{"gene":"ARHGAP10","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2005,"finding":"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.","method":"Yeast two-hybrid screen, siRNA knockdown, colocalization imaging, in vitro GAP activity assay, overexpression studies","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interaction validated, in vitro GAP activity assay, loss-of-function with defined cellular phenotypes, multiple orthogonal methods in a single focused study","pmids":["16184169"],"is_preprint":false},{"year":2001,"finding":"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.","method":"Yeast two-hybrid, in vitro pulldown (purified SH3 domain), co-immunoprecipitation, in vitro GTPase-activating assay, in vitro kinase assay","journal":"Journal of biochemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro GAP assay, direct pulldown, co-IP, and in vitro kinase assay all in one study; multiple orthogonal methods","pmids":["11432776"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Co-immunoprecipitation, Cdc42 activity assay (pulldown of GTP-bound Cdc42), overexpression in cancer cell lines","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and functional activity assay in cells, single lab, two orthogonal methods","pmids":["27010858"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Co-localization imaging, co-immunoprecipitation/pulldown identifying direct MICAL1 and WDR44 interactions, dominant-negative overexpression, CRISPR/siRNA knockout, membrane tubulation assay, trafficking assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding partners identified, knockout phenotype with specific cargo readout, dominant-negative validation, multiple orthogonal methods in a single rigorous study","pmids":["32344433"],"is_preprint":false},{"year":2020,"finding":"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.","method":"CNV/missense variant analysis, reporter mouse expression profiling, mouse model generation (missense + frameshift), phospho-Western blot, iPSC differentiation, Rho-kinase inhibitor rescue","journal":"Translational psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mouse model with pathway readout and pharmacological rescue, single lab, multiple methods; GAP domain variant assignment is biochemically inferred, not directly reconstituted","pmids":["32699248"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Phospho-Western blot (MYPT1, PAK), morphological analysis of neurons, c-Fos immunostaining, methamphetamine challenge in Arhgap10 S490P/NHEJ mice","journal":"Molecular brain","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined phosphoprotein readout in genetic mouse model, single lab, replicated from companion study","pmids":["33482876"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Pharmacological rescue with fasudil (Rho-kinase inhibitor), phospho-Western blot (MYPT1), spine density quantification, touchscreen visual discrimination task","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistatic rescue experiment linking ARHGAP10 to RhoA/ROCK pathway in vivo, single lab, multiple phenotypic readouts","pmids":["36462727"],"is_preprint":false},{"year":2019,"finding":"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.","method":"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","journal":"OncoTargets and therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss- and gain-of-function with pathway inhibitor epistasis, single lab, multiple methods","pmids":["31920339"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Overexpression and knockdown, Western blot for EMT markers and PI3K/Akt/GSK3β pathway components, immunofluorescence, IGF-1 rescue experiment, Transwell/scratch assays","journal":"Cancer cell international","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway inference by pharmacological rescue, no direct biochemical link between ARHGAP10 GAP activity and PI3K demonstrated","pmids":["34174897"],"is_preprint":false},{"year":2019,"finding":"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.","method":"CXCR4 inhibitor (AMD3100) and VEGFR2 inhibitor (SU1498) treatment, overexpression and knockdown, in vitro invasion assay, in vivo lung metastasis assay","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pharmacological epistasis without direct biochemical mechanistic linkage","pmids":["31445707"],"is_preprint":false},{"year":2024,"finding":"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.","method":"ChIP assay (SMAD4 binding to ARHGAP10 promoter), Western blot, Seahorse extracellular flux analysis (OCR/ECAR), AKT inhibitor rescue, overexpression studies","journal":"Cancer reports (Hoboken, N.J.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP directly demonstrates SMAD4-ARHGAP10 promoter binding; functional pathway inferred by inhibitor rescue, single lab","pmids":["38230565"],"is_preprint":false},{"year":2024,"finding":"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.","method":"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","journal":"Frontiers in bioscience (Landmark edition)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for epigenetic regulation, gain/loss-of-function with pharmacological rescue, single lab, multiple methods","pmids":["38812318"],"is_preprint":false},{"year":2025,"finding":"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.","method":"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","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro microtubule binding with mutagenesis, CRISPR KO with defined phenotype, complementation with structure-function analysis; single lab but multiple rigorous orthogonal methods","pmids":["40889677"],"is_preprint":false},{"year":2025,"finding":"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.","method":"CRISPR/Cas9 deletion in Xenopus tropicalis, live imaging and immunostaining (basal body localization), actin staining, cilia morphology analysis, cardiac looping phenotype assessment","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO in model organism with specific subcellular localization and defined phenotypic readouts; preprint, single lab","pmids":["41280016"],"is_preprint":true},{"year":2024,"finding":"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.","method":"Pharmacological inhibition with KD025 (selective ROCK2 inhibitor), phospho-Western blot (MYPT1), spine density quantification, behavioral assays in Arhgap10 S490P/NHEJ mice","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistatic rescue with selective inhibitor in genetic mouse model, replicated from peer-reviewed work, preprint","pmids":["bio_10.1101_2024.09.16.613372"],"is_preprint":true}],"current_model":"ARHGAP10 (GRAF2) is a multidomain RhoGAP protein (BAR-PH-RhoGAP-SH3) that functions as a GTPase-activating protein for RhoA and Cdc42 (but not Rac1), operating at cell-cell junctions (where it binds alpha-catenin and regulates cortical actin), on microtubule-associated endosomal tubules (where its BAR domain tubulates membranes and it directly interacts with MICAL1 and WDR44 to mediate Rab8/10/11-dependent exocytic trafficking of E-cadherin, MMP14, and CFTR), at osteoclast actin rings (where microtubule binding via BAR domain K37/K41/K44 and RHO-GTPase inhibition are both required for bone resorption), and at cilia basal bodies (where it recruits FAK to regulate ciliogenesis); its SH3 domain binds PKNbeta, which phosphorylates ARHGAP10, and upstream SMAD4 and histone acetylation regulate its transcription; loss of ARHGAP10 function hyperactivates RhoA/ROCK signaling, causing spine morphology defects and cognitive vulnerability relevant to schizophrenia."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2001,"claim":"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","pmids":["11432776"],"confidence":"High","gaps":["Functional consequence of PKNbeta phosphorylation of GRAF2 not determined","No cellular phenotype tied to the interaction"]},{"year":2005,"claim":"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","pmids":["16184169"],"confidence":"High","gaps":["How junctional recruitment is regulated unresolved","Relative contribution of RhoA versus Cdc42 inactivation at junctions unclear"]},{"year":2016,"claim":"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","pmids":["27010858"],"confidence":"Medium","gaps":["Single cell line","No reciprocal validation of the interaction"]},{"year":2020,"claim":"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","pmids":["32344433"],"confidence":"High","gaps":["Whether GAP activity is required for the trafficking role not dissected","Mechanism coordinating BAR tubulation with Rab handoff unresolved"]},{"year":2020,"claim":"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","pmids":["32699248"],"confidence":"Medium","gaps":["GAP-domain variant effect inferred, not reconstituted biochemically","Direct demonstration that RhoA is the relevant in vivo substrate lacking"]},{"year":2021,"claim":"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","pmids":["33482876"],"confidence":"Medium","gaps":["Cell-type specificity of the phenotype not defined","Behavioral consequences not yet causally tied to spine changes"]},{"year":2024,"claim":"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)","pmids":["36462727","bio_10.1101_2024.09.16.613372"],"confidence":"Medium","gaps":["Direct biochemical link between the S490P GAP domain and RhoA activation still inferred","Generalizability beyond the mouse model untested"]},{"year":2024,"claim":"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","pmids":["38230565","38812318"],"confidence":"Medium","gaps":["Whether metabolic/ferroptosis effects depend on GAP activity not established","Single lab and tumor context"]},{"year":2025,"claim":"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","pmids":["40889677"],"confidence":"High","gaps":["Structural basis of BAR-microtubule binding not solved","How microtubule binding and GAP activity are coordinated mechanistically unclear"]},{"year":2025,"claim":"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)","pmids":["41280016"],"confidence":"Medium","gaps":["Preprint, single model organism","Whether FAK recruitment depends on GAP or microtubule-binding activity unknown"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,2,12]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[12]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[3]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[3]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[12]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[13]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,4,6]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[3]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[4,5,6]}],"complexes":[],"partners":["CTNNA1","PKNB","CDC42","RHOA","MICAL1","WDR44","PTK2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5T5U3","full_name":"Rho GTPase-activating protein 21","aliases":["Rho GTPase-activating protein 10","Rho-type GTPase-activating protein 21"],"length_aa":1958,"mass_kda":217.5,"function":"Functions as a GTPase-activating protein (GAP) for RHOA and CDC42. Downstream partner of ARF1 which may control Golgi apparatus structure and function. Also required for CTNNA1 recruitment to adherens junctions","subcellular_location":"Golgi apparatus membrane; Cell junction; Cytoplasmic vesicle membrane; Cytoplasm, cytoskeleton","url":"https://www.uniprot.org/uniprotkb/Q5T5U3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ARHGAP10","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ARHGAP10","total_profiled":1310},"omim":[{"mim_id":"610714","title":"PROTEIN KINASE N3; PKN3","url":"https://www.omim.org/entry/610714"},{"mim_id":"609870","title":"RHO GTPase-ACTIVATING PROTEIN 21; ARHGAP21","url":"https://www.omim.org/entry/609870"},{"mim_id":"609746","title":"RHO GTPase-ACTIVATING PROTEIN 10; ARHGAP10","url":"https://www.omim.org/entry/609746"},{"mim_id":"605370","title":"RHO GTPase-ACTIVATING PROTEIN 26; ARHGAP26","url":"https://www.omim.org/entry/605370"},{"mim_id":"605022","title":"p21 PROTEIN-ACTIVATED KINASE 2; PAK2","url":"https://www.omim.org/entry/605022"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nuclear membrane","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ARHGAP10"},"hgnc":{"alias_symbol":["FLJ20896","FLJ41791","GRAF2"],"prev_symbol":[]},"alphafold":{"accession":"Q5T5U3","domains":[{"cath_id":"2.30.42.10","chopping":"50-73_97-177","consensus_level":"high","plddt":81.3566,"start":50,"end":177},{"cath_id":"2.30.29.30","chopping":"931-1042_1052-1060","consensus_level":"medium","plddt":79.9372,"start":931,"end":1060},{"cath_id":"1.10.555.10","chopping":"1155-1340","consensus_level":"high","plddt":92.4513,"start":1155,"end":1340}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5T5U3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5T5U3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5T5U3-F1-predicted_aligned_error_v6.png","plddt_mean":44.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ARHGAP10","jax_strain_url":"https://www.jax.org/strain/search?query=ARHGAP10"},"sequence":{"accession":"Q5T5U3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5T5U3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5T5U3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5T5U3"}},"corpus_meta":[{"pmid":"16184169","id":"PMC_16184169","title":"ARHGAP10 is necessary for alpha-catenin recruitment at adherens junctions and for Listeria invasion.","date":"2005","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/16184169","citation_count":90,"is_preprint":false},{"pmid":"27010858","id":"PMC_27010858","title":"ARHGAP10, downregulated in ovarian cancer, suppresses tumorigenicity of ovarian cancer cells.","date":"2016","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/27010858","citation_count":57,"is_preprint":false},{"pmid":"32699248","id":"PMC_32699248","title":"ARHGAP10, which encodes Rho GTPase-activating protein 10, is a novel gene for schizophrenia risk.","date":"2020","source":"Translational psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/32699248","citation_count":51,"is_preprint":false},{"pmid":"12056806","id":"PMC_12056806","title":"ARHGAP10, a novel human gene coding for a potentially cytoskeletal Rho-GTPase activating protein.","date":"2002","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/12056806","citation_count":49,"is_preprint":false},{"pmid":"31920339","id":"PMC_31920339","title":"ARHGAP10 Inhibits the Proliferation and Metastasis of CRC Cells via Blocking the Activity of RhoA/AKT Signaling Pathway.","date":"2019","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/31920339","citation_count":46,"is_preprint":false},{"pmid":"11432776","id":"PMC_11432776","title":"PKNbeta interacts with the SH3 domains of Graf and a novel Graf related protein, Graf2, which are GTPase activating proteins for Rho family.","date":"2001","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11432776","citation_count":43,"is_preprint":false},{"pmid":"32344433","id":"PMC_32344433","title":"GRAF2, WDR44, and MICAL1 mediate Rab8/10/11-dependent export of E-cadherin, MMP14, and CFTR ΔF508.","date":"2020","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/32344433","citation_count":32,"is_preprint":false},{"pmid":"29246308","id":"PMC_29246308","title":"miR-3174 Contributes to Apoptosis and Autophagic Cell Death Defects in Gastric Cancer Cells by Targeting ARHGAP10.","date":"2017","source":"Molecular therapy. 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N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/38230565","citation_count":5,"is_preprint":false},{"pmid":"38812318","id":"PMC_38812318","title":"ARHGAP10, Transcriptionally Regulated by Sodium Butyrate, Promotes Ferroptosis of Ovarian Cancer Cells.","date":"2024","source":"Frontiers in bioscience (Landmark edition)","url":"https://pubmed.ncbi.nlm.nih.gov/38812318","citation_count":3,"is_preprint":false},{"pmid":"41280016","id":"PMC_41280016","title":"Integrative Functional Genomics Identifies ARHGAP10 in the 4q31.2 Locus as a Novel Congenital Heart Disease and Ciliopathy Gene.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41280016","citation_count":1,"is_preprint":false},{"pmid":"40889677","id":"PMC_40889677","title":"ARHGAP10 is a novel microtubule-associated protein that regulates the resorption activity of osteoclasts.","date":"2025","source":"The Journal of biological 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Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/35614989","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.09.16.613372","title":"Antipsychotic-like effects of the selective Rho-kinase 2 inhibitor KD025 in genetic and pharmacological mouse models of schizophrenia","date":"2024-09-21","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.16.613372","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16636,"output_tokens":4604,"usd":0.059484,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12626,"output_tokens":3748,"usd":0.078415,"stage2_stop_reason":"end_turn"},"total_usd":0.137899,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid screen, siRNA knockdown, colocalization imaging, in vitro GAP activity assay, overexpression studies\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal interaction validated, in vitro GAP activity assay, loss-of-function with defined cellular phenotypes, multiple orthogonal methods in a single focused study\",\n      \"pmids\": [\"16184169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid, in vitro pulldown (purified SH3 domain), co-immunoprecipitation, in vitro GTPase-activating assay, in vitro kinase assay\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro GAP assay, direct pulldown, co-IP, and in vitro kinase assay all in one study; multiple orthogonal methods\",\n      \"pmids\": [\"11432776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, Cdc42 activity assay (pulldown of GTP-bound Cdc42), overexpression in cancer cell lines\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and functional activity assay in cells, single lab, two orthogonal methods\",\n      \"pmids\": [\"27010858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Co-localization imaging, co-immunoprecipitation/pulldown identifying direct MICAL1 and WDR44 interactions, dominant-negative overexpression, CRISPR/siRNA knockout, membrane tubulation assay, trafficking assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding partners identified, knockout phenotype with specific cargo readout, dominant-negative validation, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"32344433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"CNV/missense variant analysis, reporter mouse expression profiling, mouse model generation (missense + frameshift), phospho-Western blot, iPSC differentiation, Rho-kinase inhibitor rescue\",\n      \"journal\": \"Translational psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mouse model with pathway readout and pharmacological rescue, single lab, multiple methods; GAP domain variant assignment is biochemically inferred, not directly reconstituted\",\n      \"pmids\": [\"32699248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Phospho-Western blot (MYPT1, PAK), morphological analysis of neurons, c-Fos immunostaining, methamphetamine challenge in Arhgap10 S490P/NHEJ mice\",\n      \"journal\": \"Molecular brain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined phosphoprotein readout in genetic mouse model, single lab, replicated from companion study\",\n      \"pmids\": [\"33482876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Pharmacological rescue with fasudil (Rho-kinase inhibitor), phospho-Western blot (MYPT1), spine density quantification, touchscreen visual discrimination task\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistatic rescue experiment linking ARHGAP10 to RhoA/ROCK pathway in vivo, single lab, multiple phenotypic readouts\",\n      \"pmids\": [\"36462727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss- and gain-of-function with pathway inhibitor epistasis, single lab, multiple methods\",\n      \"pmids\": [\"31920339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Overexpression and knockdown, Western blot for EMT markers and PI3K/Akt/GSK3β pathway components, immunofluorescence, IGF-1 rescue experiment, Transwell/scratch assays\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway inference by pharmacological rescue, no direct biochemical link between ARHGAP10 GAP activity and PI3K demonstrated\",\n      \"pmids\": [\"34174897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"CXCR4 inhibitor (AMD3100) and VEGFR2 inhibitor (SU1498) treatment, overexpression and knockdown, in vitro invasion assay, in vivo lung metastasis assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pharmacological epistasis without direct biochemical mechanistic linkage\",\n      \"pmids\": [\"31445707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP assay (SMAD4 binding to ARHGAP10 promoter), Western blot, Seahorse extracellular flux analysis (OCR/ECAR), AKT inhibitor rescue, overexpression studies\",\n      \"journal\": \"Cancer reports (Hoboken, N.J.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP directly demonstrates SMAD4-ARHGAP10 promoter binding; functional pathway inferred by inhibitor rescue, single lab\",\n      \"pmids\": [\"38230565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Frontiers in bioscience (Landmark edition)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for epigenetic regulation, gain/loss-of-function with pharmacological rescue, single lab, multiple methods\",\n      \"pmids\": [\"38812318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro microtubule binding with mutagenesis, CRISPR KO with defined phenotype, complementation with structure-function analysis; single lab but multiple rigorous orthogonal methods\",\n      \"pmids\": [\"40889677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"CRISPR/Cas9 deletion in Xenopus tropicalis, live imaging and immunostaining (basal body localization), actin staining, cilia morphology analysis, cardiac looping phenotype assessment\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO in model organism with specific subcellular localization and defined phenotypic readouts; preprint, single lab\",\n      \"pmids\": [\"41280016\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Pharmacological inhibition with KD025 (selective ROCK2 inhibitor), phospho-Western blot (MYPT1), spine density quantification, behavioral assays in Arhgap10 S490P/NHEJ mice\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistatic rescue with selective inhibitor in genetic mouse model, replicated from peer-reviewed work, preprint\",\n      \"pmids\": [\"bio_10.1101_2024.09.16.613372\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"ARHGAP10 (GRAF2) is a multidomain RhoGAP protein (BAR-PH-RhoGAP-SH3) that functions as a GTPase-activating protein for RhoA and Cdc42 (but not Rac1), operating at cell-cell junctions (where it binds alpha-catenin and regulates cortical actin), on microtubule-associated endosomal tubules (where its BAR domain tubulates membranes and it directly interacts with MICAL1 and WDR44 to mediate Rab8/10/11-dependent exocytic trafficking of E-cadherin, MMP14, and CFTR), at osteoclast actin rings (where microtubule binding via BAR domain K37/K41/K44 and RHO-GTPase inhibition are both required for bone resorption), and at cilia basal bodies (where it recruits FAK to regulate ciliogenesis); its SH3 domain binds PKNbeta, which phosphorylates ARHGAP10, and upstream SMAD4 and histone acetylation regulate its transcription; loss of ARHGAP10 function hyperactivates RhoA/ROCK signaling, causing spine morphology defects and cognitive vulnerability relevant to schizophrenia.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #1, #12]. 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 [#0]. 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 \\u0394F508 to the plasma membrane [#3]. 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 [#12]. 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 [#1, #10, #11]. 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 [#4, #5, #6, #14].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"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.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro SH3 pulldown, co-IP, in vitro GAP assay, and in vitro kinase assay with PKNbeta\",\n      \"pmids\": [\"11432776\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of PKNbeta phosphorylation of GRAF2 not determined\", \"No cellular phenotype tied to the interaction\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"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.\",\n      \"evidence\": \"Yeast two-hybrid against alpha-catenin, siRNA knockdown, colocalization, in vitro GAP assay, and Listeria entry assays\",\n      \"pmids\": [\"16184169\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How junctional recruitment is regulated unresolved\", \"Relative contribution of RhoA versus Cdc42 inactivation at junctions unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP and GTP-Cdc42 pulldown activity assay in A2780 ovarian cancer cells\",\n      \"pmids\": [\"27010858\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single cell line\", \"No reciprocal validation of the interaction\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"Colocalization, direct interaction mapping (MICAL1, WDR44), membrane tubulation assay, CRISPR/siRNA knockout, and cargo trafficking assays for E-cadherin, MMP14, CFTR\",\n      \"pmids\": [\"32344433\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GAP activity is required for the trafficking role not dissected\", \"Mechanism coordinating BAR tubulation with Rab handoff unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"p.S490P missense/frameshift mouse model, phospho-Western (MYPT1, PAK), iPSC-derived neurons, and Y-27632 rescue\",\n      \"pmids\": [\"32699248\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"GAP-domain variant effect inferred, not reconstituted biochemically\", \"Direct demonstration that RhoA is the relevant in vivo substrate lacking\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Reinforced the RhoA/ROCK morphology link by showing increased spine density and pathway phosphorylation in additional brain regions of the genetic model.\",\n      \"evidence\": \"Phospho-Western (MYPT1, PAK), spine morphology analysis, and methamphetamine challenge in Arhgap10 S490P/NHEJ mice\",\n      \"pmids\": [\"33482876\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-type specificity of the phenotype not defined\", \"Behavioral consequences not yet causally tied to spine changes\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Provided epistatic proof that RhoA/ROCK hyperactivation is causal for the spine phenotype by pharmacologically rescuing it, and refined the effector to ROCK2.\",\n      \"evidence\": \"Fasudil and selective ROCK2 inhibitor KD025 rescue, phospho-MYPT1 Western, spine density quantification, and behavioral tasks (one preprint)\",\n      \"pmids\": [\"36462727\", \"bio_10.1101_2024.09.16.613372\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical link between the S490P GAP domain and RhoA activation still inferred\", \"Generalizability beyond the mouse model untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"ChIP for SMAD4 and H3K9ac at the ARHGAP10 promoter, Seahorse flux analysis, ferroptosis marker assays, and inhibitor rescue in ovarian cancer cells\",\n      \"pmids\": [\"38230565\", \"38812318\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether metabolic/ferroptosis effects depend on GAP activity not established\", \"Single lab and tumor context\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"evidence\": \"CRISPR/Cas9 knockout, direct microtubule binding assay, K37/K41/K44 mutagenesis, complementation, and bone resorption assays\",\n      \"pmids\": [\"40889677\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of BAR-microtubule binding not solved\", \"How microtubule binding and GAP activity are coordinated mechanistically unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"evidence\": \"CRISPR/Cas9 deletion in Xenopus tropicalis, basal body imaging, actin staining, and cardiac looping phenotyping (preprint)\",\n      \"pmids\": [\"41280016\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, single model organism\", \"Whether FAK recruitment depends on GAP or microtubule-binding activity unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 2, 12]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 4, 6]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [4, 5, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CTNNA1\", \"PKNB\", \"CDC42\", \"RHOA\", \"MICAL1\", \"WDR44\", \"PTK2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}