Affinage

ARHGDIA

Rho GDP-dissociation inhibitor 1 · UniProt P52565

Length
204 aa
Mass
23.2 kDa
Annotated
2026-04-28
100 papers in source corpus 40 papers cited in narrative 40 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ARHGDIA (RhoGDI-alpha/RhoGDI1) is a master regulator of Rho family GTPase signaling that controls the activation, membrane cycling, and spatiotemporal patterning of RhoA, Rac1, and Cdc42. Structurally, its flexible N-terminal arm binds the switch I/II regions of prenylated Rho GTPases to inhibit both GDP dissociation and GTP hydrolysis, while its immunoglobulin-like C-terminal domain sequesters the geranylgeranyl moiety in a hydrophobic pocket, extracting GTPases from membranes into cytosolic heterodimeric complexes with picomolar affinity for GDP-bound RhoA (PMID:10676816, PMID:22628549, PMID:9195882). Release of specific GTPases is controlled by phosphorylation—Pak1 at Ser101/Ser174 selectively dissociates Rac1 (PMID:15225553), Src at Tyr156 broadly disrupts binding to RhoA/Rac1/Cdc42 (PMID:16943322), and PKCα at Ser96 releases both RhoA and Rac1 (PMID:23776598)—as well as by displacement factors such as the neurotrophin receptor p75NTR, which directly competes for RhoGDI-bound RhoA (PMID:12692556, PMID:38253689). Loss-of-function mutations in ARHGDIA cause steroid-resistant nephrotic syndrome through selective hyperactivation of RAC1 and CDC42 in podocytes, a phenotype partially reversed by RAC1 inhibition (PMID:23867502, PMID:23434736).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1993 High

    Early biochemistry established that RhoGDI forms stable heterodimers with prenylated Rho/Rac GTPases in both nucleotide states and protects GTP-bound forms from GAP-stimulated hydrolysis, defining RhoGDI as a dual inhibitor of nucleotide exchange and GTP hydrolysis that requires geranylgeranylation for interaction.

    Evidence In vitro biochemical assays with CAAX mutants and purified proteins

    PMID:8240325 PMID:8491184

    Open questions at the time
    • No structural information on the complex
    • Mechanism of membrane extraction unknown
    • Relative affinities for different GTPases not quantified
  2. 1997 High

    Structural determination of free RhoGDI revealed the bipartite architecture—a flexible N-terminal arm and an immunoglobulin-like C-terminal domain—both required for Rac binding, while chimeric protein analysis showed that the Rho insert region of GTPases is essential for GDI-mediated inhibition.

    Evidence X-ray crystallography, NMR spectroscopy, chimeric protein reconstitution

    PMID:9195882 PMID:9334181

    Open questions at the time
    • No co-crystal structure with a GTPase yet
    • Mechanism of isoprenyl sequestration unresolved
  3. 2000 High

    Co-crystal structures of Cdc42/RhoGDI and RhoA/RhoGDI complexes revealed the molecular basis of dual inhibition: the N-terminal arm occludes GEF-binding epitopes on switch I/II while a deep hydrophobic pocket in the Ig-like domain sequesters the geranylgeranyl group, explaining both nucleotide exchange inhibition and membrane extraction.

    Evidence X-ray crystallography at 2.6 Å (Cdc42) and prior RhoA complex structure, NMR mapping of Rac1 interface

    PMID:10489445 PMID:10673424 PMID:10676816

    Open questions at the time
    • Affinity differences between GDP- and GTP-bound states not yet quantified
    • How upstream signals trigger release in cells unknown
  4. 2001 High

    Live-cell and biochemical studies established RhoGDI as the primary determinant of GTPase subcellular localization: RhoGDI extracts RhoA/Rac1/Cdc42 from membranes to cytosol, constitutively active or palmitoylated GTPases escape this regulation, and the N-terminal domain residues 1–41 are essential for GDP dissociation inhibition while residues 1–30 additionally inhibit GTP hydrolysis.

    Evidence GFP-GTPase live-cell imaging, Cdc42 R66E mutagenesis, N-terminal truncation series with NMR

    PMID:11114252 PMID:11149925 PMID:11513578 PMID:11583574

    Open questions at the time
    • Whether RhoGDI extracts GTP-bound forms in vivo not tested
    • Signal-regulated release mechanisms not identified
  5. 2003 High

    The p75NTR neurotrophin receptor was identified as a direct RhoGDI displacement factor that liberates RhoA from the complex, linking RhoGDI to axon regeneration inhibition by MAG/Nogo, while RhoGDI binding to Cdc42 was shown to be required for Cdc42-mediated cellular transformation.

    Evidence Co-immunoprecipitation, peptide displacement assay, Cdc42 R66A mutagenesis with soft-agar transformation assay

    PMID:12692556 PMID:12956948

    Open questions at the time
    • Structural basis of p75NTR–RhoGDI interaction unknown
    • Whether other receptors act as displacement factors unclear
  6. 2004 High

    Pak1 was identified as the first kinase that phosphorylates RhoGDI (Ser101/Ser174) to achieve GTPase-selective release, dissociating Rac1 but not RhoA from RhoGDI, providing the first mechanism for signal-regulated, client-selective liberation of a Rho GTPase.

    Evidence In vitro kinase assay, phospho-site mutagenesis, dominant-negative Pak1 in growth factor-stimulated cells

    PMID:15225553

    Open questions at the time
    • How phosphorylation structurally disrupts Rac1-selective binding not resolved
    • In vivo stoichiometry of phosphorylation unknown
  7. 2006 High

    Src phosphorylation of RhoGDI at Tyr156 was shown to broadly reduce binding to all three major Rho GTPases, contrasting with Pak1's Rac1 selectivity, and the phosphomimetic Y156E mutant constitutively localized to the plasma membrane and promoted cell spreading.

    Evidence In vitro kinase assay, co-immunoprecipitation, phosphomimetic mutagenesis with live-cell imaging

    PMID:16943322

    Open questions at the time
    • Whether Src and Pak1 phosphorylation are sequential or independent in physiological contexts
    • Phosphatase(s) reversing these modifications unidentified
  8. 2008 High

    In vitro reconstitution demonstrated that GEF-mediated nucleotide exchange on membrane-associated Rac1 combined with PtdIns(3,4,5)P3 is sufficient for RhoGDI dissociation, linking PI3K signaling directly to RhoGDI displacement without requiring kinase-mediated phosphorylation of RhoGDI.

    Evidence Fully reconstituted liposome system with prenylated Rac1, recombinant RhoGDI, and Rac GEFs (Trio/Tiam1)

    PMID:18505730

    Open questions at the time
    • Relative contribution of GEF-mediated versus kinase-mediated release in cells not quantified
    • Whether this mechanism operates for RhoA or Cdc42 untested
  9. 2009 High

    Sequential phosphorylation of RhoGDI—first Tyr156 releasing Cdc42, then Ser101/Ser174 releasing Rac1—was shown to coordinate the biphasic insulin secretion response to glucose in pancreatic β-cells, establishing a physiological signaling cascade in which RhoGDI phosphorylation order dictates sequential GTPase activation.

    Evidence TAP-MS, co-immunoprecipitation, phospho-site triple mutant, insulin secretion assay in β-cells

    PMID:20028975

    Open questions at the time
    • Whether this sequential model applies to other secretory cell types
    • Upstream kinase activation kinetics not resolved
  10. 2011 High

    RhoGDI was placed within a PKA-RhoA negative feedback pacemaker: PKA phosphorylation of RhoA enhances RhoGDI binding, generating periodic protrusion-retraction cycles at the leading edge of migrating cells, demonstrating that RhoGDI is not merely an inhibitor but an active component of oscillatory signaling circuits.

    Evidence Live-cell FRET biosensors for RhoA and PKA activity with correlative image analysis

    PMID:21572420

    Open questions at the time
    • Precise PKA phosphorylation site on RhoA mediating enhanced RhoGDI binding not mapped
    • Whether analogous oscillatory circuits exist for Rac1/Cdc42
  11. 2012 High

    Quantitative binding measurements revealed picomolar affinity (Kd ~5 pM) of RhoGDI for RhoA·GDP and a 25-fold reduction for GTP-bound RhoA, with the crystal structure showing that RhoGDI forces activated RhoA into a GDP-like conformation; meanwhile SUMOylation at Lys-138 was shown to further increase GTPase affinity and suppress cell motility.

    Evidence In vitro fluorescence binding assays, 2.8 Å crystal structure, SUMOylation site mutagenesis

    PMID:22393046 PMID:22628549

    Open questions at the time
    • Whether SUMOylation affects affinity for specific GTPases differentially
    • SUMO E3 ligase mediating RhoGDI SUMOylation not identified
  12. 2013 High

    Loss-of-function mutations in ARHGDIA were identified as the cause of steroid-resistant nephrotic syndrome: mutations R120X, G173V, and D185del abolish GTPase binding, selectively hyperactivate RAC1/CDC42 in podocytes, and the phenotype is partially rescued by RAC1 inhibition and recapitulated in zebrafish, establishing ARHGDIA as a Mendelian disease gene.

    Evidence Homozygosity mapping, whole-exome sequencing, GTPase activity assays, zebrafish model, patient fibroblasts

    PMID:23434736 PMID:23867502

    Open questions at the time
    • Why RHOA is not hyperactivated in disease mutants despite loss of binding
    • Full genotype-phenotype spectrum across different mutations not established
  13. 2019 High

    Direct in vivo imaging demonstrated that RhoGDI extracts both GDP- and GTP-bound RhoGTPases from membranes, contributing to the spatial patterning of RhoGTPase activity zones at cell wounds, overturning the prior assumption that only inactive GTPases are RhoGDI clients in vivo.

    Evidence Direct imaging of labeled RhoGTPases in Xenopus oocyte wounds plus in vitro reconstitution on lipid bilayers

    PMID:31647414

    Open questions at the time
    • Relative rates of extraction for GTP- versus GDP-bound forms not quantified in mammalian systems
    • Whether active extraction requires additional cofactors in vivo
  14. 2024 High

    NMR structural determination of the p75NTR–RhoGDI complex revealed that PKC phosphorylation of the RhoGDI N-terminus promotes p75NTR binding, which displaces RIP2 and enhances RhoA activation; NGF-induced RIP2 recruitment reverses this, establishing a competitive signaling switch at p75NTR that toggles RhoA activity through RhoGDI.

    Evidence NMR solution structure, co-immunoprecipitation, PKC modulation, neurite outgrowth assays

    PMID:38253689

    Open questions at the time
    • Whether this competitive switch operates in non-neuronal p75NTR-expressing cells
    • Full structural model of the ternary p75NTR–RhoGDI–RhoA complex lacking
  15. 2025 High

    The KLHL23-Cul3 E3 ligase was shown to complement RhoGDI by ubiquitylating GTP-bound CDC42 for degradation while RhoGDI sequesters GDP-bound CDC42; the two regulators compete at switch II with opposite nucleotide-state selectivity, coordinating CDC42 inactivation spatiotemporally.

    Evidence FRET assays, co-immunoprecipitation, ubiquitylation assay, mutagenesis, metastasis models

    PMID:40846997

    Open questions at the time
    • Whether analogous E3 ligase competition exists for RhoA or Rac1
    • Structural basis of switch II competition between KLHL23 and RhoGDI not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of the phosphatases that dephosphorylate RhoGDI to re-engage GTPases, the structural basis of client selectivity upon specific phosphorylation events (e.g. why Pak1 phosphorylation selectively releases Rac1), the SUMO E3 ligase responsible for Lys-138 SUMOylation, and how the stoichiometric balance between RhoGDI and the total Rho GTPase pool is sensed and maintained in different cell types.
  • Phosphatases reversing RhoGDI phosphorylation unidentified
  • Structural basis of client-selective release by specific phosphorylation events unresolved
  • How cells maintain RhoGDI:GTPase stoichiometry unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 7 GO:0140313 molecular sequestering activity 4 GO:0008289 lipid binding 3
Localization
GO:0005829 cytosol 3 GO:0005886 plasma membrane 3
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-1500931 Cell-Cell communication 2 R-HSA-1643685 Disease 2
Partners
CDC42KLHL23NGFRPAK1RAC1RHOASRCXIAP
Complex memberships
Cdc42·GDP–RhoGDI heterodimerRac1·GDP–RhoGDI heterodimerRhoA·GDP–RhoGDI heterodimer

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 Crystal structure of Cdc42/RhoGDI complex at 2.6 Å reveals two interaction sites: the RhoGDI N-terminal regulatory arm binds switch I and II of Cdc42 to inhibit GDP dissociation and GTP hydrolysis, while the geranylgeranyl moiety of Cdc42 inserts into a hydrophobic pocket in the immunoglobulin-like domain of RhoGDI to mediate membrane release. X-ray crystallography Cell High 10676816
2001 Crystal structure of Rac1-RhoGDI complex at 2.7 Å shows geranylgeranyl moiety of Rac1 inserts into hydrophobic core of RhoGDI; hydrogen bonds involve Rac1 Tyr64, Arg66, His103, His104 in switch II region; Thr35(Rac) interaction with Asp45(GDI) partly inhibits GDP-GTP exchange; effector loops of Rac1 remain accessible allowing the complex to activate NADPH oxidase. X-ray crystallography, small angle neutron scattering Biochemistry High 11513578
1997 RhoGDI structure determined by X-ray crystallography and NMR shows an immunoglobulin-like fold (residues 59–204) and a flexible, unstructured N-terminal arm (residues 1–50); both domains are required for Rac binding, with the N-terminal arm remaining largely flexible even in the complex. X-ray crystallography, NMR spectroscopy, selective proteolysis Structure High 9195882
1999 Crystal structure of the RhoA-GDP/RhoGDI complex shows the N-terminus of RhoGDI binds to switch I and switch II regions of RhoA, occluding the epitope that binds Dbl-like GEFs; the hydrophobic pocket of RhoGDI is positioned 25 Å from the last RhoA residue to accommodate the geranylgeranyl group. X-ray crystallography (MAD + MIR phasing) Acta crystallographica. Section D High 10489445
2012 RhoGDI binds prenylated RhoA·GDP with very high affinity (Kd = 5 pM); RhoA activation reduces affinity 25-fold (Kd = 3 nM); the 2.8 Å structure of RhoA·GMPPNP·RhoGDI shows complex formation forces activated RhoA into a GDP-like conformation without nucleotide hydrolysis; membrane extraction of Rho GTPase by RhoGDI is a thermodynamically favored passive process. In vitro binding assays, X-ray crystallography at 2.8 Å The Journal of biological chemistry High 22628549
1993 RhoGDI forms stable complexes with Rho and Rac in both GTP- and GDP-bound states; the Rac-GTP·RhoGDI complex is resistant to GTPase-activating proteins (RhoGAP and BCR), indicating RhoGDI can protect activated GTPases from GAP-stimulated GTP hydrolysis; geranylgeranylation and -AAX proteolysis of the CAAX motif are required for efficient RhoGDI interaction, but carboxymethylation is not. In vitro biochemical assays, CAAX mutant analysis The EMBO journal High 8491184
2004 Pak1 (p21-activated kinase) binds and phosphorylates RhoGDI at Ser101 and Ser174 in vitro and in vivo, causing selective dissociation of Rac1-RhoGDI complexes but not RhoA-RhoGDI complexes; this mechanism mediates Cdc42-induced Rac1 activation and is required for PDGF/EGF-stimulated Rac1 dissociation from RhoGDI. In vitro kinase assay, co-immunoprecipitation, phospho-site mutagenesis, dominant-negative Pak1 expression Molecular cell High 15225553
2006 Src kinase binds and phosphorylates RhoGDI at Tyr156 in vitro and in vivo; Tyr156 phosphorylation dramatically reduces RhoGDI complex formation with RhoA, Rac1, and Cdc42; phosphomimetic Y156E mutant constitutively associates with the plasma membrane/cortical actin and promotes enhanced cell spreading and membrane ruffling. In vitro kinase assay, co-immunoprecipitation, phosphomimetic mutagenesis, live-cell imaging Molecular biology of the cell High 16943322
2001 RhoGDI binding regulates subcellular localization of RhoA, Rac1, Rac2, and Cdc42hs but not RhoB or TC10 in live cells; mutations rendering GTPases constitutively active or dominant negative abrogate RhoGDI binding and redirect GTPases to plasma and internal membranes; a palmitoylation site inserted into RhoA blocks RhoGDI binding. GFP fusion live-cell imaging, overexpression of RhoGDI, palmitoylation inhibition, site-directed mutagenesis The Journal of cell biology High 11149925
1994 Neutrophil cytosol p21rac2 is almost entirely complexed with rhoGDI as a 45–50 kDa heterodimer in the GDP-bound form; NADPH oxidase activation leads to dissociation of p21rac2 from rhoGDI and its translocation to the plasma membrane together with p47phox and p67phox, establishing that rhoGDI release is a key step in NADPH oxidase activation. Cell fractionation, co-purification, cell-free oxidase assay, agonist stimulation of whole cells The Biochemical journal High 8141770
2003 The neurotrophin receptor p75NTR directly interacts with RhoGDI and acts as a displacement factor releasing prenylated RhoA from RhoGDI; this interaction is strengthened by MAG and Nogo; a peptide corresponding to the fifth alpha-helix of p75NTR inhibits p75NTR-RhoGDI interaction and blocks the inhibitory effects on axonal regeneration. Co-immunoprecipitation, biochemical displacement assay, peptide inhibition Nature neuroscience High 12692556
2002 Integrin-mediated cell adhesion promotes translocation of GTP-Rac to membranes via its polybasic C-terminal sequence; membrane-associated RhoGDI blocks effector binding to cytoplasmic GTP-Rac; release of RhoGDI after Rac membrane translocation allows spatially restricted Rac-effector interactions at cell edges. FRET-based assay, cell fractionation, integrin activation experiments Nature cell biology High 11862216
2011 PKA phosphorylates RhoA, increasing its interaction with RhoGDI; this PKA-RhoA-RhoGDI axis forms a negative feedback pacemaker controlling the cycling of RhoA activity at the leading edge of migrating cells, generating periodic protrusion-retraction cycles. Live-cell biosensor imaging, FRET, correlative image analysis, PKA inhibition Nature cell biology High 21572420
2019 RhoGDI can extract both inactive (GDP-bound) and active (GTP-bound) RhoGTPases from membranes; extraction of active RhoGTPase by RhoGDI contributes directly to spatiotemporal patterning of RhoGTPase activity zones around cell wounds in vivo. Direct in vivo imaging of labeled RhoGTPases in Xenopus, in vitro reconstitution on lipid bilayers eLife High 31647414
2013 ARHGDIA mutations (R120X and G173V) found in patients with steroid-resistant nephrotic syndrome abrogate interaction with RHO GTPases and selectively increase active GTP-bound RAC1 and CDC42 (but not RHOA), leading to enhanced podocyte migration; RAC1 inhibitors partially reverse the phenotype; arhgdia-deficient zebrafish recapitulate the nephrotic phenotype. Homozygosity mapping, whole-exome sequencing, co-immunoprecipitation, GTPase activation assays, zebrafish knockdown, RAC1 inhibitor rescue The Journal of clinical investigation High 23867502
2013 ARHGDIA p.Asp185del in-frame deletion abolishes binding to RhoA, Rac1, and Cdc42; RhoGDI knockdown in podocytes causes hyperactivation of all three Rho GTPases and impaired cell motility; patient fibroblasts show nuclear mislocalization of mutant RhoGDI and hyperactivation of Rho GTPases. Co-immunoprecipitation, GTPase activation pull-down assay, siRNA knockdown, cell motility assay, immunofluorescence Journal of medical genetics High 23434736
1997 The Rho insert region (residues 122–134) of Cdc42Hs is essential for RhoGDI-mediated inhibition of GDP dissociation and GTP hydrolysis; a Cdc42Hs/Ha-Ras chimera lacking this insert is not susceptible to GDI-mediated inhibition yet GDI can still bind it, indicating the insert region is required for functional inhibitory regulation but not for binding per se. Chimeric protein construction, in vitro GDP dissociation assay, GTP hydrolysis assay, binding assays The Journal of biological chemistry High 9334181
2001 The first 41 residues of the flexible N-terminal domain of RhoGDI are essential for inhibition of GDP dissociation; residues 1–30 are dispensable for this activity but important for inhibiting GTP hydrolysis; differences in the N-terminal domain conformation between RhoGDI and D4GDI explain their different abilities to regulate GTP-bound forms of Rho GTPases. N-terminal truncation analysis, in vitro GDP dissociation assay, GTP hydrolysis assay, NMR Journal of molecular biology High 11114252
2000 NMR spectroscopy and site-directed mutagenesis identify residues 46–57 of the flexible N-terminal domain of RhoGDI-1 as making a major contribution to Rac-1 binding energy; the folded domain binds Rac-1 via the beta4–beta5 and beta6–beta7 loops; the isoprenyl group of prenylated Rac-1 occupies a distinct pocket from the protein-protein interaction site on the folded domain. NMR spectroscopy, site-directed mutagenesis, binding assays Structure High 10673424
1996 RhoGDI binds Cdc42Hs with 1:1 stoichiometry and Kd ~30 nM for both GDP- and GTP-bound forms; binding requires isoprenylation of Cdc42Hs and an intact C-terminus (last 8 amino acids); the GDI-induced quenching of Mant-nucleotide fluorescence provides a direct assay for binding. Fluorescence spectroscopy, Mant-nucleotide binding assay, isoprenylation requirement testing The Journal of biological chemistry High 8626553
2009 RhoGDI regulates insulin secretion in pancreatic beta cells by controlling Cdc42 cycling; glucose stimulation induces Tyr156 phosphorylation of RhoGDI causing RhoGDI-Cdc42 complex dissociation, followed by Ser101/Ser174 phosphorylation causing RhoGDI-Rac1 dissociation; a triple Y156F/S101A/S174A-RhoGDI mutant selectively blocks the second phase of glucose-stimulated insulin secretion. Tandem affinity purification-MS, co-immunoprecipitation, RNAi, phospho-site mutagenesis, insulin secretion assay The Journal of biological chemistry High 20028975
2009 DGKzeta produces phosphatidic acid (PA) that activates PAK1, which phosphorylates RhoGDI causing Rac1-RhoGDI dissociation and Rac1 activation; DGKzeta stably associates with PAK1 and RhoGDI forming a complex functioning as a Rac1-selective RhoGDI dissociation factor; DGKzeta-deficient fibroblasts have attenuated PAK1 phosphorylation and Rac1-RhoGDI dissociation. DGKzeta knockout fibroblasts, PAK1 activation assay, Rac1 pull-down, co-immunoprecipitation, exogenous PA rescue Molecular biology of the cell High 19211846
2010 DGKalpha-derived PA recruits atypical PKCzeta/iota in complex with RhoGDI and Rac to membrane ruffles upon HGF stimulation; DGKalpha-dependent activation of aPKCzeta/iota mediates Rac release from the RhoGDI inhibitory complex, enabling Rac activation and membrane ruffle formation. Co-immunoprecipitation, pharmacological inhibitors, cell migration and ruffling assays Proceedings of the National Academy of Sciences Medium 20160093
2003 RhoGDI is required for Cdc42-mediated cellular transformation; Arg66 mutation in Cdc42 switch II abolishes RhoGDI binding without affecting other regulators or effectors; the RhoGDI-binding-defective Cdc42(F28L,R66A) mutant and RhoGDI siRNA both block soft-agar colony formation and low-serum growth transformation by activated Cdc42(F28L). Site-directed mutagenesis, RhoGDI siRNA, soft-agar colony formation, co-immunoprecipitation Current biology High 12956948
2011 XIAP interacts with RhoGDI via its RING domain and negatively regulates RhoGDI SUMOylation; XIAP deficiency reduces beta-actin polymerization and cell migration; E3 ligase activity of XIAP RING domain is required for cell motility but not for RhoGDI binding. XIAP knockout/knockdown, co-immunoprecipitation, actin polymerization assay, migration assay, domain mapping The Journal of biological chemistry Medium 21402697
2012 RhoGDI SUMOylation at Lys-138 increases its binding affinity to Rho GTPases and enhances inhibition of actin polymerization and cancer cell motility; XIAP RING domain negatively regulates this SUMOylation. Site-directed mutagenesis of SUMOylation site, co-immunoprecipitation, actin polymerization assay, cell motility assay The Journal of biological chemistry Medium 22393046
2003 cAMP/forskolin stimulation increases RhoA phosphorylation on serine, stabilizing its interaction with RhoGDI; increased RhoA-RhoGDI co-immunoprecipitation and decreased membrane-associated RhoA correlate with AQP2 translocation to the apical membrane in renal CD8 cells. GTP-Rac/RhoA pull-down, cell fractionation, co-immunoprecipitation, Western blotting Journal of cell science Medium 12640036
2007 RhoGDI-1 knockout mice show 2-fold increased basal pulmonary microvascular permeability due to opening of interendothelial junctions; RhoA (but not Rac1 or Cdc42) activity is significantly elevated in RhoGDI-1-/- lungs and in RhoGDI-1 siRNA-depleted endothelial cells, demonstrating that RhoGDI-1 selectively represses RhoA to maintain endothelial barrier function. RhoGDI-1 knockout mouse, siRNA knockdown, GTPase activity pull-down, permeability assay Circulation research High 17525371
2009 Absence of RhoGDI in mesangial cells increases specific activity of Rac1 (and to lesser extent RhoA and Cdc42), accompanied by compensatory decrease in Rho GTPase protein levels; RhoGDI-/- cells show decreased spreading, fewer focal contacts, and reduced proliferation/survival. RhoGDI-/- mouse-derived mesangial cell line, GTPase activity pull-down, morphological analysis Cellular signalling Medium 19765647
2001 RhoGDI-binding-defective Cdc42Hs R66E mutant is prenylated and localized predominantly to Golgi but cannot cycle to the cytosol; RhoGDI overexpression translocates wild-type Cdc42Hs from Golgi to cytosol but has no effect on R66E, demonstrating that RhoGDI interaction is required for cytosolic redistribution but not membrane targeting or filopodia formation. Point mutagenesis, immunofluorescence, differential centrifugation fractionation, RhoGDI overexpression The Biochemical journal High 11583574
2000 GTP-bound RhoA spontaneously translocates from its RhoGDI complex to liposomes in vitro, while GDP-RhoA does not; microinjection of GTP-bound G14V-RhoA/RhoGDI complex (but not GDP form) into cells elicits stress fibers and focal adhesions, showing GTP exchange is sufficient for membrane translocation. In vitro liposome binding assay, microinjection into serum-starved cells Protein science High 10716190
2008 Anionic liposomes containing phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) combined with Rac GEFs (Trio or Tiam1) and GTP cause dissociation of Rac1(GDP)·RhoGDI complexes in vitro; dissociation requires GEF-mediated GDP-to-GTP exchange on Rac1 and PtdIns(3,4,5)P3, linking PI3K products to RhoGDI displacement. In vitro reconstitution with prenylated Rac1 and recombinant RhoGDI, liposome binding, NADPH oxidase activation assay The Journal of biological chemistry High 18505730
2013 Brain-specific Cdc42 (bCdc42) with a CCaX motif can undergo tandem prenylation and palmitoylation instead of classical CaaX processing; the dually lipidated form does not interact with RhoGDIα and is enriched at the plasma membrane relative to the classically processed form, showing that alternative lipid modification regulates RhoGDI binding. Metabolic labeling, biochemical fractionation, co-immunoprecipitation, site-directed mutagenesis Molecular and cellular biology High 23358418
2014 RhoGDI facilitates geranylgeranyl transferase-I (GGTase-I)-mediated prenylation of RhoA by kinetically trapping the prenylated product, increasing catalytic efficiency; no ternary RhoGDI·RhoA·GGTase-I complex was detected, indicating sequential rather than concurrent operation. In vitro prenylation assay, fluorescence-based binding assay, gel filtration Biochemical and biophysical research communications Medium 25223799
2013 PKCα phosphorylation of RhoGDI1 at Ser96 releases both RhoA and Rac1 from RhoGDI1, mediating CCK-induced amylase secretion in pancreatic acini; overexpression of RhoGDI1 inhibits RhoA activation and CCK-induced apical amylase secretion. Phospho-site mutagenesis, co-immunoprecipitation, RhoA translocation assay, amylase secretion assay, PKC inhibitors PLoS One Medium 23776598
2024 PKC-mediated phosphorylation of the RhoGDI N-terminus promotes its interaction with the juxtamembrane domain of p75NTR; NMR structure of the complex reveals novel structures; MAG-induced PKC phosphorylation of RhoGDI displaces RIP2 from p75NTR, enhancing RhoA activity and causing stunted neurite outgrowth and apoptosis; NGF-induced RIP2 recruitment releases RhoGDI from p75NTR, decreasing RhoA activity. NMR solution structure, co-immunoprecipitation, PKC inhibition/activation, RhoA activity assay, neurite outgrowth assay EMBO reports High 38253689
2025 KLHL23-Cul3 E3 ligase polyubiquitylates CDC42·GTP for degradation, while RhoGDI sequesters CDC42·GDP; KLHL23 and RhoGDI compete for CDC42's switch II region with selectivity for GTP- and GDP-bound forms respectively; FRET assays show spatiotemporal coordination of KLHL23 and RhoGDI in CDC42 inactivation; KLHL23 depletion causes excessive membrane protrusions and promotes metastasis. FRET assay, co-immunoprecipitation, ubiquitylation assay, mutagenesis, cell biology Nature chemical biology High 40846997
2019 Ang II promotes RhoGDI ubiquitination leading to proteasomal degradation, while SUMOylation stabilizes RhoGDI; ubiquitin and SUMO competitively modify RhoGDI1 and RhoGDI2, with degradation mediated via AT1 receptor activation, regulating vascular smooth muscle cell proliferation and vascular remodeling. Co-immunoprecipitation, proteasome inhibitor treatment, RNAi, specific receptor antagonists, in vivo Ang II infusion model Atherosclerosis Medium 31362179
1993 RhoGDI inhibits carboxyl methylation of G25K (Cdc42) when Mg2+ and GDP are present; RhoGDI and G25K form a heterodimer that remains associated with either GDP or GTPgammaS bound, indicating GDI occludes the methyltransferase target site on the inactive GTPase. Co-purification, carboxymethylation assay, GDP/GTPgammaS binding Biochemical and biophysical research communications Medium 8240325
2021 Andes virus nucleocapsid (N) protein binds the C-terminus of RhoGDI (residues 69–204) but not RhoA directly; N protein sequesters RhoGDI, reducing its availability to suppress RhoA; in conjunction with PKCα-phosphorylated S34-RhoGDI (mimicking hypoxia/VEGF signaling), N protein additionally releases RhoA from phospho-RhoGDI, synergistically activating RhoA and endothelial permeability. Co-immunoprecipitation, domain mapping, phosphomimetic mutants, RhoA activation assay, permeability assay Journal of virology Medium 34133221

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Differential localization of Rho GTPases in live cells: regulation by hypervariable regions and RhoGDI binding. The Journal of cell biology 586 11149925
1999 Overcoming expression and purification problems of RhoGDI using a family of "parallel" expression vectors. Protein expression and purification 583 10024467
2000 Structure of the Rho family GTP-binding protein Cdc42 in complex with the multifunctional regulator RhoGDI. Cell 422 10676816
2003 The p75 receptor acts as a displacement factor that releases Rho from Rho-GDI. Nature neuroscience 382 12692556
2005 RhoGDI: multiple functions in the regulation of Rho family GTPase activities. The Biochemical journal 336 16083425
2002 Integrins regulate GTP-Rac localized effector interactions through dissociation of Rho-GDI. Nature cell biology 282 11862216
2004 Phosphorylation of RhoGDI by Pak1 mediates dissociation of Rac GTPase. Molecular cell 195 15225553
2013 ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling. The Journal of clinical investigation 172 23867502
1994 Activation of NADPH oxidase involves the dissociation of p21rac from its inhibitory GDP/GTP exchange protein (rhoGDI) followed by its translocation to the plasma membrane. The Biochemical journal 160 8141770
1998 Characterization of a Rac1- and RhoGDI-associated lipid kinase signaling complex. Molecular and cellular biology 135 9447972
2006 Phosphorylation of RhoGDI by Src regulates Rho GTPase binding and cytosol-membrane cycling. Molecular biology of the cell 131 16943322
2011 Protein kinase A governs a RhoA-RhoGDI protrusion-retraction pacemaker in migrating cells. Nature cell biology 129 21572420
2001 Crystal structure of the Rac1-RhoGDI complex involved in nadph oxidase activation. Biochemistry 118 11513578
1993 A novel role for RhoGDI as an inhibitor of GAP proteins. The EMBO journal 114 8491184
2001 Protein crystallization by rational mutagenesis of surface residues: Lys to Ala mutations promote crystallization of RhoGDI. Acta crystallographica. Section D, Biological crystallography 113 11320308
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
2003 cAMP-induced AQP2 translocation is associated with RhoA inhibition through RhoA phosphorylation and interaction with RhoGDI. Journal of cell science 106 12640036
1996 Characterization of the interaction between RhoGDI and Cdc42Hs using fluorescence spectroscopy. The Journal of biological chemistry 106 8626553
1997 A modulator of rho family G proteins, rhoGDI, binds these G proteins via an immunoglobulin-like domain and a flexible N-terminal arm. Structure (London, England : 1993) 95 9195882
2010 RhoGDI signaling provides targets for cancer therapy. European journal of cancer (Oxford, England : 1990) 78 20347589
2009 Diacylglycerol kinase zeta regulates actin cytoskeleton reorganization through dissociation of Rac1 from RhoGDI. Molecular biology of the cell 73 19211846
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2013 ARHGDIA: a novel gene implicated in nephrotic syndrome. Journal of medical genetics 71 23434736
2011 X-linked inhibitor of apoptosis protein (XIAP) mediates cancer cell motility via Rho GDP dissociation inhibitor (RhoGDI)-dependent regulation of the cytoskeleton. The Journal of biological chemistry 71 21402697
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2000 GDP dissociation inhibitor D4-GDI (Rho-GDI 2), but not the homologous rho-GDI 1, is cleaved by caspase-3 during drug-induced apoptosis. The Biochemical journal 69 10698706
2013 Identification of a novel prenyl and palmitoyl modification at the CaaX motif of Cdc42 that regulates RhoGDI binding. Molecular and cellular biology 68 23358418
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2009 Differential phosphorylation of RhoGDI mediates the distinct cycling of Cdc42 and Rac1 to regulate second-phase insulin secretion. The Journal of biological chemistry 55 20028975
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2012 E3 ligase activity of XIAP RING domain is required for XIAP-mediated cancer cell migration, but not for its RhoGDI binding activity. PloS one 38 22532870
2010 Endocytosis and toxicity of clostridial binary toxins depend on a clathrin-independent pathway regulated by Rho-GDI. Cellular microbiology 38 20846184
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2004 Analysis of cell-cycle specific localization of the Rdi1p RhoGDI and the structural determinants required for Cdc42p membrane localization and clustering at sites of polarized growth. Current genetics 32 15108020
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2006 Liposomes comprising anionic but not neutral phospholipids cause dissociation of Rac(1 or 2) x RhoGDI complexes and support amphiphile-independent NADPH oxidase activation by such complexes. The Journal of biological chemistry 30 16702219
2001 RhoGDI-binding-defective mutant of Cdc42Hs targets to membranes and activates filopodia formation but does not cycle with the cytosol of mammalian cells. The Biochemical journal 30 11583574
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2013 Cholecystokinin-mediated RhoGDI phosphorylation via PKCα promotes both RhoA and Rac1 signaling. PloS one 19 23776598
2017 Proteome analysis of irradiated endothelial cells reveals persistent alteration in protein degradation and the RhoGDI and NO signalling pathways. International journal of radiation biology 18 28697312
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2000 Human RhoA/RhoGDI complex expressed in yeast: GTP exchange is sufficient for translocation of RhoA to liposomes. Protein science : a publication of the Protein Society 17 10716190
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2008 Genetic disruption of calpain correlates with loss of membrane blebbing and differential expression of RhoGDI-1, cofilin and tropomyosin. The Biochemical journal 15 18076376
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1997 A somatic cell hybrid panel for distal 17q: GDIA1 maps to 17q25.3. Cytogenetics and cell genetics 10 9186513
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1999 Regulation of Rho protein binding to membranes by rhoGDI: inhibition of releasing activity by physiological ionic conditions. Biochemistry and cell biology = Biochimie et biologie cellulaire 9 10426287
2019 ROCK inhibitors alleviate myofibroblast transdifferentiation and vascular remodeling via decreasing TGFβ1-mediated RhoGDI expression. General physiology and biophysics 8 31219429
2014 RhoGDI facilitates geranylgeranyltransferase-I-mediated RhoA prenylation. Biochemical and biophysical research communications 8 25223799
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2022 Integrative Network Modeling Highlights the Crucial Roles of Rho-GDI Signaling Pathway in the Progression of non-Small Cell Lung Cancer. IEEE journal of biomedical and health informatics 7 35820010
2012 Cellular function of RhoGDI-α mediates the cycling of Rac1 and the regulation of pancreatic beta cell death. Transplantation proceedings 7 22564631
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2024 RhoGDI phosphorylation by PKC promotes its interaction with death receptor p75NTR to gate axon growth and neuron survival. EMBO reports 5 38253689
2022 Calmodulin Domain Protein Kinase PiCDPK1 Regulates Pollen Tube Growth Polarity through Interaction with RhoGDI. Plants (Basel, Switzerland) 5 35161234
2011 Functional analysis of RhoGDI inhibitory activity on vacuole membrane fusion. The Biochemical journal 4 21171963
2022 TGFβ1 induces myofibroblast transdifferentiation via increasing Smad-mediated RhoGDI-RhoGTPase signaling. General physiology and biophysics 3 36454112
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2021 ARHGDIA Confers Selective Advantage to Dissociated Human Pluripotent Stem Cells. Stem cells and development 2 34036793
2011 Concordance and interaction of guanine nucleotide dissociation inhibitor (RhoGDI) with RhoA in oogenesis and early development of the sea urchin. Development, growth & differentiation 2 21492154
2021 Binding of the Andes Virus Nucleocapsid Protein to RhoGDI Induces the Release and Activation of the Permeability Factor RhoA. Journal of virology 1 34133221
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2022 miR-497 promotes the migration and invasion of human medulloblast Daoy cell line through targeted regulation of ARHGDIA in vitro. Neuroscience letters 0 35066091