Affinage

ARHGAP9

Rho GTPase-activating protein 9 · UniProt Q9BRR9

Length
750 aa
Mass
83.3 kDa
Annotated
2026-04-28
43 papers in source corpus 10 papers cited in narrative 10 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ARHGAP9 is a multi-domain Rho-GTPase activating protein that inactivates Cdc42 and Rac1 (and weakly RhoA) to suppress cell adhesion, migration, invasion, and epithelial-mesenchymal transition. Its GAP domain catalyzes GTP hydrolysis on Rho-family GTPases, while its PH domain engages PI(4,5)P2, PI(3,4,5)P3, and PI(3,4)P2 through a structurally characterized non-canonical binding pocket, and its WW domain sequesters Erk2 and p38α MAP kinases in inactive conformations, thereby dampening MAPK signaling independently of GAP activity (PMID:11396949, PMID:17339315, PMID:17284314). Downstream of RhoGTPase inactivation, ARHGAP9 restrains cell migration and invasion through multiple effector axes including FOXJ2-dependent E-cadherin upregulation, suppression of PI3K/AKT/mTOR signaling, and DKK2-mediated inhibition of Wnt/β-catenin signaling (PMID:30206221, PMID:35679685, PMID:37454937). Its transcription is directly activated by the transcription factors GATA5 and SOX4, linking its expression to lineage-specific programs in lung and hematopoietic cells (PMID:35040754, PMID:34159626).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2001 High

    The identification of ARHGAP9 as a multi-domain RhoGAP with preferential activity toward Cdc42 and Rac1 established its enzymatic function and first linked it to cell adhesion regulation in hematopoietic cells.

    Evidence In vitro GAP activity assay with recombinant protein and adhesion assays in KG-1 leukemia cells

    PMID:11396949

    Open questions at the time
    • Mechanism by which GAP activity is regulated in cells was not addressed
    • Relative contribution of each domain to cellular adhesion phenotype not dissected
  2. 2007 High

    Structural determination of the PH domain–inositol phosphate complexes revealed a non-canonical phosphoinositide-binding pocket accommodating multiple lipid headgroups, explaining how ARHGAP9 could be recruited to diverse membrane microenvironments.

    Evidence X-ray crystallography of PH domain with Ins(1,3,4)P3, Ins(1,4,5)P3, and Ins(1,3,5)P3; mutagenesis and in vitro binding assays

    PMID:17339315

    Open questions at the time
    • Whether PH domain lipid binding is required for GAP activity in cells was not tested
    • Physiological membrane context of PH domain engagement not established
  3. 2007 Medium

    Discovery that the WW domain of ARHGAP9 directly sequesters Erk2 and p38α away from their upstream kinases uncovered a GAP-independent signaling function, demonstrating that ARHGAP9 integrates Rho-GTPase and MAP kinase pathway regulation.

    Evidence Co-immunoprecipitation, overexpression of wild-type and WW-domain mutant ARHGAP9 in Swiss 3T3 fibroblasts with EGFR stimulation

    PMID:17284314

    Open questions at the time
    • Endogenous interaction with MAP kinases not validated
    • Whether WW-mediated MAPK sequestration occurs in hematopoietic cells is unknown
    • Structural basis of WW–CD domain interaction not resolved
  4. 2009 Medium

    Characterization of the Ala370Ser polymorphism showed that a single residue change attenuates ARHGAP9's Rac-GAP activity and anti-migratory function, linking natural human genetic variation to altered ARHGAP9 activity.

    Evidence In vitro Rac-GAP assay and cell migration/spreading/adhesion assays comparing wild-type and A370S ARHGAP9

    PMID:19911011

    Open questions at the time
    • Coronary artery spasm association is genetic correlation, not mechanistically explained
    • Whether A370S affects GAP domain structure or substrate access is unresolved
  5. 2018 Medium

    Identification of the FOXJ2–E-cadherin axis as a downstream effector of ARHGAP9 provided the first transcriptional pathway through which ARHGAP9's GAP activity suppresses cell invasion.

    Evidence RNA-seq, ChIP for FOXJ2 on CDH1 promoter, luciferase reporter, FOXJ2 knockdown rescue, and in vivo lung metastasis assay in HCC models

    PMID:30206221

    Open questions at the time
    • How Rho-GTPase inactivation leads to FOXJ2 upregulation is not defined
    • Generality beyond hepatocellular carcinoma cells not established
  6. 2021 Medium

    Demonstration that SOX4 directly binds and activates the ARHGAP9 promoter in AML cells revealed a first transcriptional regulator of ARHGAP9 and linked its expression to hematopoietic cell proliferation and survival.

    Evidence ChIP assay, luciferase reporter for ARHGAP9 promoter, siRNA knockdown, flow cytometry for cell cycle and apoptosis in AML cells

    PMID:34159626

    Open questions at the time
    • Whether SOX4 regulation of ARHGAP9 operates outside AML is unknown
    • Functional rescue by re-expression of ARHGAP9 after SOX4 knockdown not performed
  7. 2022 Medium

    Placing ARHGAP9 upstream of PI3K/AKT/mTOR suppression and identification of GATA5 as a second direct transcriptional activator extended the signaling framework to colorectal cancer and lung adenocarcinoma, respectively.

    Evidence PI3K inhibitor epistasis rescue in CRC cells with xenograft validation; ChIP and luciferase for GATA5 on ARHGAP9 promoter in LUAD cells

    PMID:35040754 PMID:35679685

    Open questions at the time
    • Direct Rho-GTPase target mediating PI3K/AKT/mTOR suppression not identified
    • Whether GATA5 and SOX4 regulate ARHGAP9 in the same cell lineage is untested
  8. 2023 Medium

    Genetic epistasis experiments showed ARHGAP9 restrains Wnt/β-catenin signaling through DKK2 maintenance, adding a third downstream effector pathway.

    Evidence RNA-seq, DKK2 overexpression rescue in ARHGAP9-knockdown LUAD cells, Wnt reporter assays

    PMID:37454937

    Open questions at the time
    • Mechanism linking Rho-GTPase inactivation to DKK2 transcriptional control is undefined
    • Whether DKK2 axis operates in non-cancer contexts is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • The proximal signaling events connecting ARHGAP9's GAP activity to its diverse transcriptional effector pathways (FOXJ2, PI3K/AKT/mTOR, DKK2/Wnt) remain undefined, and the physiological integration of its GAP-dependent and WW-domain-mediated MAPK-sequestering functions has not been dissected in an endogenous setting.
  • No endogenous loss-of-function study has simultaneously assessed GAP-dependent and WW-domain-dependent signaling
  • Structural basis for how GAP activity is regulated by PH-domain membrane recruitment in cells is lacking
  • Role in normal hematopoiesis versus leukemia not genetically resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0008289 lipid binding 1 GO:0140313 molecular sequestering activity 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-1500931 Cell-Cell communication 2
Partners
CDC42DKK2FOXJ2GATA5MAPK1MAPK14RAC1SOX4

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 ARHGAP9 encodes a Rho-GTPase activating protein with a GAP domain, SH3 domain, PH domain, and WW domain; recombinant protein shows substantial GAP activity toward Cdc42Hs and Rac1 in vitro, and less toward RhoA; exogenous expression in KG-1 hematopoietic cells represses adhesion to fibronectin and collagen IV In vitro GAP activity assay with recombinant protein; overexpression in human leukemia KG-1 cells with adhesion assay readout Biochemical and biophysical research communications High 11396949
2007 The PH domain of ARHGAP9 binds phosphoinositides PI(4,5)P2, PI(3,4,5)P3, and PI(3,4)P2 through a non-canonical binding pocket; crystal structures of the ARHGAP9 PH domain in complex with Ins(1,3,4)P3, Ins(1,4,5)P3, and Ins(1,3,5)P3 reveal two adjacent phosphate positions accommodated through flipped conformations of the bound phospholipid; binding pocket mutations disrupt phosphoinositide binding in vitro X-ray crystallography (crystal structures of PH domain with inositol phosphate headgroups); in vitro phosphoinositide binding assays; mutagenesis of binding pocket residues The Journal of biological chemistry High 17339315
2007 ARHGAP9 acts as a novel MAP kinase docking protein that interacts with Erk2 and p38alpha through complementarily charged residues in its WW domain and the CD domains of Erk2/p38alpha, sequestering MAP kinases in inactive states by displacing MAP kinase kinases; overexpression of wild-type ARHGAP9 suppresses EGFR-induced Erk and p38 activation and preserves actin stress fibres, while a WW-domain mutant defective in MAP kinase binding restores MAP kinase activation and causes stress fibre disruption Co-immunoprecipitation; overexpression of wild-type and WW-domain mutant ARHGAP9 in Swiss 3T3 fibroblasts; EGFR stimulation with MAP kinase activation readout; actin stress fibre imaging Journal of molecular signaling Medium 17284314
2009 ARHGAP9 functions as a RacGAP that negatively regulates cell migration, spreading, and adhesion; the naturally occurring Ala370Ser polymorphism (rs11544238) counteracts ARHGAP9-mediated reduction of cell migration, spreading, and adhesion, and is associated with coronary artery spasm In vitro GAP activity assay for Rac; cell migration, spreading, and adhesion assays comparing wild-type and Ala370Ser variant ARHGAP9 Journal of human genetics Medium 19911011
2018 ARHGAP9 inhibits HCC cell migration and invasion through upregulation of the transcription factor FOXJ2, which directly binds the E-cadherin (CDH1) promoter and enhances its transcription; FOXJ2 knockdown attenuates ARHGAP9's anti-migratory effects; ChIP assay confirmed FOXJ2 binding to CDH1 promoter RNA-seq after ARHGAP9 overexpression; luciferase reporter assay for CDH1 promoter; ChIP assay; FOXJ2 knockdown rescue experiments; transwell migration/invasion assays; in vivo lung metastasis assay Cell death & disease Medium 30206221
2022 ARHGAP9 inhibits colorectal cancer cell proliferation, invasion, and EMT by suppressing activation of the PI3K/AKT/mTOR signaling pathway; knockdown of ARHGAP9 activates this pathway, and pharmacological blockade of PI3K/AKT/mTOR reverses the effects of ARHGAP9 knockdown Overexpression and knockdown in CRC cell lines; Western blot for PI3K/AKT/mTOR pathway components; PI3K inhibitor (LY294002) rescue; xenograft mouse model Tissue & cell Medium 35679685
2023 ARHGAP9 knockdown promotes lung adenocarcinoma metastasis by suppressing DKK2 expression, which activates the Wnt/β-catenin signaling pathway; overexpression of DKK2 in ARHGAP9-knockdown cells reverses the pro-metastatic phenotype and reduces Wnt/β-catenin activity RNA sequencing after ARHGAP9 knockdown; DKK2 overexpression rescue in ARHGAP9-knockdown cells; cell proliferation, migration, invasion assays; Wnt/β-catenin pathway reporter analysis Genomics Medium 37454937
2022 GATA5 transcription factor directly activates ARHGAP9 transcription by binding to the ARHGAP9 promoter; GATA5-induced ARHGAP9 upregulation inhibits lung adenocarcinoma cell proliferation, invasion, and migration; GATA5 silencing reverses the inhibitory effect of ARHGAP9 upregulation on malignant progression Luciferase reporter assay; ChIP assay for GATA5 binding to ARHGAP9 promoter; GATA5 knockdown and ARHGAP9 overexpression rescue experiments; CCK-8, EDU, transwell assays Bioengineered Medium 35040754
2021 SOX4 transcription factor directly binds the ARHGAP9 promoter and drives ARHGAP9 expression in AML cells; ARHGAP9 interference reduces AML cell viability, induces G1 cell cycle arrest, and promotes apoptosis with associated changes in cyclin D1, cyclin E1, CDK4, CDK6, Bcl-2, Bax, and caspase-3/9 Luciferase reporter assay; ChIP assay confirming SOX4 binding to ARHGAP9 promoter; siRNA knockdown; flow cytometry for cell cycle and apoptosis; Western blot Drug development research Medium 34159626
2025 Knockdown of ARHGAP9 significantly inhibits the proliferative capacity of vascular smooth muscle cells (VSMCs), implicating ARHGAP9 in VSMC biology relevant to abdominal aortic aneurysm In vitro ARHGAP9 knockdown in VSMCs with proliferation assay readout; machine learning-based identification from multiomics data Human mutation Low 40995065

Source papers

Stage 0 corpus · 43 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Non-canonical interaction of phosphoinositides with pleckstrin homology domains of Tiam1 and ArhGAP9. The Journal of biological chemistry 82 17339315
2003 Structural and biochemical analysis of Cellvibrio japonicus xylanase 10C: how variation in substrate-binding cleft influences the catalytic profile of family GH-10 xylanases. The Journal of biological chemistry 78 14670951
2005 Protonation, photobleaching, and photoactivation of yellow fluorescent protein (YFP 10C): a unifying mechanism. Biochemistry 77 15807545
2005 Birch PR-10c interacts with several biologically important ligands. Phytochemistry 66 16246382
2001 Isolation of a novel human gene, ARHGAP9, encoding a rho-GTPase activating protein. Biochemical and biophysical research communications 55 11396949
2020 Purple acid phosphatase 10c encodes a major acid phosphatase that regulates plant growth under phosphate-deficient conditions in rice. Journal of experimental botany 53 32270183
2002 Birch PR-10c is induced by factors causing oxidative stress but appears not to confer tolerance to these agents. The New phytologist 38 33873308
2018 ARHGAP9 suppresses the migration and invasion of hepatocellular carcinoma cells through up-regulating FOXJ2/E-cadherin. Cell death & disease 30 30206221
2007 Anomalous negative fluorescence anisotropy in yellow fluorescent protein (YFP 10C): quantitative analysis of FRET in YFP dimers. Biochemistry 30 18027983
2015 Transmission-blocking activity of antibodies to Plasmodium falciparum GLURP.10C chimeric protein formulated in different adjuvants. Malaria journal 27 26552428
2007 ArhGAP9, a novel MAP kinase docking protein, inhibits Erk and p38 activation through WW domain binding. Journal of molecular signaling 27 17284314
2018 Bradykinin-potentiating PEPTIDE-10C, an argininosuccinate synthetase activator, protects against H2O2-induced oxidative stress in SH-SY5Y neuroblastoma cells. Peptides 20 29605732
2009 Mutation of ARHGAP9 in patients with coronary spastic angina. Journal of human genetics 20 19911011
2017 ARHGAP9 siRNA inhibits gastric cancer cell proliferation and EMT via inactivating Akt, p38 signaling and inhibiting MMP2 and MMP9. International journal of clinical and experimental pathology 17 31966562
2007 Tissue distribution in mice of BPP 10c, a potent proline-rich anti-hypertensive peptide of Bothrops jararaca. Toxicon : official journal of the International Society on Toxinology 17 18160089
2021 miR-10c Facilitates White Spot Syndrome Virus Infection by Targeting Toll3 in Litopenaeus vannemei. Frontiers in immunology 16 34950131
2018 Silencing ARHGAP9 correlates with the risk of breast cancer and inhibits the proliferation, migration, and invasion of breast cancer. Journal of cellular biochemistry 16 29905031
2010 Enhancement of the citrulline-nitric oxide cycle in astroglioma cells by the proline-rich peptide-10c from Bothrops jararaca venom. Brain research 16 20875803
2021 The role of ARHGAP9: clinical implication and potential function in acute myeloid leukemia. Journal of translational medicine 15 33579308
1997 Study on the production of a xylanolytic complex from Penicillium canescens 10-10c. Applied biochemistry and biotechnology 13 9382490
2017 Antitumor Activities of the Novel Isosteviol Derivative 10C Against Liver Cancer. Anticancer research 11 28373419
2023 ARHGAP9 knockdown promotes lung adenocarcinoma metastasis by activating Wnt/β-catenin signaling pathway via suppressing DKK2. Genomics 10 37454937
2022 GATA binding protein 5 (GATA5) induces Rho GTPase activating protein 9 (ARHGAP9) to inhibit the malignant process of lung adenocarcinoma cells. Bioengineered 9 35040754
2022 ARHGAP9 inhibits colorectal cancer cell proliferation, invasion and EMT via targeting PI3K/AKT/mTOR signaling pathway. Tissue & cell 9 35679685
2017 Expression, Purification and Characterization of GMZ2'.10C, a Complex Disulphide-Bonded Fusion Protein Vaccine Candidate against the Asexual and Sexual Life-Stages of the Malaria-Causing Plasmodium falciparum Parasite. Pharmaceutical research 9 28646324
2021 SOX4-induced upregulation of ARHGAP9 promotes the progression of acute myeloid leukemia. Drug development research 8 34159626
2021 Mummichog gill and operculum exhibit functionally consistent claudin-10 paralog profiles and Claudin-10c hypersaline response. Biology open 6 34308991
2018 BJ-PRO-7A and BJ-PRO-10C induce vasodilatation and inotropic effects in normotensive and hypertensive rats: Role of nitric oxide and muscarinic receptors. Peptides 6 30355532
2013 A bradykinin-potentiating peptide (BPP-10c) from Bothrops jararaca induces changes in seminiferous tubules. The journal of venomous animals and toxins including tropical diseases 6 24195771
2020 Diagnostic performance of the ClearLLab 10C B cell tube. Cytometry. Part B, Clinical cytometry 5 32961011
2014 Isoindolone derivative QSN-10c induces leukemic cell apoptosis and suppresses angiogenesis via PI3K/AKT signaling pathway inhibition. Acta pharmacologica Sinica 4 24786233
2000 Underutilization of the V kappa 10C gene in the B cell repertoire is due to the loss of productive VJ rearrangements during B cell development. Journal of immunology (Baltimore, Md. : 1950) 4 10878359
2023 The Moonlighting Function of Soybean Disordered Methyl-CpG-Binding Domain 10c Protein. International journal of molecular sciences 3 37240035
2022 Rho GTPase Activating Protein 9 (ARHGAP9) in Human Cancers. Recent patents on anti-cancer drug discovery 3 34365932
2018 Clinical impact of the alpha-galactosidase A gene single nucleotide polymorphism -10C>T: A single-center observational study. Medicine 3 29794742
2025 miR-10c Targets dgat2 and Affects the Expression of Genes Involved in Fatty Acid and Triglyceride Metabolism in Oreochromis niloticus Under Heat Stress. International journal of molecular sciences 1 41096982
2024 ClearLLab 10C reagents panel can be applied to analyze paucicellular samples by flow cytometry. Cytometry. Part B, Clinical cytometry 1 39558485
2002 Influence of a new axial impeller on K(L)a and xylanase production by Penicillium canescens 10-10c. Applied biochemistry and biotechnology 1 12018228
2025 Generation of an induced pluripotent stem cell line (NCHi023-A) from a 41-year-old male with nemaline myopathy carrying autosomal dominant ACTA1 c.809-10C>A mutation. Stem cell research 0 40147060
2025 Identification of ARHGAP9 as a Key Diagnostic Marker for Abdominal Aortic Aneurysm by Multiomics and Experimental Validation. Human mutation 0 40995065
2024 The potential Role of CYP2D6*10(c.100 C>T) Gene Polymorphism in Kidney Injury of Patients with Hypertension Complicated with Non-Elevated Cystatin C. Cardiovascular toxicology 0 38867055
2023 rol-6 and dpy-10C. elegans mutants have normal mitochondrial function after normalizing to delayed development. microPublication biology 0 37215639
2023 Bj-PRO-10c, as an allosteric regulator of argininosuccinate synthase, is a potential therapy for neuroblastoma metastasis. Toxicon : official journal of the International Society on Toxinology 0 37479190