Affinage

RHOG

Rho-related GTP-binding protein RhoG · UniProt P84095

Length
191 aa
Mass
21.3 kDa
Annotated
2026-06-10
82 papers in source corpus 47 papers cited in narrative 46 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

RHOG is a Rho-family GTPase that functions as a signaling switch coupling upstream receptor and GEF inputs to Rac1- and Cdc42-driven actin remodeling, governing cell migration, phagocytosis, apoptotic-cell clearance, and membrane trafficking (PMID:9614181, PMID:16339170, PMID:42182105). Its canonical output is the activation of Rac1 through a conserved module in which GTP-bound RhoG binds ELMO directly and forms a ternary complex with DOCK180-family GEFs (DOCK180, DOCK4, DOCK5), an arrangement required for integrin-mediated spreading, growth-factor-induced neurite outgrowth, lamellipodial migration, and dendritic spine morphogenesis (PMID:12879077, PMID:15620647, PMID:16339170, PMID:17027967, PMID:21900250); cryo-EM of DOCK5/ELMO1 shows RhoG contacts both ELMO1 and DOCK5 to drive a closed-to-open transition that enhances Rac GEF activity, with the RhoG lipidation site aligning to the DOCK5 phosphoinositide-binding site for coincident membrane engagement (PMID:38857861). RhoG is loaded by multiple specific GEFs—Trio, SGEF, Ephexin4, P-Rex1, Vav2, and PLEKHG6—that connect it to distinct receptors and locales including ICAM1, EphA2, and ezrin-organized apical membrane (PMID:10652265, PMID:15133129, PMID:12376551, PMID:17875742, PMID:17881735, PMID:20679435, PMID:24659802), and it is restrained by RhoGDI-3, which targets it to the Golgi, and by a syndecan-4/synectin/RhoGDI1 complex released upon PKCα phosphorylation (PMID:8939998, PMID:11967128, PMID:19581409). Beyond the ELMO/DOCK axis, RhoG signals independently of Rac1 by binding the PI3K regulatory subunit p85α to stimulate Akt and suppress anoikis (PMID:17570359), engages kinectin for microtubule- and kinesin-dependent lysosomal transport (PMID:11689693), and binds Munc13-4 to dock cytotoxic granules for exocytosis (PMID:33513601). RhoG operates in phagocytosis through FcγR, CR3, and TCR-coupled uptake, in leukocyte trans-endothelial migration and NADPH oxidase activation, and is exploited by Yersinia Invasin (and inactivated by the effector YopE) during bacterial invasion (PMID:17875742, PMID:16621998, PMID:21820331, PMID:21878497, PMID:19208761). Biallelic loss-of-function mutations in RHOG cause hemophagocytic lymphohistiocytosis through defective cytotoxic granule exocytosis (PMID:33513601).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1996 High

    Establishing how RhoG is held inactive defined its regulatory boundaries before its effectors were known, identifying a dedicated GDI with unusual membrane association.

    Evidence Yeast two-hybrid, in vitro GDP/GTP exchange inhibition, and membrane fractionation identifying RhoGDI-3 binding to RhoB and RhoG

    PMID:8939998

    Open questions at the time
    • Did not define RhoG's downstream effectors
    • Specificity for RhoG versus RhoB regulation in vivo not resolved
  2. 1998 High

    Demonstrating that active RhoG phenocopies combined Rac1/Cdc42 activation but acts through them rather than their direct effectors placed RhoG upstream as a hierarchical regulator of the other GTPases.

    Evidence GFP-fusion expression, dominant-negative epistasis, and nocodazole microtubule depolymerization in cultured cells

    PMID:9614181

    Open questions at the time
    • Molecular link between RhoG and Rac1/Cdc42 activation unidentified
    • Microtubule dependence mechanistically unexplained
  3. 2000 High

    Identifying Trio's N-terminal GEF domain as a RhoG-preferring exchange factor provided the first defined upstream activator and a route to the cytoskeleton via filamin.

    Evidence In vitro nucleotide exchange assays, cell-based epistasis, and filamin-deficient cell reconstitution

    PMID:10652265 PMID:11146652

    Open questions at the time
    • Receptor inputs activating Trio not defined
    • Effector linking RhoG to actin still unknown at this stage
  4. 2001 High

    Identification of kinectin as a GTP-dependent RhoG effector explained RhoG's microtubule requirement, linking it to kinesin-driven organelle transport.

    Evidence Yeast two-hybrid, co-precipitation, antibody injection, and time-lapse imaging of lysosomal transport

    PMID:11689693

    Open questions at the time
    • Relationship between kinectin output and Rac1/Cdc42 activation unresolved
    • Not connected to a specific receptor pathway
  5. 2002 High

    Placing RhoG within NGF/Ras-driven neurite outgrowth and identifying Vav2/p85α/Akt and PI3K-dependent survival outputs revealed both the Rac/Cdc42 and Rac-independent branches of RhoG signaling.

    Evidence Constitutive/dominant-negative GTPase epistasis, GTP-dependent effector pulldowns, PI3K co-IP, and Akt/JNK/apoptosis assays

    PMID:10982854 PMID:11803464 PMID:11864571 PMID:12376551

    Open questions at the time
    • Direct effector for the Rac1-independent lamellipodia output not defined
    • Physiological GEF coupling for survival signaling unclear
  6. 2002 High

    Defining how RhoGDI-3 targets RhoG to the Golgi via its N-terminal amphipathic helix established spatial control of RhoG inactivation.

    Evidence Confocal microscopy, immuno-isolation, and N-terminal domain mutagenesis with GFP-targeting

    PMID:11967128

    Open questions at the time
    • Signal releasing RhoG from the Golgi pool not identified
    • Functional consequence of Golgi sequestration in vivo unaddressed
  7. 2004 High

    Establishing the conserved TRIO→RhoG→ELMO→DOCK180→Rac module across worm and mammal, with SGEF as a RhoG-specific GEF and a crystal structure rationalizing Trio's RhoG preference, crystallized the core RhoG signaling pathway.

    Evidence C. elegans genetic epistasis, mammalian engulfment assays, GST pulldowns/domain mapping, in vitro exchange with specificity mutants, and X-ray crystallography of TrioN DH/PH

    PMID:12879077 PMID:15133129 PMID:15199069 PMID:15620647

    Open questions at the time
    • Structural basis of the RhoG-ELMO-DOCK ternary complex not yet resolved
    • Membrane recruitment dynamics of the complex undefined
  8. 2005 High

    Loss-of-function knockdown demonstrated that endogenous RhoG drives Rac1 activation, lamellipodia, and migration through ELMO/DOCK180, confirming the pathway's requirement rather than mere sufficiency.

    Evidence RNAi in HeLa cells with migration assays, Rac1 activation pulldowns, and pathway rescue

    PMID:16339170

    Open questions at the time
    • Crk-independence of DOCK180 in this context not mechanistically explained
  9. 2006 High

    Knockout and screen-based studies showed RhoG controls neutrophil NADPH oxidase activity and engages DOCK4/ELMO, extending the module to innate immune effector functions and a second DOCK GEF.

    Evidence RhoG knockout mice with oxidase/Rac activation assays, and co-IP plus localization for DOCK4

    PMID:16621998 PMID:17027967

    Open questions at the time
    • Why Rac1/Rac2 reduction is transient unexplained
    • Selectivity between DOCK180 and DOCK4 across cell types unresolved
  10. 2007 High

    Linking RhoG to ICAM1/SGEF in endothelium, ezrin/PLEKHG6 at the apical pole, and a Rac-independent p85α/PI3K survival pathway connected RhoG to receptor-proximal recruitment and anoikis resistance.

    Evidence siRNA knockdown, reciprocal co-IP, TEM and macropinocytosis assays, and RhoG-p85α co-IP with anoikis assays

    PMID:17570359 PMID:17875742 PMID:17881735

    Open questions at the time
    • How distinct GEFs partition RhoG between Rac-dependent and PI3K-dependent outputs unclear
    • Direct structural basis of RhoG-p85α binding not determined
  11. 2009 High

    Defining the syndecan-4/synectin/RhoGDI1 brake released by PKCα, a proliferation role requiring PI3K but not ELMO, and pathogen hijacking of RhoG by Yersinia revealed both physiological regulation and exploitation of the switch.

    Evidence Ternary-complex co-IP with phospho-site mutagenesis, in utero electroporation with PI3K/ELMO epistasis, and FRET biosensors with bacterial invasion assays

    PMID:19208761 PMID:19581409 PMID:19720752 PMID:19812248

    Open questions at the time
    • Effectors mediating ELMO-independent proliferation undefined
    • How YopE Golgi/ER localization confers RhoG specificity not fully resolved
  12. 2011 High

    A burst of loss-of-function and in vivo studies established RhoG as a broad mediator of phagocytic uptake (FcγR, CR3, TCR), integrin endocytosis, dendritic spine formation, and EphA2/Ephexin4-driven invasion and anoikis resistance.

    Evidence RNAi screens, RhoG knockout mice with wound-healing and integrin trafficking assays, phagocytosis and spine morphometry, and knockdown-rescue epistasis

    PMID:20237158 PMID:20679435 PMID:21621533 PMID:21820331 PMID:21878497 PMID:21900250 PMID:21982645

    Open questions at the time
    • Mechanism connecting RhoG to RhoA downstream of CR3 unexplained
    • How a single GTPase coordinates such diverse receptor inputs spatially undefined
  13. 2013 High

    miR-124 control of RhoG expression and platelet GPVI-specific functions showed transcript-level regulation and receptor-restricted physiological roles in neuronal complexity and granule secretion/thrombosis.

    Evidence miRNA target validation with neuron morphometry, and RhoG knockout mice with platelet aggregation, granule secretion, and in vivo thrombosis assays

    PMID:22588079 PMID:24106269 PMID:24106270

    Open questions at the time
    • GPVI-proximal mechanism coupling Src-family kinases to RhoG activation incomplete
    • Effector mediating granule secretion at this stage unidentified
  14. 2014 High

    Identifying P-Rex1 as a RhoG GEF placing RhoG upstream of DOCK2 in neutrophils, and Anillin and the ELMO2/ILK (ERI) complex as effectors, broadened the effector repertoire to actin-stabilizing and microtubule-stabilizing outputs.

    Evidence In vitro GEF assays with knockout mice, DOCK2 localization, direct RhoG-Anillin binding with CRISPR genetics, and ERI co-IP with microtubule dynamics imaging

    PMID:24659802 PMID:25843030 PMID:25995380

    Open questions at the time
    • Coordination between DOCK2 and DOCK180/ELMO recruitment by RhoG unresolved
    • ERI complex role across non-keratinocyte tissues untested
  15. 2017 Medium

    Studies of invadopodia disassembly, focal adhesion dynamics, and PDGF-driven dorsal ruffles refined RhoG's roles in turnover of adhesive and protrusive structures, often opposing or independent of Rac1.

    Evidence siRNA knockdown with live-cell invadopodia/FA imaging, paxillin phosphorylation immunoblot, and macropinocytosis/internalization assays with signaling inhibitors

    PMID:28202690 PMID:28468978 PMID:30914742

    Open questions at the time
    • Effectors mediating Rac1-independent FA and CDR control not identified
    • Findings from single labs without cross-system replication
  16. 2021 High

    Discovery of biallelic RHOG loss-of-function in a patient with HLH and a direct RhoG-Munc13-4 interaction tied RhoG to cytotoxic granule docking and human disease.

    Evidence Patient genetics, RHOG ablation in CTLs, CG exocytosis and plasma-membrane proximity assays, and RhoG-Munc13-4 co-IP

    PMID:33513601

    Open questions at the time
    • Whether Munc13-4 docking requires the ELMO/DOCK axis or is independent unresolved
    • Structural basis of RhoG-Munc13-4 binding undetermined
  17. 2024 High

    Cryo-EM of DOCK5/ELMO1 with RhoG and Rac1, plus an M-phase Ephexin4 phosphorylation event, provided the structural mechanism of RhoG-driven DOCK activation and a cell-cycle-coupled regulatory layer.

    Evidence Cryo-EM with in vitro Rac GEF and SPR assays, and Ephexin4 phospho-mutant rescue with chromosome alignment and RhoG activity assays

    PMID:38857861 PMID:39675713

    Open questions at the time
    • Structures of RhoG with DOCK180 or DOCK4 not determined
    • In vivo relevance of the M-phase RhoG localization pathway untested
  18. 2026 High

    Optogenetic and dual-biosensor causal analysis directly demonstrated that RhoG unidirectionally activates Rac1 via DOCK180 and independently activates Cdc42, resolving the causal hierarchy among the GTPases.

    Evidence Photoactivatable RhoG, FRET biosensors, causal inference, and DOCK180 epistasis in live cells (preprint)

    PMID:42182105

    Open questions at the time
    • Effectors for the Cdc42-independent protrusion outputs unidentified
    • Preprint not yet peer-reviewed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RhoG selects among its many GEFs, effectors, and Rac-dependent versus Rac-independent outputs in a given cellular context remains the central unresolved question.
  • No unified model of context-dependent effector choice
  • Structural basis of RhoG-p85α, RhoG-kinectin, and RhoG-Munc13-4 binding undetermined
  • Mechanism converting upstream GEF identity into distinct downstream programs unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Localization
GO:0005886 plasma membrane 5 GO:0005794 Golgi apparatus 2 GO:0005829 cytosol 2 GO:0005764 lysosome 1 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-168256 Immune System 5 R-HSA-1266738 Developmental Biology 4 R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-1643685 Disease 2
Partners
DOCK180DOCK5ELMO1EPHEXIN4KINECTINMUNC13-4SGEFTRIO
Complex memberships
ELMO2-ILK-RhoG (ERI) complexRhoG-ELMO-DOCK180 complexsyndecan-4/synectin/RhoGDI1 ternary complex

Evidence

Reading pass · 46 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 RhoG interacts directly with Elmo in a GTP-dependent manner and forms a ternary complex with Dock180 to induce activation of Rac1. This RhoG-Elmo-Dock180 pathway is required for integrin-mediated Rac1 activation and cell spreading, as well as NGF-induced neurite outgrowth. Co-immunoprecipitation, pulldown assays, dominant-negative and constitutively active mutant expression, cell spreading and neurite outgrowth assays Nature High 12879077
1998 Constitutively active RhoG produces cytoskeletal changes (ruffles, lamellipodia, filopodia, microvilli) similar to simultaneous activation of Rac1 and Cdc42Hs. RhoG does not directly interact with Rac1/Cdc42 effectors PAK-1, POR1, or WASP, but requires endogenous Rac1 and Cdc42 activities. RhoG's morphogenic activity requires the microtubule network, and microtubule depolymerization reverses the RhoG phenotype. GFP-fusion protein expression, dominant-negative co-expression epistasis, nocodazole treatment, immunofluorescence microscopy Molecular biology of the cell High 9614181
2000 Trio's N-terminal GEF domain (TrioGEF1/TrioD1) directly activates RhoG with higher in vitro GEF activity on RhoG than on Rac1. In fibroblasts, dominant-negative RhoG abolishes TrioD1 signaling, and TrioD1 requires the microtubule network and relocalizes RhoG to active plasma membrane sites. In vitro nucleotide exchange assay, dominant-negative mutant epistasis, immunofluorescence, nocodazole treatment Journal of cell science High 10652265
2000 Trio GEFD1 interacts through its PH domain with the actin-filament-crosslinking protein filamin. Trio GEFD1 induces actin-based ruffling in filamin-expressing but not filamin-deficient cells, or cells transfected with filamin lacking the Trio-binding domain. Filamin binding does not affect Trio GEFD1 exchange activity. Co-immunoprecipitation, pulldown, filamin-deficient cell reconstitution, actin ruffle assays Nature cell biology High 11146652
2001 Kinectin is identified as a RhoG effector: RhoG(GTP) specifically interacts with the central domain of kinectin. RhoG, kinectin, and kinesin colocalize in the endoplasmic reticulum and lysosomes. RhoG morphogenic activity requires kinectin interaction and kinesin activity. RhoG activation facilitates microtubule-dependent lysosomal transport via kinectin. Yeast two-hybrid screen, co-precipitation, antibody injection to block interaction, time-lapse videomicroscopy, immunofluorescence Molecular and cellular biology High 11689693
1996 RhoGDI-3 is a GDP dissociation inhibitor that specifically interacts with both GDP- and GTP-bound forms of RhoB and RhoG (but not RhoA, RhoC, or Rac1). RhoGDI-3 inhibits GDP/GTP exchange of RhoB and releases GDP-bound but not GTP-bound RhoB from cell membranes. Unlike other GDIs, RhoGDI-3 associates with a detergent-insoluble membranous/cytoskeletal fraction. Yeast two-hybrid, in vitro GDP/GTP exchange inhibition assay, membrane fractionation The Journal of biological chemistry High 8939998
2002 RhoGDI-3 inhibits activation of RhoG and targets RhoG to the Golgi apparatus. The unique N-terminal amphipathic alpha-helix of RhoGDI-3 mediates Golgi association and is required for both Golgi targeting and stability of the cytoplasmic RhoG/RhoGDI-3 complex. Confocal microscopy, immuno-isolation, RhoGDI-3 N-terminal domain mutants, GFP-targeting experiments Traffic (Copenhagen, Denmark) High 11967128
2004 RhoG (and its C. elegans ortholog MIG-2) functions upstream of ELMO/CED-12 in a conserved signaling module (TRIO/UNC-73 → RhoG/MIG-2 → ELMO/CED-12 → Dock180 → Rac) required for phagocytosis of apoptotic cells. Armadillo (ARM) repeats within CED-12/ELMO mediate direct interaction with activated MIG-2/RhoG. Genetic epistasis in C. elegans, mammalian cell engulfment assays, GST pulldowns, domain mapping Current biology : CB High 15620647
2004 SGEF is a GEF that specifically activates RhoG but not Rac1 or Rac3. Recombinant SGEF DH/PH domain exchanges nucleotide on RhoG in vitro. SGEF-induced dorsal ruffles are morphologically similar to those from constitutively active RhoG, and both SGEF and RhoG stimulate macropinocytosis (dextran uptake), requiring a catalytically active DH domain. In vitro nucleotide exchange assay, scanning electron microscopy, dextran uptake assay, dominant-negative and catalytic-dead mutants Molecular biology of the cell High 15133129
2004 The crystal structure of the TrioN (GEFD1) DH/PH domain was determined to 1.7 Å resolution. In vitro exchange experiments show RhoG is ~3× more efficiently exchanged than Rac by TrioN; residues 54 and 69 (not conserved between RhoG and Rac) determine this specificity. The RhoG C-terminal basic tail enables TrioN-PH domain binding to PtdIns(3,4)P2 with micromolar affinity, a function not seen with Rac. X-ray crystallography, in vitro nucleotide exchange assay, dot-blot phospholipid binding, surface plasmon resonance/affinity binding The Journal of biological chemistry High 15199069
2005 RhoG promotes cell migration via the ELMO-Dock180 pathway to activate Rac1 and form lamellipodia at the leading edge. RNAi knockdown of RhoG in HeLa cells reduces Rac1 activation, lamellipodia formation, and migration. Active RhoG promotes migration through ELMO and Dock180, but Dock180-Crk interaction is dispensable for this effect. RNAi knockdown, scratch-wound and Transwell migration assays, Rac1 activation pulldown assay, dominant-negative/active mutant epistasis Journal of cell science High 16339170
2002 RhoG activates Rac1 and Cdc42 downstream of NGF/Ras to mediate neurite outgrowth in PC12 cells. Dominant-negative Rac1 or Cdc42 inhibits RhoG-induced neurite outgrowth; constitutively active RhoG elevates endogenous Rac1 and Cdc42 activities. Dominant-negative RhoG suppresses both NGF-induced and Ras-induced neurite outgrowth. Transient expression of constitutively active/dominant-negative mutants, Rac1/Cdc42 activity assays, epistasis analysis Molecular and cellular biology High 10982854
2002 Trio GEFD1 acts upstream of RhoG in the NGF pathway to induce neurite outgrowth in PC12 cells. The spectrin repeats and SH3-1 domain of Trio are required for GEFD1-mediated neurite outgrowth. Trio protein levels increase upon NGF stimulation. Dominant-negative RhoG epistasis, Trio domain deletion mutants, PC12 neurite outgrowth assays Current biology : CB Medium 11864571
2002 Vav2 and (to a lesser extent) Dbs activate RhoG in vitro. RhoG interacts in a GTP-dependent manner with IQGAP2, MLK-3, and PLD1, but not PAKs, POSH, WASP, Par-6, or IRSp53. Activated RhoG stimulates JNK and Akt but not SRF or NF-κB. Dominant-negative Rac1 does not inhibit lamellipodia induced by activated RhoG, suggesting RhoG can signal independently of Rac1. In vitro GEF exchange assays, GTP-dependent pulldown assays, JNK/Akt/SRF/NF-κB reporter assays, tat-Rac1(17N) transduction The Journal of biological chemistry High 12376551
2002 Constitutively active Rac1 and RhoG (but not RhoA or Cdc42) protect cells from UV-induced apoptosis. This anti-apoptotic effect is independent of NF-κB but requires direct interaction of RhoG (and Rac1) with PI3K and stimulation of Akt. RhoG also activates JNK through a separate pathway. Expression of constitutively active GTPase mutants, apoptosis assays, PI3K co-immunoprecipitation, Akt phosphorylation assays, NF-κB reporter Oncogene Medium 11803464
2007 RhoG is activated downstream of ICAM1 engagement in endothelial cells, requiring the intracellular domain of ICAM1. ICAM1 colocalizes with RhoG and binds to the RhoG-specific GEF SGEF via SGEF's SH3 domain. RhoG depletion by siRNA decreases endothelial cup formation and inhibits leukocyte trans-endothelial migration (TEM) without affecting leukocyte adhesion. SGEF silencing also reduces RhoG activity, cup formation, and TEM. siRNA knockdown, RhoG activation assay, co-immunoprecipitation (ICAM1-SGEF), confocal microscopy, TEM assays The Journal of cell biology High 17875742
2007 PLEKHG6 is a RhoG-specific GEF recruited by ezrin to the apical pole of epithelial cells. PLEKHG6 activates RhoG (and to lesser extent Rac1). Ezrin forms a ternary complex with PLEKHG6 and RhoG, and also with PLEKHG6 and the RhoG effector ELMO. Both PLEKHG6 and ezrin are required for macropinocytosis (dextran uptake) downstream of EGF. Co-immunoprecipitation, dominant-negative RhoG epistasis, dextran uptake assays, siRNA knockdown Molecular biology of the cell High 17881735
2006 RhoG depletion impairs GPCR agonist (C5a/fMLP)-stimulated NADPH oxidase activity and oxidant generation in neutrophils. Loss of RhoG causes early, transient reduction of Rac1 and Rac2 activation by fMLP. Chemotaxis and other signaling events (PKB phosphorylation, p38MAPK, PLD activation, calcium flux) are unaffected. RhoG knockout mice, NADPH oxidase activity assay, Rac1/Rac2 activation pulldown assay, chemotaxis assay Journal of immunology High 16621998
2006 Dock4 is regulated by RhoG through ELMO: active RhoG induces translocation of the Dock4-ELMO complex from cytoplasm to the plasma membrane and enhances Dock4/ELMO-dependent Rac1 activation and cell migration. Co-immunoprecipitation, subcellular fractionation/localization, Rac1 activation pulldown assay, RNAi knockdown, migration assays Experimental cell research Medium 17027967
2009 RhoG is maintained in an inactive state by a ternary complex of syndecan-4 (S4), synectin, and RhoGDI1. PKCα phosphorylates RhoGDI1 at Ser96 upon S4 clustering, releasing RhoG and leading to polarized Rac1 activation. This pathway is downstream of FGF2 signaling for angiogenesis. Co-immunoprecipitation (ternary complex), phosphorylation site mutation, Rac1 activation assays, siRNA knockdown, endothelial migration assays The Journal of cell biology High 19581409
2010 Ephexin4 is a GEF for RhoG that interacts with EphA2. Ligand-independent EphA2 activates RhoG via Ephexin4, which recruits ELMO2 and Dock4 to form a complex with EphA2 at cortactin-rich protrusion tips. Dock4-mediated Rac activation downstream of this pathway promotes breast cancer cell migration and invasion. siRNA knockdown/rescue experiments, co-immunoprecipitation, RhoG and Rac activity assays, invasion/migration assays, immunofluorescence The Journal of cell biology High 20679435
2010 EGF stimulation causes rapid, strong activation of endogenous RhoG in epithelial cells, mediated by Vav family GEFs (and in some cell types PLEKHG6). RhoG activation after EGF is independent of Rac1 activation. RhoG has roles in EGF-stimulated cell migration and EGF receptor internalization. RhoG nucleotide-free pulldown assay, siRNA knockdown of Vav/PLEKHG6, EGF receptor internalization assay, migration assay Molecular biology of the cell Medium 20237158
2011 TC21 (RRas2) co-translocates with the TCR to the immunological synapse and drives TCR internalization via a RhoG-dependent phagocytic mechanism. RhoG is required for TCR-triggered phagocytosis of beads and uptake of MHC from antigen-presenting cells. siRNA knockdown, phagocytosis assays (1–6 μm beads), TCR internalization assays, live-cell imaging Immunity High 21820331
2011 Syndecan-4 binding by fibronectin triggers PKCα-dependent RhoG activation, leading to dynamin- and caveolin-dependent α5β1-integrin endocytosis. Genetic disruption of RhoG in mice retards dermal wound closure due to defective migration of fibroblasts and keratinocytes. Atomic force microscopy (cell avidity), co-immunoprecipitation, RhoG knockout mouse model, wound healing assay, integrin internalization assay Developmental cell High 21982645
2011 RhoG is required for particle uptake through both FcγR and CR3 in macrophages, demonstrated by RNAi screen. RhoG is recruited and activated at phagocytic cups downstream of both receptors. Unexpectedly, RhoG connects to RhoA signaling downstream of CR3. RNAi screen (20 Rho GTPases individually depleted), phagocytosis assays, RhoG recruitment/activation at phagocytic cups Journal of cell science High 21878497
2011 The RhoG/ELMO1/Dock180 signaling module is required for dendritic spine morphogenesis in hippocampal neurons. Depletion of Dock180 inhibits spine formation; ELMO1 acts with Dock180 in a complex to activate Rac GTPase for this process; RhoG functions upstream of the ELMO1/Dock180 complex in spine formation. RNAi screen of 70 Rho GEFs, siRNA knockdown, overexpression, Rac GTPase activation assay, confocal microscopy The Journal of biological chemistry Medium 21900250
2011 Ephexin4-mediated RhoG activation is required for resistance to anoikis (suspension-induced apoptosis) downstream of EphA2. Knockdown of Ephexin4 decreases RhoG activity and Akt phosphorylation in suspended cells; rescue requires active RhoG and PI3K/Akt. siRNA knockdown/rescue, RhoG activity assay, Akt phosphorylation assay, anoikis assay Experimental cell research Medium 21621533
2012 miR-124 suppresses RhoG expression in neurons, and RhoG inhibits dendritic branching via ELMO/Dock180/Rac1 signaling and inhibits axonal branching in a Cdc42-dependent manner. miR-124 directly targets the RhoG 3'UTR to regulate neuronal process complexity. miRNA overexpression/knockdown, RhoG siRNA, dominant-negative GTPase epistasis, hippocampal neuron morphometry in vitro and in vivo The EMBO journal High 22588079
2012 RhoG mediates glioblastoma cell invasion through brain slices. RhoG is activated by HGF and EGF. Depletion of RhoG strongly inhibits Rac1 activation by both growth factors and impairs lamellipodia and invadopodia formation. siRNA depletion, ex vivo brain slice invasion assay, Rac1 activation pulldown, lamellipodia/invadopodia imaging Molecular cancer Medium 22966858
2013 RhoG is expressed in platelets and activated by collagen-related peptide (CRP) via a Src family kinase-dependent, Syk- and PI3K-independent mechanism. RhoG deficiency impairs GPVI-specific granule secretion (α-granules, dense granules, lysosomes) and integrin activation, leading to reduced thrombus formation in vivo. RhoG function is GPVI-specific and does not affect thrombin signaling. RhoG knockout mice, platelet aggregation assay, granule secretion assay, integrin activation assay, in vivo thrombosis model, kinase inhibitor studies The Journal of biological chemistry High 24106269 24106270
2014 P-Rex1 acts as a GEF for RhoG (in addition to Rac1) both in vitro and in GPCR-stimulated primary mouse neutrophils. Loss of P-Rex1 or RhoG causes equivalent reductions in GPCR-driven Rac activation and NADPH oxidase activity. RhoG loss impairs GPCR-driven DOCK2 recruitment and F-actin polarization to the leading edge, placing RhoG upstream of DOCK2-mediated Rac activation in neutrophils. In vitro GEF exchange assay, RhoG knockout mice, Rac activation assay, NADPH oxidase assay, DOCK2 localization by immunofluorescence Journal of cell science High 24659802
2015 Anillin is recruited to the leading edge by active RhoG (MIG-2) in C. elegans Q neuroblasts. The active form of RhoG/MIG-2 directly binds to Anillin. Anillin stabilizes F-actin at the leading edge by antagonizing Cofilin-mediated severing, transducing the RhoG signal to the actin cytoskeleton during neuronal migration and neurite growth. CRISPR-Cas9 conditional mutations, live imaging, biochemical F-actin stabilization assay, direct binding assay (RhoG–Anillin), C. elegans neuronal migration assay Current biology : CB High 25843030
2015 ELMO2 simultaneously binds ILK and RhoG, forming a tripartite ERI complex. In differentiated keratinocytes, ERI complexes (independently of integrins) promote microtubule stability via Rac1-dependent phosphorylation and inactivation of stathmin and GSK-3β/CRMP2. Co-immunoprecipitation, Ilk gene inactivation (KO), microtubule dynamics imaging, RhoG/ELMO2 overexpression, Rac1 activity assay Molecular biology of the cell Medium 25995380
2007 RhoG regulates anoikis through a PI3K-dependent mechanism independent of ELMO/Dock180-mediated Rac1 activation. Constitutively active RhoG binds to the PI3K regulatory subunit p85α and induces PI3K-dependent Akt phosphorylation to suppress anoikis. RNAi knockdown, co-immunoprecipitation (RhoG–p85α), Akt phosphorylation assay, anoikis assay, constitutively active/dominant-negative mutant epistasis Experimental cell research Medium 17570359
2017 RhoG and its GEF SGEF regulate invadopodia disassembly in breast cancer cells. Silencing RhoG or SGEF stabilizes invadopodia (longer lifetime). RhoG and Rac1 have independent and opposing roles in invadopodia dynamics. RhoG/SGEF modulate paxillin phosphorylation, a key step in invadopodia disassembly. siRNA knockdown, live-cell invadopodia assay (lifetime measurement), paxillin phosphorylation immunoblot Journal of cell science Medium 28202690
2017 RhoG and its exchange factor Trio regulate circular dorsal ruffle (CDR) dynamics, macropinocytosis, and receptor internalization downstream of PDGF in a PI3K- and Src-dependent manner. RhoG regulation of CDR area is independent of Rac1. siRNA knockdown, CDR area quantification, macropinocytosis (dextran uptake) assay, receptor internalization assay, signaling inhibitor experiments Molecular biology of the cell Medium 28468978
2019 RhoG modulates focal adhesion (FA) dynamics: RhoG silencing increases FA stability, number, size, and maturity, and increases stress fiber thickness and contractility. RhoG plays a role in microtubule-mediated FA disassembly. siRNA knockdown, live-cell FA dynamics imaging (TIRF), blebbistatin treatment, immunofluorescence Scientific reports Medium 30914742
2021 Biallelic loss-of-function mutations in RHOG in a patient cause hemophagocytic lymphohistiocytosis (HLH) due to impaired cytotoxic granule (CG) exocytosis. RhoG retains CGs in the vicinity of the plasma membrane. RhoG directly interacts with Munc13-4, an exocytosis factor essential for CG fusion; this interaction is required for docking of Munc13-4+ CGs to the plasma membrane and subsequent membrane fusion and CG content release. Patient genetic analysis, RHOG ablation in cell lines and primary CTLs, CG exocytosis assay, proximity to plasma membrane assay, co-immunoprecipitation (RhoG–Munc13-4) Blood High 33513601
2016 Tyrosine phosphorylation of SGEF at Y530 (within the DH domain) by Src suppresses SGEF interaction with RhoG, reduces RhoG activity elevation, and inhibits SGEF-mediated cell migration. The Y530F mutation blocks the inhibitory effect of Src. Site-directed mutagenesis, kinase assay, co-immunoprecipitation, RhoG activity assay, migration assay PloS one Medium 27437949
2018 Ephexin4 undergoes autoinhibition through an intermolecular interaction that impedes RhoG binding to Ephexin4. A mutation at E295A (in the intermolecular interaction region) disrupts autoinhibition, increases RhoG binding, augments RhoG activation, and increases phagocytosis of apoptotic cells. Ephexin4 oligomerization mutant analysis, co-immunoprecipitation, RhoG activation assay, phagocytosis assay Cells Medium 30445756
2024 Cryo-EM structures of DOCK5/ELMO1 alone and in complex with RhoG and Rac1 reveal that RhoG binds both ELMO1 and DOCK5, facilitating a closed-to-open conformational transition in DOCK5/ELMO1. RhoG binding enhances the Rac GEF activity of DOCK5/ELMO1 and increases its binding affinity for Rac1 (confirmed by SPR). The DOCK5 phosphatidylinositol(3,4,5)-trisphosphate binding site aligns with the RhoG C-terminal lipidation site, suggesting simultaneous plasma membrane binding. Cryo-EM structure determination, in vitro Rac GEF activity assay, surface plasmon resonance (SPR), biochemical binding assays The Journal of biological chemistry High 38857861
2009 Yersinia enterocolitica Invasin activates RhoG at bacterial contact sites to promote cell invasion, while the type III effector YopE (acting as a GAP) deactivates RhoG. YopE localizes to Golgi/ER, which determines its RhoG specificity. RhoG and Elmo/Dock180 control both Rac1 activation by Invasin and Rac1 deactivation by YopE. FRET-based RhoG biosensor, siRNA knockdown, bacterial invasion assay, YopE GAP activity assay, confocal microscopy Journal of cell science High 19208761
2009 Y. pseudotuberculosis Invasin recruits RhoG to bacterial attachment sites via high-affinity beta1-integrin association. YopE (a GAP) efficiently inactivates RhoG. YopT (a prenylcysteine endoprotease) mislocalizes RhoG. RhoG activation can bypass a deficit in Rac1 activity for bacterial internalization. FRET-based RhoG activation biosensor, siRNA knockdown, bacterial internalization assay, fluorescence microscopy Infection and immunity Medium 19720752
2009 RhoG promotes neural progenitor cell (NPC) proliferation in the ventricular zone during cortical development. Active RhoG promotes BrdU incorporation and Ki67 positivity; RhoG knockdown suppresses these. RhoG-induced proliferation requires PI3K activity but not ELMO interaction. In utero electroporation, RNAi knockdown, constitutively active RhoG, BrdU/Ki67 assays, PI3K inhibitor and ELMO binding mutant epistasis Molecular biology of the cell Medium 19812248
2024 Ephexin4 is phosphorylated at Ser41 specifically during M phase. This phosphorylation is required for RhoG localization to the plasma membrane, chromosome alignment, and normal M-phase progression. Loss of Ephexin4 or the S41A phospho-dead mutant causes chromosome misalignment via spindle assembly checkpoint activation (BubR1 at kinetochores). Phospho-mimic S41E mutant enhances active RhoG levels. Ephexin4 knockdown/rescue with phospho mutants, chromosome alignment assay, BubR1 localization, RhoG activity assay, MDCK cyst morphogenesis assay The Journal of biological chemistry Medium 39675713
2026 Using a photoactivatable RhoG, a RhoG biosensor, and simultaneous two-GTPase visualization, RhoG activation was shown to unidirectionally activate Rac1 in cell protrusions. RhoG activates Rac1 predominantly through DOCK180. RhoG also independently activates Cdc42 independently of Rac1. Specific aspects of protrusion behavior are controlled by RhoG beyond those mediated through Rac1. Optogenetics (photoactivatable RhoG), FRET biosensors (RhoG, Rac1), causal inference analysis, live-cell protrusion imaging, DOCK180 epistasis bioRxivpreprint High 42182105

Source papers

Stage 0 corpus · 82 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 RhoG activates Rac1 by direct interaction with the Dock180-binding protein Elmo. Nature 291 12879077
2000 The Rac1- and RhoG-specific GEF domain of Trio targets filamin to remodel cytoskeletal actin. Nature cell biology 184 11146652
2007 RhoG regulates endothelial apical cup assembly downstream from ICAM1 engagement and is involved in leukocyte trans-endothelial migration. The Journal of cell biology 177 17875742
2004 Phagocytosis of apoptotic cells is regulated by a UNC-73/TRIO-MIG-2/RhoG signaling module and armadillo repeats of CED-12/ELMO. Current biology : CB 168 15620647
2011 T cell receptor internalization from the immunological synapse is mediated by TC21 and RhoG GTPase-dependent phagocytosis. Immunity 161 21820331
2000 TrioGEF1 controls Rac- and Cdc42-dependent cell structures through the direct activation of rhoG. Journal of cell science 151 10652265
2002 Rac1 and RhoG promote cell survival by the activation of PI3K and Akt, independently of their ability to stimulate JNK and NF-kappaB. Oncogene 146 11803464
2005 Activation of Rac1 by RhoG regulates cell migration. Journal of cell science 145 16339170
1998 RhoG GTPase controls a pathway that independently activates Rac1 and Cdc42Hs. Molecular biology of the cell 135 9614181
2002 The Human Rho-GEF trio and its target GTPase RhoG are involved in the NGF pathway, leading to neurite outgrowth. Current biology : CB 134 11864571
2010 Ephexin4 and EphA2 mediate cell migration through a RhoG-dependent mechanism. The Journal of cell biology 127 20679435
2000 Small GTPase RhoG is a key regulator for neurite outgrowth in PC12 cells. Molecular and cellular biology 122 10982854
2011 A syndecan-4 hair trigger initiates wound healing through caveolin- and RhoG-regulated integrin endocytosis. Developmental cell 114 21982645
1996 RhoGDI-3 is a new GDP dissociation inhibitor (GDI). Identification of a non-cytosolic GDI protein interacting with the small GTP-binding proteins RhoB and RhoG. The Journal of biological chemistry 109 8939998
1992 Growth-regulated expression of rhoG, a new member of the ras homolog gene family. Molecular and cellular biology 105 1620121
2012 miR-124-regulated RhoG reduces neuronal process complexity via ELMO/Dock180/Rac1 and Cdc42 signalling. The EMBO journal 93 22588079
2004 SGEF, a RhoG guanine nucleotide exchange factor that stimulates macropinocytosis. Molecular biology of the cell 93 15133129
2002 RhoG signals in parallel with Rac1 and Cdc42. The Journal of biological chemistry 91 12376551
1997 The small GTPases Cdc42Hs, Rac1 and RhoG delineate Raf-independent pathways that cooperate to transform NIH3T3 cells. Current biology : CB 89 9285711
2009 A cell active chemical GEF inhibitor selectively targets the Trio/RhoG/Rac1 signaling pathway. Chemistry & biology 87 19549603
2002 Kalirin Dbl-homology guanine nucleotide exchange factor 1 domain initiates new axon outgrowths via RhoG-mediated mechanisms. The Journal of neuroscience : the official journal of the Society for Neuroscience 80 12177196
2006 Dock4 is regulated by RhoG and promotes Rac-dependent cell migration. Experimental cell research 77 17027967
2009 Suppression of RhoG activity is mediated by a syndecan 4-synectin-RhoGDI1 complex and is reversed by PKCalpha in a Rac1 activation pathway. The Journal of cell biology 67 19581409
2001 Kinectin is a key effector of RhoG microtubule-dependent cellular activity. Molecular and cellular biology 66 11689693
2007 Interaction of ezrin with the novel guanine nucleotide exchange factor PLEKHG6 promotes RhoG-dependent apical cytoskeleton rearrangements in epithelial cells. Molecular biology of the cell 63 17881735
2012 The small GTPase RhoG mediates glioblastoma cell invasion. Molecular cancer 60 22966858
2014 P-Rex1 directly activates RhoG to regulate GPCR-driven Rac signalling and actin polarity in neutrophils. Journal of cell science 59 24659802
2011 RhoG is required for both FcγR- and CR3-mediated phagocytosis. Journal of cell science 58 21878497
2015 Anillin Regulates Neuronal Migration and Neurite Growth by Linking RhoG to the Actin Cytoskeleton. Current biology : CB 53 25843030
2004 Immunological function in mice lacking the Rac-related GTPase RhoG. Molecular and cellular biology 53 14701744
2011 Ephexin4 and EphA2 mediate resistance to anoikis through RhoG and phosphatidylinositol 3-kinase. Experimental cell research 47 21621533
2017 A RhoG-mediated signaling pathway that modulates invadopodia dynamics in breast cancer cells. Journal of cell science 46 28202690
2021 RhoG deficiency abrogates cytotoxicity of human lymphocytes and causes hemophagocytic lymphohistiocytosis. Blood 44 33513601
2011 The RhoG/ELMO1/Dock180 signaling module is required for spine morphogenesis in hippocampal neurons. The Journal of biological chemistry 44 21900250
2008 Endogenous RhoG is dispensable for integrin-mediated cell spreading but contributes to Rac-independent migration. Journal of cell science 44 18505794
2004 The C-terminal basic tail of RhoG assists the guanine nucleotide exchange factor trio in binding to phospholipids. The Journal of biological chemistry 44 15199069
2002 RhoGDI-3 regulates RhoG and targets this protein to the Golgi complex through its unique N-terminal domain. Traffic (Copenhagen, Denmark) 43 11967128
2010 Endogenous RhoG is rapidly activated after epidermal growth factor stimulation through multiple guanine-nucleotide exchange factors. Molecular biology of the cell 36 20237158
2009 Yersinia enterocolitica differentially modulates RhoG activity in host cells. Journal of cell science 35 19208761
2006 Involvement of the Rho/Rac family member RhoG in caveolar endocytosis. Oncogene 35 16568096
2006 RhoG regulates the neutrophil NADPH oxidase. Journal of immunology (Baltimore, Md. : 1950) 34 16621998
2017 Regulation of circular dorsal ruffles, macropinocytosis, and cell migration by RhoG and its exchange factor, Trio. Molecular biology of the cell 33 28468978
2007 RhoG regulates anoikis through a phosphatidylinositol 3-kinase-dependent mechanism. Experimental cell research 32 17570359
2019 RHOG Activates RAC1 through CDC42 Leading to Tube Formation in Vascular Endothelial Cells. Cells 31 30781697
2016 MicroRNA-124 Controls Transforming Growth Factor β1-Induced Epithelial-Mesenchymal Transition in the Retinal Pigment Epithelium by Targeting RHOG. Investigative ophthalmology & visual science 31 26746014
2009 Yersinia pseudotuberculosis virulence determinants invasin, YopE, and YopT modulate RhoG activity and localization. Infection and immunity 31 19720752
2013 RhoG protein regulates platelet granule secretion and thrombus formation in mice. The Journal of biological chemistry 28 24106270
2017 GRHL2 suppresses tumor metastasis via regulation of transcriptional activity of RhoG in non-small cell lung cancer. American journal of translational research 27 28979695
2014 Arhgef16, a novel Elmo1 binding partner, promotes clearance of apoptotic cells via RhoG-dependent Rac1 activation. Biochimica et biophysica acta 27 25063526
2015 An ELMO2-RhoG-ILK network modulates microtubule dynamics. Molecular biology of the cell 26 25995380
2012 Dock3 regulates BDNF-TrkB signaling for neurite outgrowth by forming a ternary complex with Elmo and RhoG. Genes to cells : devoted to molecular & cellular mechanisms 26 22734669
2016 Involvement of Tiam1, RhoG and ELMO2/ILK in Rac1-mediated phagocytosis in human trabecular meshwork cells. Experimental cell research 25 27539661
2009 RhoG promotes neural progenitor cell proliferation in mouse cerebral cortex. Molecular biology of the cell 25 19812248
2013 miR-124-regulated RhoG: A conductor of neuronal process complexity. Small GTPases 18 23303397
2013 RhoG protein regulates glycoprotein VI-Fc receptor γ-chain complex-mediated platelet activation and thrombus formation. The Journal of biological chemistry 18 24106269
2021 miR‑124‑3p inhibits the viability and motility of glioblastoma multiforme by targeting RhoG. International journal of molecular medicine 17 33649803
2016 Design of novel lead molecules against RhoG protein as cancer target - a computational study. Journal of biomolecular structure & dynamics 16 27691842
2002 Developmental changes in expression of small GTPase RhoG mRNA in the rat brain. Brain research. Molecular brain research 16 12393274
2022 RhoG's Role in T Cell Activation and Function. Frontiers in immunology 15 35280994
2010 A novel, retromer-independent role for sorting nexins 1 and 2 in RhoG-dependent membrane remodeling. Traffic (Copenhagen, Denmark) 15 20604901
2021 In silico identification and characterization of small-molecule inhibitors specific to RhoG/Rac1 signaling pathway. Journal of biomolecular structure & dynamics 14 34877916
2019 RhoG and Cdc42 can contribute to Rac-dependent lamellipodia formation through WAVE regulatory complex-binding. Small GTPases 14 31451035
2016 Different roles of the small GTPases Rac1, Cdc42, and RhoG in CALEB/NGC-induced dendritic tree complexity. Journal of neurochemistry 14 27412363
2019 The small GTPase RhoG regulates microtubule-mediated focal adhesion disassembly. Scientific reports 13 30914742
2016 RHOG-DOCK1-RAC1 Signaling Axis Is Perturbed in DHEA-Induced Polycystic Ovary in Rat Model. Reproductive sciences (Thousand Oaks, Calif.) 13 27662902
2016 Immunological and Functional Characterization of RhoGDI3 and Its Molecular Targets RhoG and RhoB in Human Pancreatic Cancerous and Normal Cells. PloS one 13 27832197
2012 RRas2, RhoG and T-cell phagocytosis. Small GTPases 12 22790196
2016 Tyrosine Phosphorylation of SGEF Regulates RhoG Activity and Cell Migration. PloS one 9 27437949
2023 Role of RhoG as a regulator of cellular functions: integrating insights on immune cell activation, migration, and functions. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 8 37378671
2018 The Intermolecular Interaction of Ephexin4 Leads to Autoinhibition by Impeding Binding of RhoG. Cells 8 30445756
2018 RhoG-ELMO1-RAC1 is involved in phagocytosis suppressed by mono-butyl phthalate in TM4 cells. Environmental science and pollution research international 7 30350139
1997 Structure of the human ARHG locus encoding the Rho/Rac-like RhoG GTPase. Genomics 7 9177787
2023 RhoG-Binding Domain of Elmo1 Ameliorates Excessive Process Elongation Induced by Autism Spectrum Disorder-Associated Sema5A. Pathophysiology : the official journal of the International Society for Pathophysiology 6 38133141
2021 RhoG-Rac1 Signaling Pathway Mediates Metabolic Dysfunction of the Pancreatic Beta-Cells Under Chronic Hyperglycemic Conditions. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 6 33851799
2019 RhoG/Rac1 signaling pathway involved in migration and invasion of salivary adenoid cystic carcinoma cells. Oral diseases 6 31793126
2024 RhoG facilitates a conformational transition in the guanine nucleotide exchange factor complex DOCK5/ELMO1 to an open state. The Journal of biological chemistry 3 38857861
2024 Phosphorylation of Ephexin4 at Ser-41 contributes to chromosome alignment via RhoG activation in cell division. The Journal of biological chemistry 3 39675713
2010 Bayesian integrated modeling of expression data: a case study on RhoG. BMC bioinformatics 2 20515463
2026 [Retracted] miR‑124‑3p inhibits the viability and motility of glioblastoma multiforme by targeting RhoG. International journal of molecular medicine 0 41614420
2026 The RhoG-Binding Domain of ELMO1 Rescues the PTENopathy-like Phenotype in Oligodendroglial FBD-102b Cells. International journal of molecular sciences 0 42074101
2026 RhoG, Rac1 and Cdc42 cooperation in cell protrusion revealed by multiplexed optogenetics and biosensor imaging. bioRxiv : the preprint server for biology 0 42182105
2025 Serine protease Rv2569c inhibits inflammatory response and promotes intracellular survival of Mycobacterium tuberculosis by targeting the RhoG-NF-κB-NLRP3 pathway. International journal of biological macromolecules 0 40228763

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