Affinage

RHOA

Transforming protein RhoA · UniProt P61586

Length
193 aa
Mass
21.8 kDa
Annotated
2026-06-10
100 papers in source corpus 43 papers cited in narrative 42 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

RHOA is a ~21 kDa small GTPase that cycles between inactive GDP-bound and active GTP-bound states to control actomyosin contractility, cell shape, and motility across diverse cell types (PMID:2501657, PMID:12538643). In its active form it engages effectors to drive stress fiber and focal adhesion formation, mitotic cortical rigidity and rounding, and tension-dependent processes; its principal contractile output runs through ROCK, which sustains myosin light-chain phosphorylation by inhibiting myosin phosphatase via the scaffold M-RIP that targets the phosphatase to actomyosin filaments (PMID:12538643, PMID:17661354). Active RHOA membrane residence is stabilized at the cortex by anillin, which binds GTP-RHOA and concentrates PIP2 to repeatedly reset its dissociation kinetics ('kinetic scaffolding'), a mechanism critical for cortical effector recruitment and cytokinesis/abscission, where citron kinase acts upstream to maintain active RHOA and anillin at the midbody (PMID:31105010, PMID:21849473). RHOA activity is set by an extensive regulatory network: it is activated downstream of GPCRs through Gα13 and of receptors and mechanical inputs including CD44, syndecan-4/integrin/kindlin-2, podocalyxin, Dectin-1, Wnt5a-Daam1, and CDC42 (PMID:19940064, PMID:31907416, PMID:25101858, PMID:15339978, PMID:31964711, PMID:29207169, PMID:32567555), and is restrained by GAPs (C-GAP, ARHGAP29, and DLC1/2 acting through FKBP51), by p120 catenin, by the atypical inhibitor Fam65b, and by ubiquitin-mediated degradation via Smurf1 (countered by synaptopodin) and the KCTD13/CUL3 ligase (PMID:27551058, PMID:30659117, PMID:28032931, PMID:10980705, PMID:30254631, PMID:16622418, PMID:29088697). Phosphorylation of RHOA at Ser188 by cGMP-dependent kinase inactivates it and blocks its membrane translocation (PMID:11162591). Beyond cytoskeletal regulation, RHOA directly binds and stimulates the kinase MEKK1, contacts the TRPV4 ankyrin-repeat domain to suppress channel activity, and governs transcriptional programs through MRTF-A/SRF and the Hippo effector YAP (PMID:14581471, PMID:37353478, PMID:33979620, PMID:25101858). Through these activities RHOA shapes specialized cellular programs including B-cell receptor signaling via PIP2/PLCγ2, TH2 differentiation, osteoclast differentiation via Akt-mTOR-NFATc1, cardiac mitochondrial quality control via a ROCK-N-Myc-Parkin axis, Schwann cell differentiation via JNK, and dendritic Golgi outpost biogenesis (PMID:15664190, PMID:26100081, PMID:37020186, PMID:36758801, PMID:29940159, PMID:25802147). The recurrent somatic RHOA p.Gly17Val mutation, which abolishes GTP binding and acts dominant-negatively, drives angioimmunoblastic T-cell lymphoma by inducing T follicular helper specification through ICOS/PI3K signaling, particularly in cooperation with Tet2 loss (PMID:24413737, PMID:24584070, PMID:29398449).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1989 Medium

    Established that RHOA is a ~21 kDa GTPase whose elevated wild-type expression is transforming, motivating mechanistic study of its signaling outputs.

    Evidence Overexpression in NIH 3T3 fibroblasts with focus/soft-agar and nude mouse tumorigenicity assays

    PMID:2501657

    Open questions at the time
    • No downstream pathway defined beyond protein identity
    • Mechanism of transformation not resolved
  2. 2001 High

    Defined how RHOA is switched off post-translationally, showing cGMP-dependent kinase phosphorylates Ser188 to block stress fiber formation and membrane translocation.

    Evidence In vitro kinase assay, Ser188Ala mutagenesis, and actin imaging in cells

    PMID:11162591

    Open questions at the time
    • Does not address how this integrates with GEF/GAP regulation in vivo
    • Tissue contexts where this dominates unclear
  3. 2003 High

    Showed RHOA drives mitotic cortical rigidity and rounding through ROCK and downregulation of p190RhoGAP, linking RHOA activity to cell-cycle-coupled mechanics.

    Evidence Dominant-negative/CA RhoA, p190RhoGAP phosphorylation analysis, atomic force microscopy, time-lapse imaging

    PMID:12538643

    Open questions at the time
    • GEF responsible for mitotic RhoA activation not identified here
    • How phosphorylation suppresses p190RhoGAP unresolved
  4. 2003 High

    Revealed a non-cytoskeletal effector function: RHOA-GTP directly binds and stimulates MEKK1 kinase activity, connecting RHOA to MAPK signaling.

    Evidence Co-IP, in vitro kinase assay toward MEK4, and MEKK1 PHD-domain mutagenesis

    PMID:14581471

    Open questions at the time
    • Physiological contexts for RhoA-MEKK1 coupling not established
    • Selectivity over Rac/Cdc42 in cells not tested in vivo
  5. 2005 High

    Connected RHOA to immune-receptor signaling, demonstrating it is required downstream of PI3K for BCR-driven PIP2 synthesis, PLCγ2 activation, and calcium flux.

    Evidence Dominant-negative RhoA, C3 toxin, PI3K inhibition, calcium flux, and exogenous PIP2 rescue

    PMID:15664190

    Open questions at the time
    • The effector linking RhoA to PIP2 synthesis not identified
    • GEF activating RhoA downstream of BCR unknown
  6. 2006 High

    Identified ubiquitin-dependent control of RHOA abundance, showing synaptopodin stabilizes RhoA by blocking Smurf1-mediated ubiquitination to maintain stress fibers.

    Evidence siRNA knockdown, ubiquitination and degradation assays, actin/migration phenotypes in podocytes

    PMID:16622418

    Open questions at the time
    • Whether Smurf1 selectively targets active vs inactive RhoA not resolved
    • Generality beyond podocytes untested
  7. 2008 Medium

    Clarified how RHOA-effector coupling to myosin phosphatase is organized in space, identifying M-RIP as a scaffold targeting myosin phosphatase to actomyosin for RhoA/ROCK-mediated inhibition.

    Evidence Co-IP, in vitro binding, siRNA knockdown, MYPT1 phosphorylation assay

    PMID:17661354

    Open questions at the time
    • Structural basis of M-RIP binding both RhoA and MYPT1 not defined
    • In vivo requirement not shown
  8. 2014 High

    Established RHOA as a disease driver, showing the recurrent AITL p.Gly17Val mutant fails to bind GTP and acts dominant-negatively.

    Evidence GTP-binding and dominant-negative functional assays; replicated across two studies

    PMID:24413737 PMID:24584070

    Open questions at the time
    • Cellular consequences of dominant-negative RhoA in T cells not yet defined here
    • Why a loss-of-function GTPase mutant is oncogenic unresolved at this stage
  9. 2016 High

    Showed how RHOA activity is spatially patterned to produce pulsatile contractility, with a GAP (C-GAP) restricting RhoA pathway activity and coordinating with RhoGEF2 to drive activity cycling during apical constriction.

    Evidence Drosophila genetic loss-of-function, FRET RhoA biosensor, live imaging, epistasis with RhoGEF2

    PMID:27551058

    Open questions at the time
    • Molecular trigger initiating each pulse not defined
    • How GEF/GAP activities are temporally synchronized unresolved
  10. 2017 High

    Demonstrated in vivo that RHOA abundance is controlled by the KCTD13/CUL3 ligase, and that excess RhoA impairs synaptic transmission reversibly by RhoA inhibition.

    Evidence Kctd13 KO mouse, RhoA protein measurement, electrophysiology, RhoA-inhibitor rescue; replicated in zebrafish

    PMID:29088697

    Open questions at the time
    • Direct ubiquitination of RhoA by KCTD13/CUL3 inferred, not shown biochemically here
    • Effector pathway altering synaptic transmission not defined
  11. 2018 High

    Resolved the oncogenic mechanism of RHOA G17V, showing it induces Tfh specification via ICOS/PI3K and cooperates with Tet2 loss to drive AITL in vivo.

    Evidence Conditional Rhoa G17V expression, Tet2/G17V double-mutant mice, ICOS/PI3K inhibitor treatment, flow cytometry

    PMID:29398449

    Open questions at the time
    • How a GTP-binding-deficient mutant activates ICOS/PI3K mechanistically unclear
    • Contribution of dominant-negative versus neomorphic activity not separated
  12. 2019 High

    Defined the biophysical basis of RHOA cortical residence, showing anillin binds GTP-RhoA and concentrates PIP2 to repeatedly reset its dissociation kinetics ('kinetic scaffolding').

    Evidence FRAP, optogenetics, anillin-RhoA binding mutants, PIP2 manipulation

    PMID:31105010

    Open questions at the time
    • How anillin density is regulated in vivo not addressed
    • Generality across non-cytokinetic contexts untested
  13. 2019 High

    Quantitatively linked RHOA activity dynamics to junction remodeling, showing pulse duration determines reversible versus irreversible deformation via formin-mediated E-cadherin clustering and dynamin endocytosis.

    Evidence Optogenetic pulsatile RhoA activation, live imaging, formin/dynamin inhibitors, vertex modeling

    PMID:31883774

    Open questions at the time
    • Endogenous GEF/GAP dynamics producing such pulses not mapped
    • Molecular memory underlying irreversibility incompletely defined
  14. 2020 High

    Showed RHOA integrates mechanical force, identifying a syndecan-4/kindlin-2/β1 integrin/RhoA axis that tunes cell mechanics in a PI3K-dependent manner.

    Evidence Magnetic twisting cytometry, RhoA GLISA, PI3K inhibition, integrin/kindlin-2 knockdowns, YAP readout

    PMID:31907416

    Open questions at the time
    • GEF converting tension into RhoA activation not identified
    • Coupling between RhoA and YAP downstream not mechanistically detailed here
  15. 2021 High

    Separated RHOA's roles in a developmental program, showing RhoA/Cdc42 are dispensable for megakaryocyte polyploidization but essential for cytoplasmic maturation and proplatelet formation via MKL1/SRF.

    Evidence Conditional RhoA/Cdc42 double-KO mice, protein/mRNA profiling, proplatelet assays

    PMID:33979620

    Open questions at the time
    • Individual contribution of RhoA versus Cdc42 not separated
    • Direct SRF target genes driving maturation not defined
  16. 2023 High

    Provided a structural view of a non-canonical RHOA function, showing direct binding to the TRPV4 ankyrin-repeat domain that suppresses channel activity, with interface residues mutated in neuropathies.

    Evidence Cryo-EM structure of the TRPV4-RhoA complex and channel functional assays

    PMID:37353478

    Open questions at the time
    • Whether GDP/GTP state governs the interaction not fully resolved
    • Physiological signaling consequence of channel suppression in neurons untested here
  17. 2023 High

    Extended RHOA function to organelle quality control, defining a cardiomyocyte RhoA-ROCK-N-Myc-Parkin axis required for mitophagy and cardiac function.

    Evidence Cardiomyocyte-specific RhoA KO, Parkin re-expression rescue, N-Myc phosphorylation analysis, mitophagy and echocardiography

    PMID:36758801

    Open questions at the time
    • Direct N-Myc phosphorylation by ROCK not biochemically isolated
    • Whether this axis operates in non-cardiac tissues unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the full GEF/GAP/GDI network, post-translational modifications, and degradation pathways are integrated to produce the precise spatiotemporal RhoA activity patterns required by each cellular program remains unresolved.
  • No unified model linking upstream activators to context-specific effector choice (ROCK vs JNK vs MEKK1)
  • How loss-of-function G17V produces gain-of-function oncogenic phenotypes mechanistically unclear
  • Endogenous activity dynamics in most tissues not measured with biosensors

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0003924 GTPase activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005829 cytosol 2 GO:0005856 cytoskeleton 2
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-1640170 Cell Cycle 2 R-HSA-1643685 Disease 2
Partners
ANILLINFAM65BM-RIPMEKK1RHOGDIRHOTEKINROCKTRPV4

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1989 Human rhoH12 (RHOA) protein is a ~21 kDa GTPase; amplification of normal rhoH12 in NIH 3T3 cells reduced serum dependence, increased saturation density, and conferred tumorigenicity in nude mice, establishing that elevated wild-type RHOA expression has transforming activity. Transfection/overexpression in NIH 3T3 fibroblasts, Western immunoblot, immunoprecipitation, focus/soft-agar assays, nude mouse tumorigenicity Molecular and cellular biology Medium 2501657
2000 p120 catenin selectively inhibits RhoA activity in vitro and in vivo; its interaction with cadherins and its inhibition of RhoA are mutually exclusive, suggesting p120 regulates RhoA recruitment at nascent cell-cell contacts. In vitro RhoA activity assay, cell-based RhoA activity assay, co-immunoprecipitation Nature cell biology High 10980705
2001 cGMP-dependent protein kinase (cGK) phosphorylates RhoA at Ser188 in vitro, and constitutively active cGK blocks stress fiber formation induced by LPA or constitutively active RhoA; a Ser188Ala RhoA mutant is resistant to this inhibition, and cGK expression inhibits membrane translocation of RhoA. In vitro kinase assay, site-directed mutagenesis (Ser188Ala), cell transfection with constitutively active cGK, actin stress fiber imaging Biochemical and biophysical research communications High 11162591
2001 RhoA activity is required for polyamine-dependent intestinal epithelial cell migration; elevated intracellular Ca2+ induced by polyamines increases RhoA protein synthesis and stability, and inhibition of RhoA with C3 transferase blocks myosin II stress fiber formation and prevents cell migration. C3 transferase inhibition, RhoA activity assay, Ca2+ ionophore and chelator experiments, Western blot American journal of physiology. Cell physiology Medium 11245616
2003 RhoA is required for cortical retraction and increased cortical rigidity during mitotic cell rounding; RhoA activity is elevated in rounded preanaphase mitotic cells, coinciding with serine/threonine phosphorylation-mediated decrease of p190RhoGAP activity; Rho-kinase mediates these RhoA effects. Dominant-negative/constitutively active RhoA expression, p190RhoGAP phosphorylation analysis, atomic force microscopy for cortical rigidity, time-lapse imaging The Journal of cell biology High 12538643
2003 RhoA (but not Rac or Cdc42) directly binds to the amino-terminal regulatory domain of MEKK1; this interaction requires an intact PHD domain cysteine in MEKK1; RhoA-GTP stimulates MEKK1 kinase activity toward MEK4 up to 10-fold. Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis of MEKK1 PHD domain The Journal of biological chemistry High 14581471
2004 RhoA/ROCK signaling suppresses Sox9 expression and chondrogenesis: RhoA overexpression decreases glycosaminoglycan synthesis and Sox9 levels via repression of the Sox9 promoter, while ROCK inhibition (Y27632) has opposite effects; effects on Sox9 are mediated through cortical actin reorganization. RhoA overexpression, ROCK inhibitor (Y27632) treatment, Sox9 promoter-luciferase assay, actin cytoskeleton imaging The Journal of biological chemistry Medium 15665004
2004 RhoA overexpression in chondrogenic ATDC5 cells increases proliferation, delays hypertrophic differentiation, activates cyclin D1 transcription, and represses the collagen X promoter; dominant-negative RhoA inhibits PTH-related peptide induction of cyclin D1; ROCK inhibition partially rescues RhoA overexpression effects. RhoA overexpression, dominant-negative RhoA, ROCK inhibitor Y27632, luciferase promoter assays, alkaline phosphatase and mineralization assays The Journal of biological chemistry Medium 14726536
2004 RhoA activation downstream of podocalyxin (PC) requires NHERF and ezrin; full-length PC (but not the NHERF-binding-site mutant) increases RhoA activity and redistributes actin toward the apical membrane in MDCK cells; PC interacts directly with ezrin via its juxtamembrane cytoplasmic region. Stable cell lines expressing full-length vs. truncated PC, RhoA pulldown activity assay, immunofluorescence, co-immunoprecipitation/pulldown Journal of the American Society of Nephrology Medium 15339978
2005 RhoA activation is sufficient to stimulate β1 and β2 integrin-mediated adhesion in thymocytes; loss of Rho function impairs VCAM-1 adhesion and prevents integrin activation induced by Rac-1 and Rap1A; RhoA activity is critical for integrin-mediated thymocyte migration to chemokines. Dominant-negative RhoA expression, C3 transferase inhibition, integrin adhesion assays, migration assays Journal of immunology Medium 15972668
2005 RhoA activity regulates B cell receptor (BCR) signaling: BCR stimulation activates RhoA downstream of PI3K; dominant-negative RhoA and C3 toxin inhibit BCR-dependent calcium flux and cell proliferation; RhoA is required for PtdIns-4,5-P2 synthesis and PLCγ2 activation (but not PLCγ2 tyrosine phosphorylation); exogenous PtdIns-4,5-P2 restores calcium flux in RhoA-inhibited cells. Dominant-negative RhoA expression, C3 toxin, PI3K inhibitor, calcium flux assay, proliferation assay, PtdIns-4,5-P2 measurement Molecular cell High 15664190
2006 Synaptopodin induces actin stress fibers by competitively blocking Smurf1-mediated ubiquitination of RhoA, thereby preventing proteasomal degradation of RhoA; gene silencing of synaptopodin causes loss of stress fibers and impairs cell migration in kidney podocytes. siRNA knockdown of synaptopodin, ubiquitination assays, RhoA degradation assays, actin imaging, migration assays Nature cell biology High 16622418
2007 p66Shc mediates anoikis through RhoA activation; re-expression of p66Shc in p66Shc-null cells restores anoikis through a mechanism requiring focal adhesion targeting and RhoA activation (but not cytochrome c-binding motif); this pathway stimulates focal adhesions, stress fibers, and tension-dependent cell death upon detachment. p66Shc re-expression in knockout cells, RhoA activity assay, focal adhesion imaging, cell death assays The Journal of cell biology Medium 17908916
2007 In bovine spermatozoa, the GNA13-RhoA-ROCK2-LIMK2-cofilin signaling cascade is present; RhoA interacts with AKAP4 (identified by overlay, immunoprecipitation, and mass spectrometry); AKAP3 phosphorylation increases its interaction with PRKAR2 and ROPN1 (RhoA-interacting proteins). Western blot, overlay assay, co-immunoprecipitation, mass spectrometry, pulldown Biology of reproduction Medium 17928627
2008 RhoA-GDP (not RhoA-GTP) regulates RhoB protein stability via a mechanism requiring RhoGDIα; RhoGDIα is rate-limiting in basal conditions, and silencing RhoA makes RhoGDI available to stabilize RhoB; a RhoA mutant (R68E) unable to bind RhoGDIα cannot rescue RhoB up-regulation after RhoA silencing. siRNA knockdown of RhoA, RhoGDIα manipulation, half-life measurement, RhoA mutant (R68E) rescue experiment, Western blot The Journal of biological chemistry Medium 18524772
2008 Myosin phosphatase-RhoA interacting protein (M-RIP) directly binds both RhoA and the myosin-binding subunit of myosin phosphatase in vitro, targets myosin phosphatase to the actomyosin contractile filament, and is required for RhoA/ROCK-mediated inhibition of myosin phosphatase; M-RIP silencing prevents LPA-mediated MYPT1 phosphorylation and inhibition of myosin phosphatase activity; M-RIP silencing leads to loss of stress fiber-associated RhoA. Co-immunoprecipitation, in vitro binding, siRNA knockdown, MYPT1 phosphorylation assay Journal of cellular biochemistry Medium 17661354
2009 Only activated (GTP-bound) RhoA and ROCK1 are sequestered into stress granules (SGs) during cellular stress; sequestration of activated ROCK1 in SGs prevents ROCK1 from interacting with JIP-3 and activating the JNK apoptotic pathway, protecting cells from apoptosis. Immunofluorescence, co-immunoprecipitation, stress granule fractionation, apoptosis assays Cellular signalling Medium 20004716
2009 In mouse pancreatic acini, CCK activates RhoA specifically through Gα13 (not Gα12 or Gαq); the RGS domain of p115-RhoGEF (Gα12/13-specific inhibitor) abolishes CCK-stimulated RhoA activation. Constitutively active Gα subunit expression, RhoA and Rac1 activity assays, RGS domain inhibitor constructs American journal of physiology. Cell physiology Medium 19940064
2010 PLCδ3 negatively regulates RhoA protein expression; PLCδ3 knockdown prevents the differentiation-induced decrease in RhoA protein levels in Neuro2a cells; dominant-negative RhoA or ROCK inhibitor Y27632 rescues neurite extension defects caused by PLCδ3 knockdown, placing RhoA downstream of PLCδ3 in neurite outgrowth regulation. siRNA knockdown, dominant-negative RhoA, ROCK inhibitor, Western blot, neurite outgrowth assays The Journal of biological chemistry Medium 21187285
2011 Citron kinase (CIT-K) acts as an upstream regulator (not downstream effector) of RhoA during late cytokinesis/abscission; CIT-K depletion displaces active RhoA and anillin from the midbody; CIT-K overexpression-induced abscission delay is reversed by RhoA inactivation; CIT-K physically interacts with anillin. CIT-K siRNA depletion, RhoA inactivation, co-immunoprecipitation (CIT-K with anillin), live-cell imaging of cytokinesis Molecular biology of the cell Medium 21849473
2012 Protein kinase D phosphorylates rhotekin (at Ser-435), an effector of RhoA; a phosphomimetic S435E rhotekin mutant increases active RhoA levels and enhances RhoA membrane anchoring, resulting in increased stress fiber formation. In vitro kinase assay, site-directed mutagenesis (S435E), RhoA activity assay, immunofluorescence The Journal of biological chemistry Medium 22228765
2014 The RHOA p.Gly17Val mutant found in AITL does not bind GTP and inhibits wild-type RHOA function (dominant-negative), demonstrating that this recurrent somatic mutation causes loss of RHOA GTPase activity. GTP-binding assay, dominant-negative functional assay Nature genetics High 24413737 24584070
2014 CD44 acts upstream of RhoA to regulate YAP expression and nuclear localization; CD44 knockdown reduces RhoA expression; constitutively active RhoA (RhoA-V14) rescues YAP reduction caused by CD44 knockdown; RhoA knockdown similarly reduces YAP, placing RhoA between CD44 and YAP in the Hippo pathway. siRNA knockdown of CD44 and RhoA, constitutively active RhoA rescue, Western blot, nuclear localization assay Cellular signalling Medium 25101858
2015 Fam65b is an atypical inhibitor of RhoA that restricts spontaneous RhoA activation in resting T lymphocytes; chemokine stimulation phosphorylates Fam65b, decreasing its affinity for RhoA and causing its translocation from plasma membrane to cytosol, thereby relieving tonic RhoA inhibition and allowing RhoA-dependent actin polymerization and T cell migration. Fam65b-deficient mouse (conditional KO), RhoA activity assay, phosphorylation analysis, intranodal migration imaging, in vitro migration assay Frontiers in immunology Medium 30254631
2015 RhoA deficiency in T cells inhibits TH2 (but not TH1) differentiation, prevents allergic airway inflammation, and causes defects in glycolysis and oxidative phosphorylation; RhoA couples glycolysis to TH2 differentiation through regulation of IL-4 receptor mRNA expression and TH2-specific signaling; ROCK inhibition also blocks TH2 differentiation. Conditional RhoA knockout mice (RhoA flox/flox × CD2-Cre), metabolic assay (Seahorse XF24), cytokine measurement (ELISA, intracellular staining), in vivo allergy model The Journal of allergy and clinical immunology Medium 26100081
2015 RhoA GTPase controls Golgi outpost (GOP) formation in dendrites via a RhoA-ROCK-LIMK1-PKD1-slingshot-cofilin-dynamin pathway that regulates tubule fission from the somatic Golgi; live-cell imaging demonstrated that GOPs are generated from somatic GA tubules, and perturbation of RhoA pathway arrests tubule fission. Live-cell imaging, confocal microscopy, pharmacological inhibition of pathway components, dominant-negative and constitutively active constructs Current biology Medium 25802147
2016 In Drosophila apical constriction, a RhoA GAP (C-GAP) spatially restricts RhoA pathway activity to a central apical cortex position and is required for pulsatile actomyosin contractility; C-GAP coordinates with RhoGEF2 to drive RhoA activity cycling underlying contractile pulses; C-GAP expression level governs the transition from reversible to irreversible cell shape change. Genetic loss-of-function (C-GAP mutants), live imaging, FRET-based RhoA biosensor, epistasis analysis with RhoGEF2 The Journal of cell biology High 27551058
2017 Deletion of Kctd13 in mice elevates RhoA protein levels (consistent with KCTD13/CUL3 ubiquitin ligase targeting RhoA for degradation) and reduces synaptic transmission; pharmacological inhibition of RhoA reverses the reduced synaptic transmission phenotype. Kctd13 gene deletion (mouse KO), RhoA protein level measurement, synaptic transmission electrophysiology, RhoA inhibitor rescue Nature High 29088697
2017 Daam1 activates RhoA downstream of Wnt5a to promote glioblastoma cell invasion; siRNA knockdown of Daam1 inhibits Wnt5a-induced RhoA activation and stress fiber formation; RhoA inhibitor (CCG-1423) also blocks Wnt5a-induced invasion, placing Daam1 upstream of RhoA in Wnt5a→Daam1→RhoA→invasion pathway. siRNA knockdown, pulldown assays for Daam1 and RhoA activation, cell invasion assay, RhoA inhibitor Oncology reports Medium 29207169
2017 RhoA promotes Schwann cell differentiation via the JNK pathway rather than ROCK; inhibition of RhoA (with C3 transferase or siRNA) activates JNK and p38 MAPK in differentiating Schwann cells; JNK inhibitor (but not p38 inhibitor) rescues SC differentiation under RhoA inhibition. siRNA knockdown, C3 transferase inhibition, ROCK inhibitor (no effect), JNK/p38 inhibitors, differentiation assays Experimental neurology Medium 29940159
2017 FKBP51 promotes RhoA activity and ROCK signaling by interacting with RhoGAPs DLC1 and DLC2 (identified by immunoprecipitation and mass spectrometry); FKBP51 overexpression increases RhoA activity and invasion, while FKBP51 depletion causes cortical actin redistribution and decreases RhoA activity and cell motility. Immunoprecipitation + mass spectrometry, RhoA activity assay, siRNA knockdown, overexpression, actin imaging Cancer science Medium 28032931
2018 RHOA G17V expression in CD4+ T cells induces T follicular helper (Tfh) cell specification with increased ICOS upregulation and PI3K/MAPK signaling; combined with Tet2 loss, RHOA G17V drives AITL development in mice; in vivo tumor proliferation is inhibited by ICOS/PI3K-specific blockade. Transgenic/conditional expression of Rhoa G17V in CD4+ T cells, Tet2 KO/RHOA G17V double-mutant mouse model, ICOS/PI3K inhibitor treatment, flow cytometry Cancer cell High 29398449
2019 Anillin directly binds GTP-RhoA at the cortical membrane to antagonize its otherwise labile membrane association, promoting effector recruitment; anillin also concentrates membrane PIP2 to retain RhoA after it disengages from anillin; cyclic re-binding of RhoA to anillin (regulated by anillin cortical density) repeatedly resets RhoA dissociation kinetics ('kinetic scaffolding'), substantially increasing RhoA dwell time. FRAP, live-cell imaging, optogenetics, mutant analysis (anillin-RhoA binding mutants), PIP2 manipulation Developmental cell High 31105010
2019 Optogenetic activation of RhoA in model epithelium shows: short pulses drive reversible junction contractions; longer pulses produce irreversible junction length changes; junction remodeling requires formin-mediated E-cadherin clustering and dynamin-dependent endocytosis downstream of RhoA; irreversible deformation involves thresholded tension remodeling and continuous strain relaxation. Optogenetics (pulsatile RhoA activation), live imaging, dynamin inhibitor, formin inhibitor, vertex model Developmental cell High 31883774
2019 ARHGAP29 induction under hypoxia suppresses RhoA activity and MRTF-A signaling, reversing myofibroblast differentiation; decreased RhoA activity under hypoxia is causally linked to reduced αSMA expression and altered contractility. Hypoxia treatment, ARHGAP29 induction measurement, RhoA activity assay, MRTF-A localization, siRNA knockdown, actin imaging Journal of cell science Medium 30659117
2020 Dectin-1 stimulation by β-glucan activates RHOA downstream of SRC family kinases (SFK, not SYK) to drive ROCK-myosin light chain (MLC) pathway, generating mechanical force/areal contraction and mediating phagocytosis of C. albicans. RHOA activity assay, SYK and SFK inhibitors, traction force microscopy, phagocytosis assay, stress fiber imaging Journal of cell science Medium 31964711
2020 Tension on syndecan-4 activates the kindlin-2/β1 integrin/RhoA axis in a PI3K-dependent manner to tune cell mechanics; syndecan-4 cytoplasmic variable region is indispensable for mechanical adaptation; a syndecan-4/α-actinin/F-actin scaffold assembles at the bead adhesion site. Magnetic twisting cytometry (local tension application), RhoA activity assay (GLISA), PI3K inhibitor, β1 integrin knockdown, kindlin-2 knockdown, YAP activation measurement Nature materials High 31907416
2020 CDC42 drives RHOA activation during sperm capacitation; RHOA activation and its effect on actin polymerization begin when CDC42 reaches maximum activity; RHOA's role in capacitation and acrosomal reaction is independent of ROCK1. CDC42/RHOA inhibitors, ROCK1 inhibitor, actin polymerization kinetics assay, capacitation assay, acrosome reaction assay Reproduction Medium 32567555
2021 RhoA/Cdc42 signaling is dispensable for megakaryocyte polyploidization (endomitosis) but is essential for cytoplasmic maturation and proplatelet formation; RhoA/Cdc42 double KO causes macrothrombocytopenia; the maturation defect is associated with downregulation of MLC2 and β1-tubulin, upregulation of LIMK1 and cofilin-1, and impaired MKL1/SRF signaling. Conditional RhoA/Cdc42 double-KO mice, bone marrow analyses, protein/mRNA profiling, proplatelet formation assay Cell reports High 33979620
2023 Cardiomyocyte-specific RhoA KO mice develop dilated cardiomyopathy and enhanced senescence with impaired mitophagy; RhoA-ROCK phosphorylates N-Myc leading to its degradation and Parkin upregulation; loss of RhoA reduces Parkin, impairing mitophagy; re-expression of Parkin in RhoA-depleted cardiomyocytes rescues mitophagy and cardiac function in vitro and in vivo. Cardiomyocyte-specific RhoA conditional KO mouse, Parkin re-expression rescue, N-Myc phosphorylation analysis, mitophagy assay, cardiac function measurement (echocardiography) The Journal of biological chemistry High 36758801
2023 Human TRPV4 forms a direct structural complex with RhoA, with RhoA interacting with the membrane-facing surface of TRPV4 ankyrin repeat domains; contact interface residues are mutated in neuropathies; RhoA suppresses TRPV4 channel activity; agonist (4α-PDD) causes pore opening while inhibitor (HC-067047) induces a π-to-α transition in the pore-forming helix S6. Cryo-EM structure of TRPV4-RhoA complex, functional channel assays Nature communications High 37353478
2023 Conditional deletion of RhoA in osteoclast lineage causes osteopetrosis due to suppressed bone resorption; RhoA deficiency suppresses Akt-mTOR-NFATc1 signaling during osteoclast differentiation; RhoA activation in osteoclast precursors prevented OVX-induced bone loss in mice. Osteoclast-specific RhoA conditional KO mice, OVX model, bone marrow macrophage differentiation assay, Akt/mTOR/NFATc1 pathway analysis Molecular medicine Medium 37020186

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 Somatic RHOA mutation in angioimmunoblastic T cell lymphoma. Nature genetics 532 24413737
2004 Why three Rho proteins? RhoA, RhoB, RhoC, and cell motility. Experimental cell research 389 15501444
2000 Inhibition of RhoA by p120 catenin. Nature cell biology 389 10980705
2016 RhoA/Rho-Kinase in the Cardiovascular System. Circulation research 370 26838319
2006 Synaptopodin orchestrates actin organization and cell motility via regulation of RhoA signalling. Nature cell biology 351 16622418
2014 A recurrent inactivating mutation in RHOA GTPase in angioimmunoblastic T cell lymphoma. Nature genetics 317 24584070
2005 RhoA/ROCK signaling regulates Sox9 expression and actin organization during chondrogenesis. The Journal of biological chemistry 251 15665004
2003 RhoA is required for cortical retraction and rigidity during mitotic cell rounding. The Journal of cell biology 249 12538643
2001 cGMP-dependent protein kinase phosphorylates and inactivates RhoA. Biochemical and biophysical research communications 189 11162591
2018 RHOA G17V Induces T Follicular Helper Cell Specification and Promotes Lymphomagenesis. Cancer cell 181 29398449
2012 From mechanical force to RhoA activation. Biochemistry 181 22931484
2010 RhoA/Rho-kinase and vascular diseases: what is the link? Cellular and molecular life sciences : CMLS 141 20668910
2013 RhoA, RhoB and RhoC have different roles in cancer cell migration. Journal of microscopy 139 23488932
1989 Characterization and expression of the human rhoH12 gene product. Molecular and cellular biology 113 2501657
2016 RhoA GTPase inhibition organizes contraction during epithelial morphogenesis. The Journal of cell biology 112 27551058
1988 Expression of the ras-related ralA, rho12 and rab genes in adult mouse tissues. Oncogene 111 2457862
2017 Kctd13 deletion reduces synaptic transmission via increased RhoA. Nature 109 29088697
2004 RhoA/ROCK signaling suppresses hypertrophic chondrocyte differentiation. The Journal of biological chemistry 108 14726536
2018 Regulation of RhoA GTPase and various transcription factors in the RhoA pathway. Journal of cellular physiology 107 29377108
2004 Podocalyxin activates RhoA and induces actin reorganization through NHERF1 and Ezrin in MDCK cells. Journal of the American Society of Nephrology : JASN 107 15339978
2011 Citron kinase controls abscission through RhoA and anillin. Molecular biology of the cell 101 21849473
2009 RhoA/ROCK1 signaling regulates stress granule formation and apoptosis. Cellular signalling 101 20004716
2010 The role of RhoA/Rho kinase pathway in endothelial dysfunction. Journal of cardiovascular disease research 100 21264179
1998 Activation of RhoA and SAPK/JNK signalling pathways by the RhoA-specific exchange factor mNET1. The EMBO journal 98 9670022
2019 Mechanotransduction: from the cell surface to the nucleus via RhoA. Philosophical transactions of the Royal Society of London. Series B, Biological sciences 97 31431179
2005 Rac1/Cdc42 and RhoA GTPases antagonistically regulate chondrocyte proliferation, hypertrophy, and apoptosis. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 90 15883643
2020 Syndecan-4 tunes cell mechanics by activating the kindlin-integrin-RhoA pathway. Nature materials 89 31907416
2017 ASIC1 and ASIC3 contribute to acidity-induced EMT of pancreatic cancer through activating Ca2+/RhoA pathway. Cell death & disease 89 28518134
2016 Rac1 and RhoA: Networks, loops and bistability. Small GTPases 87 27533896
2015 RhoA orchestrates glycolysis for TH2 cell differentiation and allergic airway inflammation. The Journal of allergy and clinical immunology 87 26100081
2014 Regulation of RhoA activity by adhesion molecules and mechanotransduction. Current molecular medicine 85 24467208
2019 RhoA Mediates Epithelial Cell Shape Changes via Mechanosensitive Endocytosis. Developmental cell 84 31883774
2008 RhoA/Rho-kinase as a therapeutic target in asthma. Current medicinal chemistry 83 18991642
2022 RhoA Signaling in Neurodegenerative Diseases. Cells 82 35563826
2001 Ca2+-RhoA signaling pathway required for polyamine-dependent intestinal epithelial cell migration. American journal of physiology. Cell physiology 79 11245616
2015 A RhoA Signaling Pathway Regulates Dendritic Golgi Outpost Formation. Current biology : CB 76 25802147
2019 RhoA/ROCK pathway: implication in osteoarthritis and therapeutic targets. American journal of translational research 74 31632513
2019 Anillin Promotes Cell Contractility by Cyclic Resetting of RhoA Residence Kinetics. Developmental cell 73 31105010
2015 CMKLR1 and GPR1 mediate chemerin signaling through the RhoA/ROCK pathway. Molecular and cellular endocrinology 72 26363224
2012 Lysophospholipid receptor activation of RhoA and lipid signaling pathways. Biochimica et biophysica acta 70 22986288
2003 RhoA binds to the amino terminus of MEKK1 and regulates its kinase activity. The Journal of biological chemistry 68 14581471
2008 RhoA-GDP regulates RhoB protein stability. Potential involvement of RhoGDIalpha. The Journal of biological chemistry 67 18524772
2011 RhoA can lead the way in tumor cell invasion and metastasis. Frontiers in bioscience (Landmark edition) 61 21196273
2005 RhoA GTPase regulates B cell receptor signaling. Molecular cell 61 15664190
2007 p66Shc mediates anoikis through RhoA. The Journal of cell biology 58 17908916
2023 Structure of human TRPV4 in complex with GTPase RhoA. Nature communications 57 37353478
2014 CD44 acts through RhoA to regulate YAP signaling. Cellular signalling 57 25101858
2007 Identification and characterization of RHOA-interacting proteins in bovine spermatozoa. Biology of reproduction 56 17928627
2005 Integrin regulation by RhoA in thymocytes. Journal of immunology (Baltimore, Md. : 1950) 56 15972668
2022 A current overview of RhoA, RhoB, and RhoC functions in vascular biology and pathology. Biochemical pharmacology 55 36306821
2008 Targeting by myosin phosphatase-RhoA interacting protein mediates RhoA/ROCK regulation of myosin phosphatase. Journal of cellular biochemistry 53 17661354
2005 Prolonged lesional expression of RhoA and RhoB following spinal cord injury. The Journal of comparative neurology 53 15880494
2001 RhoA/Rho-kinase, vascular changes, and hypertension. Current hypertension reports 53 11276396
2020 RhoA/Rho-kinases in asthma: from pathogenesis to therapeutic targets. Clinical & translational immunology 52 32355562
2014 mTOR regulate EMT through RhoA and Rac1 pathway in prostate cancer. Molecular carcinogenesis 50 25043657
2021 RhoA: a dubious molecule in cardiac pathophysiology. Journal of biomedical science 48 33906663
2018 Agonist-induced CXCR4 and CB2 Heterodimerization Inhibits Gα13/RhoA-mediated Migration. Molecular cancer research : MCR 44 29330286
2010 Revisited and revised: is RhoA always a villain in cardiac pathophysiology? Journal of cardiovascular translational research 44 20559774
2018 LncRNA PCGEM1 Induces Ovarian Carcinoma Tumorigenesis and Progression Through RhoA Pathway. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 43 29949791
2017 RhoA, RhoB and RhoC differentially regulate endothelial barrier function. Small GTPases 43 28949796
2019 RHOA in Gastric Cancer: Functional Roles and Therapeutic Potential. Frontiers in genetics 42 31156701
2016 Pathophysiological effects of RhoA and Rho-associated kinase on cardiovascular system. Journal of hypertension 40 26556565
2015 Galectin 3 regulates HCC cell invasion by RhoA and MLCK activation. Laboratory investigation; a journal of technical methods and pathology 39 26146960
2017 RhoA as a target to promote neuronal survival and axon regeneration. Neural regeneration research 38 28553321
2010 Cytokinesis and cancer: Polo loves ROCK'n' Rho(A). Journal of genetics and genomics = Yi chuan xue bao 38 20347825
2016 Silencing Drp1 inhibits glioma cells proliferation and invasion by RHOA/ ROCK1 pathway. Biochemical and biophysical research communications 37 27495873
2008 G protein-coupled receptors go extracellular: RhoA integrates the integrins. Molecular interventions 37 18829842
2017 Daam1 activates RhoA to regulate Wnt5a‑induced glioblastoma cell invasion. Oncology reports 36 29207169
2010 Phospholipase Cdelta3 regulates RhoA/Rho kinase signaling and neurite outgrowth. The Journal of biological chemistry 36 21187285
2016 Variegated RHOA mutations in human cancers. Experimental hematology 33 27693615
2023 RhoA regulation in space and time. FEBS letters 32 36658753
2014 Genistein induces cytokinesis failure through RhoA delocalization and anaphase chromosome bridging. Journal of cellular biochemistry 32 24453048
2013 Phosphorylation-mediated regulation of GEFs for RhoA. Cell adhesion & migration 30 24589508
2021 Role of Small GTPase RhoA in DNA Damage Response. Biomolecules 29 33546351
2017 Regulation of RhoA GTPase and novel target proteins for ROCK. Small GTPases 29 29199510
2018 RhoA regulates Schwann cell differentiation through JNK pathway. Experimental neurology 28 29940159
2022 TRPV4: A trigger of pathological RhoA activation in neurological disease. BioEssays : news and reviews in molecular, cellular and developmental biology 27 35297520
2012 Protein kinase D regulates RhoA activity via rhotekin phosphorylation. The Journal of biological chemistry 26 22228765
2009 CCK activates RhoA and Rac1 differentially through Galpha13 and Galphaq in mouse pancreatic acini. American journal of physiology. Cell physiology 26 19940064
2003 Vasoconstriction, RhoA/Rho-kinase and the erectile response. International journal of impotence research 26 14551573
2023 RhoA promotes osteoclastogenesis and regulates bone remodeling through mTOR-NFATc1 signaling. Molecular medicine (Cambridge, Mass.) 25 37020186
2018 Afadin and RhoA control pancreatic endocrine mass via lumen morphogenesis. Genes & development 25 29330353
2018 Fam65b Phosphorylation Relieves Tonic RhoA Inhibition During T Cell Migration. Frontiers in immunology 25 30254631
2023 RhoA rescues cardiac senescence by regulating Parkin-mediated mitophagy. The Journal of biological chemistry 23 36758801
2021 RhoA within myofibers controls satellite cell microenvironment to allow hypertrophic growth. iScience 23 35106464
2020 Role of Macrophages and RhoA Pathway in Atherosclerosis. International journal of molecular sciences 23 33379334
2020 CDC42 drives RHOA activity and actin polymerization during capacitation. Reproduction (Cambridge, England) 22 32567555
2019 Hypoxia suppresses myofibroblast differentiation by changing RhoA activity. Journal of cell science 22 30659117
2014 RhoA controls Wnt upregulation on microstructured titanium surfaces. BioMed research international 22 24949442
2010 Compromized geranylgeranylation of RhoA and Rac1 in mevalonate kinase deficiency. Journal of inherited metabolic disease 22 20814828
2005 RhoA and resistance artery remodeling. American journal of physiology. Heart and circulatory physiology 22 15706042
2019 Cytoskeletal Associated Filamin A and RhoA Affect Neural Progenitor Specification During Mitosis. Cerebral cortex (New York, N.Y. : 1991) 21 29462287
2018 Mapping Interactions between p27 and RhoA that Stimulate Cell Migration. Journal of molecular biology 21 29410088
2016 Control of cell mechanics by RhoA and calcium fluxes during epithelial scattering. Tissue barriers 21 27583192
2014 Influence of ARHGEF3 and RHOA knockdown on ACTA2 and other genes in osteoblasts and osteoclasts. PloS one 21 24840563
2024 Untangling the role of RhoA in the heart: protective effect and mechanism. Cell death & disease 19 39122698
2021 RhoA/Cdc42 signaling drives cytoplasmic maturation but not endomitosis in megakaryocytes. Cell reports 19 33979620
2020 RHOA-mediated mechanical force generation through Dectin-1. Journal of cell science 19 31964711
2017 FKBP51 regulates cell motility and invasion via RhoA signaling. Cancer science 19 28032931
2011 Ameloblastin regulates cell attachment and proliferation through RhoA and p27. European journal of oral sciences 19 22243257

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