2008 Diacylglycerol kinase zeta rescues G alpha q-induced heart failure in transgenic mice. Circulation journal : official journal of the Japanese Circulation Society 23 18219172
2006 Differential effects of RGS proteins on G alpha(q) and G alpha(11) activity. Cellular signalling 23 16843638
1997 Pituitary adenomas: screening for G alpha q mutations. The Journal of clinical endocrinology and metabolism 23 9398737
2023 High-throughput chemogenetic drug screening reveals PKC-RhoA/PKN as a targetable signaling vulnerability in GNAQ-driven uveal melanoma. Cell reports. Medicine 22 37858338
2019 Heterogeneity in Mitogen-Activated Protein Kinase (MAPK) Pathway Activation in Uveal Melanoma With Somatic GNAQ and GNA11 Mutations. Investigative ophthalmology & visual science 22 31173078
2018 The oncolytic virus H101 combined with GNAQ siRNA-mediated knockdown reduces uveal melanoma cell viability. Journal of cellular biochemistry 22 30320917
2022 GNAQ mutations drive port wine birthmark-associated Sturge-Weber syndrome: A review of pathobiology, therapies, and current models. Frontiers in human neuroscience 21 36405075
2017 Frequent and Yet Unreported GNAQ and GNA11 Mutations are Found in Uveal Melanomas. Pathology oncology research : POR 21 29209985
2015 Detection of GNAQ mutations and reduction of cell viability in uveal melanoma cells with functionalized gold nanoparticles. Biomedical microdevices 21 25653058
2024 MRC1 and LYVE1 expressing macrophages in vascular beds of GNAQ p.R183Q driven capillary malformations in Sturge Weber syndrome. Acta neuropathologica communications 20 38532508
2023 Developmental expression of the Sturge-Weber syndrome-associated genetic mutation in Gnaq: a formal test of Happle's paradominant inheritance hypothesis. Genetics 20 37098137
2011 G alpha(q) signal in osteoblasts is inhibitory to the osteoanabolic action of parathyroid hormone. The Journal of biological chemistry 20 21345793
1997 Dexamethasone increases G alpha q-11 expression and hormone-stimulated phospholipase C activity in UMR-106-01 cells. The American journal of physiology 19 9316442
2023 GNAQ/GNA11 Mosaicism Causes Aberrant Calcium Signaling Susceptible to Targeted Therapeutics. The Journal of investigative dermatology 18 37802293
2022 Targeting GNAQ in hypothalamic nerve cells to regulate seasonal estrus in sheep. Theriogenology 18 35065460
2019 GNAQQ209L expression initiated in multipotent neural crest cells drives aggressive melanoma of the central nervous system. Pigment cell & melanoma research 18 31680437
2022 MITF deficiency accelerates GNAQ-driven uveal melanoma. Proceedings of the National Academy of Sciences of the United States of America 17 35512098
2014 GNAQ mutation in a patient with metastatic mucosal melanoma. BMC cancer 17 25030020
2012 BRAF and GNAQ mutations in melanocytic tumors of the oral cavity. Oral surgery, oral medicine, oral pathology and oral radiology 17 23159116

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