Affinage

ARHGAP10

Rho GTPase-activating protein 21 · UniProt Q5T5U3

Length
1958 aa
Mass
217.5 kDa
Annotated
2026-06-09
25 papers in source corpus 15 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ARHGAP10 (GRAF2) is a multidomain RhoGAP that inactivates the small GTPases RhoA and Cdc42, but not Rac1, and couples this activity to actin remodeling and membrane trafficking at multiple cellular sites (PMID:16184169, PMID:11432776, PMID:40889677). It localizes to cell-cell junctions where it binds alpha-catenin, controls cortical actin organization, and is exploited as an entry route by Listeria monocytogenes (PMID:16184169). Through its BAR domain it tubulates membranes and operates on endosomal tubules, where direct interactions with MICAL1 (linking it to Rab8/10) and WDR44 (linking it to Rab11) drive the exocytic export of newly synthesized E-cadherin, MMP14, and CFTR ΔF508 to the plasma membrane (PMID:32344433). In osteoclasts the BAR-PH module directly binds microtubules via lysines K37/K41/K44, and both microtubule binding and Rho-GTPase inhibitory activity are jointly required for actin ring formation and bone resorption (PMID:40889677). ARHGAP10 transcription is activated by SMAD4 binding at its promoter and by H3K9 acetylation, while its SH3 domain binds PKNbeta, which in turn phosphorylates ARHGAP10 (PMID:11432776, PMID:38230565, PMID:38812318). Loss of ARHGAP10 GAP function hyperactivates RhoA/ROCK2 signaling, elevating MYPT1 and PAK phosphorylation and producing dendritic spine and neurite abnormalities that are reversed by Rho-kinase inhibition, a circuit linked to schizophrenia through a patient-derived p.S490P GAP-domain variant [PMID:32699248, PMID:33482876, PMID:36462727, PMID:bio_10.1101_2024.09.16.613372].

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2001 High

    Established the core biochemical identity of GRAF2/ARHGAP10 as a selective RhoGAP and identified its first physical partner, defining its substrate specificity and a candidate regulatory input.

    Evidence Yeast two-hybrid, in vitro SH3 pulldown, co-IP, in vitro GAP assay, and in vitro kinase assay with PKNbeta

    PMID:11432776

    Open questions at the time
    • Functional consequence of PKNbeta phosphorylation of GRAF2 not determined
    • No cellular phenotype tied to the interaction
  2. 2005 High

    Placed ARHGAP10 at adherens junctions and connected its GAP activity to cortical actin organization, showing it is a junctional regulator and a target of bacterial invasion machinery.

    Evidence Yeast two-hybrid against alpha-catenin, siRNA knockdown, colocalization, in vitro GAP assay, and Listeria entry assays

    PMID:16184169

    Open questions at the time
    • How junctional recruitment is regulated unresolved
    • Relative contribution of RhoA versus Cdc42 inactivation at junctions unclear
  3. 2016 Medium

    Confirmed Cdc42 as a cellular substrate by demonstrating direct binding and suppression of Cdc42 activity, extending the in vitro GAP specificity into a cancer cell context.

    Evidence Co-IP and GTP-Cdc42 pulldown activity assay in A2780 ovarian cancer cells

    PMID:27010858

    Open questions at the time
    • Single cell line
    • No reciprocal validation of the interaction
  4. 2020 High

    Defined a trafficking function distinct from GAP activity: the BAR domain tubulates membranes and recruits MICAL1 and WDR44 to drive Rab8/10/11-dependent exocytic delivery of specific cargo.

    Evidence Colocalization, direct interaction mapping (MICAL1, WDR44), membrane tubulation assay, CRISPR/siRNA knockout, and cargo trafficking assays for E-cadherin, MMP14, CFTR

    PMID:32344433

    Open questions at the time
    • Whether GAP activity is required for the trafficking role not dissected
    • Mechanism coordinating BAR tubulation with Rab handoff unresolved
  5. 2020 Medium

    Linked ARHGAP10 loss-of-function to RhoA/Rho-kinase hyperactivation and neuronal morphology defects, establishing a disease-relevant signaling axis via a schizophrenia patient variant.

    Evidence p.S490P missense/frameshift mouse model, phospho-Western (MYPT1, PAK), iPSC-derived neurons, and Y-27632 rescue

    PMID:32699248

    Open questions at the time
    • GAP-domain variant effect inferred, not reconstituted biochemically
    • Direct demonstration that RhoA is the relevant in vivo substrate lacking
  6. 2021 Medium

    Reinforced the RhoA/ROCK morphology link by showing increased spine density and pathway phosphorylation in additional brain regions of the genetic model.

    Evidence Phospho-Western (MYPT1, PAK), spine morphology analysis, and methamphetamine challenge in Arhgap10 S490P/NHEJ mice

    PMID:33482876

    Open questions at the time
    • Cell-type specificity of the phenotype not defined
    • Behavioral consequences not yet causally tied to spine changes
  7. 2024 Medium

    Provided epistatic proof that RhoA/ROCK hyperactivation is causal for the spine phenotype by pharmacologically rescuing it, and refined the effector to ROCK2.

    Evidence Fasudil and selective ROCK2 inhibitor KD025 rescue, phospho-MYPT1 Western, spine density quantification, and behavioral tasks (one preprint)

    PMID:36462727 PMID:bio_10.1101_2024.09.16.613372

    Open questions at the time
    • Direct biochemical link between the S490P GAP domain and RhoA activation still inferred
    • Generalizability beyond the mouse model untested
  8. 2024 Medium

    Identified transcriptional and epigenetic control of ARHGAP10, showing SMAD4 and H3K9 acetylation activate its expression and linking it to metabolic and ferroptosis programs in cancer.

    Evidence ChIP for SMAD4 and H3K9ac at the ARHGAP10 promoter, Seahorse flux analysis, ferroptosis marker assays, and inhibitor rescue in ovarian cancer cells

    PMID:38230565 PMID:38812318

    Open questions at the time
    • Whether metabolic/ferroptosis effects depend on GAP activity not established
    • Single lab and tumor context
  9. 2025 High

    Revealed ARHGAP10 as a microtubule-associated protein whose dual microtubule-binding and Rho-GTPase inhibitory activities are both required for osteoclast actin ring formation and bone resorption.

    Evidence CRISPR/Cas9 knockout, direct microtubule binding assay, K37/K41/K44 mutagenesis, complementation, and bone resorption assays

    PMID:40889677

    Open questions at the time
    • Structural basis of BAR-microtubule binding not solved
    • How microtubule binding and GAP activity are coordinated mechanistically unclear
  10. 2025 Medium

    Extended ARHGAP10 function to ciliogenesis, showing it localizes to basal bodies and recruits FAK to ciliary adhesion complexes, with deletion causing cilia and left-right patterning defects.

    Evidence CRISPR/Cas9 deletion in Xenopus tropicalis, basal body imaging, actin staining, and cardiac looping phenotyping (preprint)

    PMID:41280016

    Open questions at the time
    • Preprint, single model organism
    • Whether FAK recruitment depends on GAP or microtubule-binding activity unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ARHGAP10's distinct activities — GAP catalysis, BAR-domain membrane/microtubule binding, and partner-mediated recruitment — are integrated and selected for context-specific roles across junctions, endosomes, osteoclasts, cilia, and neurons remains unresolved.
  • No structural model integrating BAR, PH, GAP, and SH3 functions
  • Substrate selection (RhoA vs Cdc42) per cellular context undefined
  • Physiological regulator of GAP activity in vivo unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0060090 molecular adaptor activity 2 GO:0008092 cytoskeletal protein binding 1 GO:0008289 lipid binding 1
Localization
GO:0005886 plasma membrane 2 GO:0005768 endosome 1 GO:0005815 microtubule organizing center 1 GO:0005856 cytoskeleton 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-112316 Neuronal System 3 R-HSA-5653656 Vesicle-mediated transport 1
Partners
CDC42CTNNA1MICAL1PKNBPTK2RHOAWDR44

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 ARHGAP10 was identified as a direct binding partner of alpha-catenin via yeast two-hybrid screen; it colocalizes with alpha-catenin at cell-cell junctions and is recruited to Listeria monocytogenes entry sites. Knockdown impairs alpha-catenin recruitment at cell-cell contacts and L. monocytogenes entry. The GAP domain exhibits GTPase-activating activity toward RhoA and Cdc42. Overexpression disrupts actin cables and enhances cortical actin and alpha-catenin levels at junctions. Yeast two-hybrid screen, siRNA knockdown, colocalization imaging, in vitro GAP activity assay, overexpression studies Nature cell biology High 16184169
2001 GRAF2 (ARHGAP10) was identified as a binding partner of PKNbeta via yeast two-hybrid screening; the SH3 domain of GRAF2 directly binds the proline-rich linker region of PKNbeta in vitro and co-immunoprecipitates with PKNbeta in COS-7 cells. Recombinant GRAF2 exhibits GTPase-activating activity toward RhoA and Cdc42Hs but not Rac1 in vitro. Catalytically active PKNbeta phosphorylates GRAF2 in vitro. Yeast two-hybrid, in vitro pulldown (purified SH3 domain), co-immunoprecipitation, in vitro GTPase-activating assay, in vitro kinase assay Journal of biochemistry High 11432776
2016 ARHGAP10 directly interacts with Cdc42 (shown by co-immunoprecipitation) and overexpression inhibits Cdc42 GTPase activity in ovarian cancer cells (A2780), consistent with its role as a GAP for Cdc42. Co-immunoprecipitation, Cdc42 activity assay (pulldown of GTP-bound Cdc42), overexpression in cancer cell lines Cell death & disease Medium 27010858
2020 ARHGAP10 (GRAF2) colocalizes extensively with Rab8a/b and partially with Rab10 on tubular endosomes; its BAR domain mediates membrane tubulation; it interacts directly with MICAL1 (which links GRAF2 to Rab8/10) and with WDR44 (which binds Rab11). GRAF2 is required for the formation of WDR44-positive tubular endosomes and for the export of neosynthesized E-cadherin, MMP14, and CFTR ΔF508 to the plasma membrane via a Rab8/10/11-dependent pathway. Co-localization imaging, co-immunoprecipitation/pulldown identifying direct MICAL1 and WDR44 interactions, dominant-negative overexpression, CRISPR/siRNA knockout, membrane tubulation assay, trafficking assays The Journal of cell biology High 32344433
2020 A missense variant (p.S490P) in the RhoGAP domain of ARHGAP10 found in a schizophrenia patient is relevant to its association with the active form of RhoA, implying reduced GAP activity toward RhoA. Mouse models carrying this variant plus a frameshift show increased phosphorylation of myosin phosphatase-targeting subunit 1 (MYPT1) and p21-activated kinases in the striatum, consistent with elevated RhoA/Rho-kinase signaling. Primary neurons from these mice exhibit immature neurites, and patient iPSC-derived neurons show reduced neurite length and branching reversed by the Rho-kinase inhibitor Y-27632. CNV/missense variant analysis, reporter mouse expression profiling, mouse model generation (missense + frameshift), phospho-Western blot, iPSC differentiation, Rho-kinase inhibitor rescue Translational psychiatry Medium 32699248
2021 Arhgap10 S490P/NHEJ mice (schizophrenia model) show increased phosphorylation of MYPT1 (Rho-kinase substrate) and PAK in striatum and nucleus accumbens, increased neuronal dendritic spine density and complexity in those regions, indicating that loss of normal ARHGAP10 GAP activity activates RhoA/Rho-kinase signaling and alters neuronal morphology. Phospho-Western blot (MYPT1, PAK), morphological analysis of neurons, c-Fos immunostaining, methamphetamine challenge in Arhgap10 S490P/NHEJ mice Molecular brain Medium 33482876
2022 Rho-kinase inhibitor fasudil suppresses elevated MYPT1 phosphorylation in striatum and mPFC of Arhgap10 S490P/NHEJ mice and rescues reduced spine density in mPFC layer 2/3 pyramidal neurons, establishing that RhoA/Rho-kinase hyperactivation downstream of ARHGAP10 loss-of-function is causal for the spine morphology phenotype. Pharmacological rescue with fasudil (Rho-kinase inhibitor), phospho-Western blot (MYPT1), spine density quantification, touchscreen visual discrimination task Pharmacological research Medium 36462727
2019 In colorectal cancer cells, ARHGAP10 overexpression negatively regulates both RhoA activity and AKT phosphorylation (p-AKT); a Rho/MRTF/SRF inhibitor (CCG-1423) blocks p-AKT elevation caused by ARHGAP10 siRNA, placing ARHGAP10 upstream of RhoA-mediated AKT phosphorylation in CRC. siRNA knockdown, lentiviral overexpression, Western blot for p-AKT, RhoA activity assay, PI3K/AKT inhibitor (LY294002) and CCG-1423 rescue, in vivo lung metastasis model OncoTargets and therapy Medium 31920339
2021 ARHGAP10 overexpression inhibits EMT in NSCLC cells via the PI3K/Akt/GSK3β signaling pathway; activation of IGF-1 signaling reverses ARHGAP10-regulated EMT, placing ARHGAP10 upstream of PI3K/Akt/GSK3β in lung cancer cells. Overexpression and knockdown, Western blot for EMT markers and PI3K/Akt/GSK3β pathway components, immunofluorescence, IGF-1 rescue experiment, Transwell/scratch assays Cancer cell international Low 34174897
2019 CXCL12 stimulation of ovarian cancer cells suppresses ARHGAP10 expression via CXCR4 and downstream VEGF/VEGFR2 signaling; ARHGAP10 overexpression blocks CXCL12-induced invasion, and ARHGAP10 knockdown diminishes the inhibitory effect of VEGFR2 blockade on invasion and lung metastasis, placing ARHGAP10 downstream of the CXCL12/CXCR4/VEGFR2 axis. CXCR4 inhibitor (AMD3100) and VEGFR2 inhibitor (SU1498) treatment, overexpression and knockdown, in vitro invasion assay, in vivo lung metastasis assay Biochemical and biophysical research communications Low 31445707
2024 SMAD4 transcriptionally activates ARHGAP10 expression (demonstrated by ChIP assay showing SMAD4 binding to the ARHGAP10 promoter); ARHGAP10 overexpression suppresses glycolysis in ovarian cancer cells through the PI3K/AKT/HK2 pathway, and this is reversed by the AKT inhibitor LY294002. ChIP assay (SMAD4 binding to ARHGAP10 promoter), Western blot, Seahorse extracellular flux analysis (OCR/ECAR), AKT inhibitor rescue, overexpression studies Cancer reports (Hoboken, N.J.) Medium 38230565
2024 ARHGAP10 overexpression promotes ferroptosis in ovarian cancer cells, decreasing GPX4 and increasing PTGS2 expression and lipid ROS levels; the ferroptosis inhibitor Fer-1 blocks these effects. Sodium butyrate (SB) transcriptionally upregulates ARHGAP10 via H3K9 acetylation at its promoter (shown by ChIP), establishing an SB/ARHGAP10/GPX4 ferroptosis axis. Lentiviral overexpression/silencing, Western blot, flow cytometry (lipid ROS), CCK-8 viability, ChIP assay (H3K9ac at ARHGAP10 promoter), ferroptosis inhibitor/inducer rescue, in vivo tumorigenicity assay Frontiers in bioscience (Landmark edition) Medium 38812318
2025 ARHGAP10 is a novel microtubule-associated protein in osteoclasts: its BAR-PH domain directly binds microtubules, requiring positively charged lysine residues K37, K41, and K44 in the BAR domain. CRISPR/Cas9 knockout of Arhgap10 disrupts actin ring morphology and dynamics and impairs osteoclast bone resorption activity. Complementation experiments show that both microtubule binding and RHO-GTPase (CDC42/RHOA) inhibitory activity are essential for ARHGAP10's role in osteoclast resorption. CRISPR/Cas9 knockout, direct microtubule binding assay, site-directed mutagenesis (K37/K41/K44), complementation with mutant constructs, actin ring morphology/dynamics imaging, bone resorption activity assay The Journal of biological chemistry High 40889677
2025 In Xenopus tropicalis, gap10 (ARHGAP10 ortholog) localizes to basal bodies of motile cilia in multiciliated cells; its deletion disrupts basal body organization, apical actin enrichment, ciliogenesis, and left-right organizer formation, leading to cardiac looping defects. GAP10 recruits focal adhesion kinase (FAK) to specialized ciliary adhesion complexes at basal bodies. CRISPR/Cas9 deletion in Xenopus tropicalis, live imaging and immunostaining (basal body localization), actin staining, cilia morphology analysis, cardiac looping phenotype assessment bioRxivpreprint Medium 41280016
2024 ARHGAP10 negatively regulates RhoA/ROCK2 signaling; selective ROCK2 inhibitor KD025 suppresses elevated MYPT1 phosphorylation and rescues reduced spine density in mPFC of Arhgap10 S490P/NHEJ mice, corroborating that ROCK2 is the downstream effector of RhoA activated by ARHGAP10 loss. Pharmacological inhibition with KD025 (selective ROCK2 inhibitor), phospho-Western blot (MYPT1), spine density quantification, behavioral assays in Arhgap10 S490P/NHEJ mice bioRxivpreprint Medium bio_10.1101_2024.09.16.613372

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 ARHGAP10 is necessary for alpha-catenin recruitment at adherens junctions and for Listeria invasion. Nature cell biology 90 16184169
2016 ARHGAP10, downregulated in ovarian cancer, suppresses tumorigenicity of ovarian cancer cells. Cell death & disease 57 27010858
2020 ARHGAP10, which encodes Rho GTPase-activating protein 10, is a novel gene for schizophrenia risk. Translational psychiatry 51 32699248
2002 ARHGAP10, a novel human gene coding for a potentially cytoskeletal Rho-GTPase activating protein. Biochemical and biophysical research communications 49 12056806
2019 ARHGAP10 Inhibits the Proliferation and Metastasis of CRC Cells via Blocking the Activity of RhoA/AKT Signaling Pathway. OncoTargets and therapy 46 31920339
2001 PKNbeta interacts with the SH3 domains of Graf and a novel Graf related protein, Graf2, which are GTPase activating proteins for Rho family. Journal of biochemistry 43 11432776
2020 GRAF2, WDR44, and MICAL1 mediate Rab8/10/11-dependent export of E-cadherin, MMP14, and CFTR ΔF508. The Journal of cell biology 32 32344433
2017 miR-3174 Contributes to Apoptosis and Autophagic Cell Death Defects in Gastric Cancer Cells by Targeting ARHGAP10. Molecular therapy. Nucleic acids 32 29246308
2020 Serum-Derived Exosomes-Mediated Circular RNA ARHGAP10 Modulates the Progression of Non-Small Cell Lung Cancer Through the miR-638/FAM83F Axis. Cancer biotherapy & radiopharmaceuticals 29 32783691
2017 The roles of ARHGAP10 in the proliferation, migration and invasion of lung cancer cells. Oncology letters 29 28943961
2004 Characterization of human ARHGAP10 gene in silico. International journal of oncology 27 15375573
2019 miR‑337‑3p inhibits gastric tumor metastasis by targeting ARHGAP10. Molecular medicine reports 21 31789419
2021 Mice carrying a schizophrenia-associated mutation of the Arhgap10 gene are vulnerable to the effects of methamphetamine treatment on cognitive function: association with morphological abnormalities in striatal neurons. Molecular brain 17 33482876
2019 CXCL12 promotes human ovarian cancer cell invasion through suppressing ARHGAP10 expression. Biochemical and biophysical research communications 15 31445707
2022 Inhibition of Rho-kinase ameliorates decreased spine density in the medial prefrontal cortex and methamphetamine-induced cognitive dysfunction in mice carrying schizophrenia-associated mutations of the Arhgap10 gene. Pharmacological research 13 36462727
2021 ARHGAP10 inhibits the epithelial-mesenchymal transition of non-small cell lung cancer by inactivating PI3K/Akt/GSK3β signaling pathway. Cancer cell international 12 34174897
2019 Downregulated expression of ARHGAP10 correlates with advanced stage and high Ki-67 index in breast cancer. PeerJ 8 31396458
2023 CircRNA ARHGAP10 promotes osteogenic differentiation through the miR-335-3p/RUNX2 pathway in aortic valve calcification. Journal of thoracic disease 6 38090284
2022 Rho GTPase-activating protein 10 (ARHGAP10/GRAF2) is a novel autoantibody target in patients with autoimmune encephalitis. Journal of neurology 6 35624318
2024 SMAD4 inhibits glycolysis in ovarian cancer through PI3K/AKT/HK2 signaling pathway by activating ARHGAP10. Cancer reports (Hoboken, N.J.) 5 38230565
2024 ARHGAP10, Transcriptionally Regulated by Sodium Butyrate, Promotes Ferroptosis of Ovarian Cancer Cells. Frontiers in bioscience (Landmark edition) 3 38812318
2025 Integrative Functional Genomics Identifies ARHGAP10 in the 4q31.2 Locus as a Novel Congenital Heart Disease and Ciliopathy Gene. bioRxiv : the preprint server for biology 1 41280016
2026 The ARHGAP10-202aa protein encoded by circARHGAP10 promotes skeletal muscle development and regeneration. Journal of genetics and genomics = Yi chuan xue bao 0 41617081
2025 ARHGAP10 is a novel microtubule-associated protein that regulates the resorption activity of osteoclasts. The Journal of biological chemistry 0 40889677
2022 Retraction Notice to: miR-3174 Contributes to Apoptosis and Autophagic Cell Death Defects in Gastric Cancer Cells by Targeting ARHGAP10. Molecular therapy. Nucleic acids 0 35614989

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