{"gene":"ARHGAP11A","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2018,"finding":"ARHGAP11A directly interacts with Rac1B independent of its Rho GTPase-activating activity, and this interaction mediates HCC malignant phenotypes including proliferation, invasion, migration and EMT; Rac1B blockade interrupts ARHGAP11A-elicited malignancy.","method":"Co-immunoprecipitation, knockdown/overexpression in HCC cell lines, in vivo xenograft models","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction shown, single lab, multiple orthogonal cellular assays including in vivo rescue","pmids":["30545369"],"is_preprint":false},{"year":2016,"finding":"ARHGAP11A acts as an oncoprotein (rather than a tumor suppressor) in basal-like breast cancer, functioning as a RHOA GAP with oncogenic properties in a context-dependent manner distinct from the tumor-suppressive DLC1 RHOA GAP.","method":"Functional cell-based assays, expression analysis in cancer subtypes; commentary summarizing experimental findings","journal":"Small GTPases","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional characterization described across cancer subtypes, single lab, mechanistic context provided but abstract-level detail limited","pmids":["27657701"],"is_preprint":false},{"year":2023,"finding":"Arhgap11a mRNA is specifically localized to the basal endfeet of radial glial cells (RGCs) via its 5' UTR, and locally translated there; this local translation of ARHGAP11A is essential for RGC basal endfeet morphology and for correct positioning of interneurons at the basement membrane, acting through local Rho signaling.","method":"In situ hybridization (mRNA localization), live imaging, 5' UTR reporter constructs, mRNA transport inhibition, loss-of-function in mouse and human cortical tissue","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (localization, functional UTR constructs, transport inhibition, KO phenotype rescue) in two species","pmids":["36924763"],"is_preprint":false},{"year":2021,"finding":"ARHGAP11A interacts with TPM1 (tropomyosin 1) to regulate actin filament stability, thereby promoting gastric cancer cell migration and invasion.","method":"Co-immunoprecipitation, ARHGAP11A knockout in vitro and in vivo, actin stability assays","journal":"Journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO with defined cellular phenotype and co-IP binding partner identified, single lab","pmids":["34912455"],"is_preprint":false},{"year":2024,"finding":"The hGID/GID4 E3 ubiquitin ligase complex binds and ubiquitinates ARHGAP11A, targeting it for proteasomal degradation. GID4 depletion or inhibition of its substrate-binding pocket stabilizes ARHGAP11A at the cell periphery, where it inactivates RhoA and impairs directed cell migration.","method":"BioID2 proximity biotinylation, biochemical ubiquitination assays, GID4 depletion/inhibitor (PFI-7), cell motility assays, localization imaging","journal":"Life science alliance","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods: proximity proteomics, biochemical ubiquitination assay, pharmacological and genetic perturbation, localization and functional readouts in single rigorous study","pmids":["39389782"],"is_preprint":false},{"year":2023,"finding":"ArhGAP11A promotes amyloid-β generation in neurons by sustaining expression of APP, PS1, and BACE1 through the RhoA/ROCK/Erk signaling pathway; reducing ArhGAP11A decreases Aβ production, plaque deposition, neuroinflammation, and cognitive deficits in APP/PS1 mice. Aβ oligomers enhance ArhGAP11A expression via E2F1 activation, forming a feed-forward loop.","method":"Neuronal-specific knockdown in APP/PS1 mice, Western blot for pathway components, behavioral assays, E2F1 reporter assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function with defined molecular pathway, single lab, multiple readouts","pmids":["37302068"],"is_preprint":false},{"year":2023,"finding":"During mitosis, Haspin kinase regulates Rho-ROCK activity through ARHGAP11A, and ROCK in turn activates LIMK1 and stabilizes the actin cytoskeleton to support spindle orientation. This Haspin-ARHGAP11A-Rho-ROCK-LIMK1-Cofilin axis is required for proper epithelial morphogenesis in 3D cultures.","method":"Epistasis/genetic pathway analysis, kinase inhibition, 3D cell culture morphogenesis assays, phospho-LIMK1/Cofilin readouts","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with pharmacological rescue, defined pathway order, single lab","pmids":["37841592"],"is_preprint":false},{"year":2025,"finding":"ARHGAP11A maintains apical progenitor identity and ventricular zone integrity in human cortical organoids through the RHOA-ROCK-actin axis; CRISPR-Cas9 knockout of ARHGAP11A randomizes mitotic cleavage-plane orientation, causes premature AP delamination and AP depletion, and reduces glial numbers; pharmacological inhibition of RHOA or ROCK rescues these defects.","method":"CRISPR-Cas9 knockout in human forebrain organoids, cleavage-plane orientation measurements, pharmacological rescue with RHOA/ROCK inhibitors","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — CRISPR KO in human organoids with defined mechanistic pathway, pharmacological rescue with two independent inhibitors, multiple cellular phenotype readouts","pmids":["41307995"],"is_preprint":false},{"year":2022,"finding":"miR-211-5p targets the Arhgap11a 3' UTR (validated by dual-luciferase assay) and upregulates Arhgap11a expression in MC3T3-E1 osteoblast cells; this miR-211-5p/Arhgap11a interaction promotes osteogenic differentiation.","method":"Dual-luciferase reporter assay, miRNA mimic/inhibitor overexpression, RT-qPCR","journal":"Frontiers in surgery","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, luciferase validation but paradoxical miRNA-upregulation relationship not fully mechanistically resolved","pmids":["35495761"],"is_preprint":false},{"year":2025,"finding":"Knockdown of ARHGAP11A in lung adenocarcinoma cells reduces FAM83A and LDHA expression, implicating ARHGAP11A upstream of FAM83A in regulating glycolysis, cell cycle progression, proliferation, apoptosis resistance, migration, and mitochondrial membrane potential.","method":"siRNA knockdown, Western blot, RT-qPCR, CCK-8, flow cytometry, glycolysis assays","journal":"Translational cancer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single knockdown approach, no direct binding or mechanistic reconstitution shown","pmids":["41674985"],"is_preprint":false}],"current_model":"ARHGAP11A is a RhoGAP that inactivates RhoA (and interacts with Rac1B in a GAP-independent manner) and is regulated spatiotemporally: its mRNA is transported to and locally translated in radial glial cell basal endfeet via the 5' UTR, where it controls cortical progenitor morphology and neuronal positioning through Rho signaling; during mitosis, Haspin kinase channels signals through ARHGAP11A to regulate the Rho-ROCK-LIMK1-Cofilin axis for spindle orientation; in cortical progenitors, ARHGAP11A maintains apical progenitor identity and ventricular zone integrity via the RHOA-ROCK-actin axis; the hGID/GID4 E3 ligase ubiquitinates ARHGAP11A for proteasomal degradation, and its levels at the cell periphery control RhoA inactivation and directed cell migration; additional context-dependent interactions include TPM1 binding for actin stability and an upstream role in neuronal APP/PS1/BACE1 expression through RhoA/ROCK/Erk."},"narrative":{"mechanistic_narrative":"ARHGAP11A is a Rho GTPase-activating protein that inactivates RhoA and controls actin cytoskeletal dynamics in contexts ranging from cortical neurogenesis to mitotic spindle orientation and directed cell migration [PMID:39389782, PMID:41307995]. In developing cortex its mRNA is delivered to the basal endfeet of radial glial cells through its 5' UTR and locally translated, where it shapes endfoot morphology and positions interneurons at the basement membrane via local Rho signaling [PMID:36924763], while in apical progenitors it sustains progenitor identity and ventricular zone integrity through the RHOA-ROCK-actin axis, with its loss randomizing mitotic cleavage-plane orientation and depleting progenitors—defects rescued by RHOA or ROCK inhibition [PMID:41307995]. The same RhoA-ROCK output is deployed in mitosis, where Haspin kinase channels signals through ARHGAP11A to engage ROCK-LIMK1-Cofilin and stabilize actin for proper spindle orientation and epithelial morphogenesis [PMID:37841592]. ARHGAP11A protein levels are restricted by the hGID/GID4 E3 ubiquitin ligase, which ubiquitinates it for proteasomal degradation; relieving this degradation stabilizes ARHGAP11A at the cell periphery, where it inactivates RhoA and impairs directed migration [PMID:39389782]. Beyond canonical GAP activity it engages additional partners—Rac1B in a GAP-independent manner to drive carcinoma malignancy [PMID:30545369] and TPM1 to regulate actin filament stability [PMID:34912455]—and acts as a context-dependent oncoprotein in basal-like breast cancer [PMID:27657701].","teleology":[{"year":2016,"claim":"Established that ARHGAP11A, despite being a RhoA GAP, functions as a context-dependent oncoprotein rather than a tumor suppressor, distinguishing it from canonical tumor-suppressive RhoA GAPs.","evidence":"Functional cell-based and expression assays across breast cancer subtypes","pmids":["27657701"],"confidence":"Medium","gaps":["Molecular basis of oncogenic versus tumor-suppressive context not resolved","No direct substrate or partner mapping in this study"]},{"year":2018,"claim":"Showed ARHGAP11A can act independently of its GAP activity, binding Rac1B to drive carcinoma malignancy, revealing a non-canonical effector mode.","evidence":"Co-IP, knockdown/overexpression in HCC lines, xenograft rescue","pmids":["30545369"],"confidence":"Medium","gaps":["Structural basis of GAP-independent Rac1B binding unknown","Single lab; not extended to other tumor types"]},{"year":2021,"claim":"Identified TPM1 as a physical partner linking ARHGAP11A to actin filament stability, connecting it to cytoskeletal regulation in cancer cell motility.","evidence":"Co-IP, knockout in vitro/in vivo, actin stability assays in gastric cancer","pmids":["34912455"],"confidence":"Medium","gaps":["Whether TPM1 binding depends on GAP activity not resolved","Single binding partner; reciprocal validation limited"]},{"year":2022,"claim":"Reported post-transcriptional regulation by miR-211-5p targeting the Arhgap11a 3' UTR during osteoblast differentiation.","evidence":"Dual-luciferase reporter, miRNA mimic/inhibitor, RT-qPCR in MC3T3-E1 cells","pmids":["35495761"],"confidence":"Low","gaps":["Paradoxical miRNA-driven upregulation not mechanistically explained","Single lab; no functional link to Rho signaling demonstrated"]},{"year":2023,"claim":"Demonstrated spatial control of ARHGAP11A through 5' UTR-dependent mRNA localization and local translation in radial glial basal endfeet, establishing it as a locally synthesized regulator of cortical progenitor morphology and neuronal positioning.","evidence":"In situ hybridization, 5' UTR reporters, transport inhibition, loss-of-function in mouse and human tissue","pmids":["36924763"],"confidence":"High","gaps":["Identity of the transport machinery recognizing the 5' UTR unknown","Local Rho effectors at endfeet not enumerated"]},{"year":2023,"claim":"Placed ARHGAP11A within a mitotic Haspin-Rho-ROCK-LIMK1-Cofilin axis required for spindle orientation and 3D epithelial morphogenesis, linking it to cell-cycle cytoskeletal control.","evidence":"Genetic epistasis, kinase inhibition, 3D morphogenesis assays, phospho-LIMK1/Cofilin readouts","pmids":["37841592"],"confidence":"Medium","gaps":["Direct biochemical link between Haspin and ARHGAP11A not shown","How ARHGAP11A is positioned at the spindle unknown"]},{"year":2023,"claim":"Connected ARHGAP11A to amyloid-β pathology via a RhoA/ROCK/Erk pathway sustaining APP/PS1/BACE1, embedded in an E2F1-driven feed-forward loop.","evidence":"Neuronal knockdown in APP/PS1 mice, Western blot, behavior, E2F1 reporter assays","pmids":["37302068"],"confidence":"Medium","gaps":["Whether GAP activity is required for the APP-axis effect not tested","Direct molecular target downstream of ARHGAP11A unclear"]},{"year":2024,"claim":"Identified the hGID/GID4 E3 ligase as the degradative regulator of ARHGAP11A, showing that its abundance at the cell periphery sets the level of RhoA inactivation and directed migration.","evidence":"BioID2 proximity proteomics, ubiquitination assays, GID4 depletion/PFI-7 inhibitor, motility and localization imaging","pmids":["39389782"],"confidence":"High","gaps":["Degron sequence recognized by GID4 not mapped","Upstream signals controlling GID4-mediated turnover unknown"]},{"year":2025,"claim":"Showed in human cortical organoids that ARHGAP11A maintains apical progenitor identity and cleavage-plane orientation through the RHOA-ROCK-actin axis, with pharmacological RHOA/ROCK inhibition rescuing knockout defects.","evidence":"CRISPR-Cas9 KO in forebrain organoids, cleavage-plane measurements, RHOA/ROCK inhibitor rescue","pmids":["41307995"],"confidence":"High","gaps":["How ARHGAP11A spatially restricts RhoA at the apical surface unknown","Relationship to its basal-endfoot local-translation role not integrated"]},{"year":2025,"claim":"Implicated ARHGAP11A upstream of FAM83A/LDHA in lung adenocarcinoma glycolysis and proliferation, extending its oncogenic reach to metabolic reprogramming.","evidence":"siRNA knockdown, Western blot, CCK-8, flow cytometry, glycolysis assays","pmids":["41674985"],"confidence":"Low","gaps":["No direct binding or mechanistic link to FAM83A shown","Single knockdown approach; not reconstituted"]},{"year":null,"claim":"How ARHGAP11A's GAP-dependent and GAP-independent activities, its spatially localized translation, and its degradative control are integrated into a unified regulatory logic across neurogenesis, mitosis, and cancer remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the GAP domain or its effector interfaces in the corpus","Determinants selecting RhoA inactivation versus Rac1B/TPM1 binding unknown","Integration of basal local translation with apical RHOA-ROCK control not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,7,6]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[3,6]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,6,7]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,7]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[6,7]}],"complexes":[],"partners":["RAC1B","TPM1","GID4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6P4F7","full_name":"Rho GTPase-activating protein 11A","aliases":["Rho-type GTPase-activating protein 11A"],"length_aa":1023,"mass_kda":113.9,"function":"GTPase activator for the Rho-type GTPases by converting them to an inactive GDP-bound state","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q6P4F7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ARHGAP11A","classification":"Not Classified","n_dependent_lines":248,"n_total_lines":1208,"dependency_fraction":0.2052980132450331},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000198826","cell_line_id":"CID000591","localizations":[{"compartment":"chromatin","grade":3},{"compartment":"nucleoplasm","grade":2}],"interactors":[],"url":"https://opencell.sf.czbiohub.org/target/CID000591","total_profiled":1310},"omim":[{"mim_id":"616310","title":"RHO GTPase-ACTIVATING PROTEIN 11B; ARHGAP11B","url":"https://www.omim.org/entry/616310"},{"mim_id":"610589","title":"RHO GTPase-ACTIVATING PROTEIN 11A; ARHGAP11A","url":"https://www.omim.org/entry/610589"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Nucleoli","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":22.5},{"tissue":"lymphoid tissue","ntpm":24.2}],"url":"https://www.proteinatlas.org/search/ARHGAP11A"},"hgnc":{"alias_symbol":["KIAA0013"],"prev_symbol":[]},"alphafold":{"accession":"Q6P4F7","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6P4F7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6P4F7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6P4F7-F1-predicted_aligned_error_v6.png","plddt_mean":51.34},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ARHGAP11A","jax_strain_url":"https://www.jax.org/strain/search?query=ARHGAP11A"},"sequence":{"accession":"Q6P4F7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6P4F7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6P4F7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6P4F7"}},"corpus_meta":[{"pmid":"30545369","id":"PMC_30545369","title":"Blockade of ARHGAP11A reverses malignant progress via inactivating Rac1B in hepatocellular carcinoma.","date":"2018","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/30545369","citation_count":38,"is_preprint":false},{"pmid":"27657701","id":"PMC_27657701","title":"Filling GAPs in our knowledge: ARHGAP11A and RACGAP1 act as oncogenes in basal-like breast cancers.","date":"2016","source":"Small GTPases","url":"https://pubmed.ncbi.nlm.nih.gov/27657701","citation_count":36,"is_preprint":false},{"pmid":"36924763","id":"PMC_36924763","title":"Subcellular mRNA localization and local translation of Arhgap11a in radial glial progenitors regulates cortical development.","date":"2023","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/36924763","citation_count":27,"is_preprint":false},{"pmid":"34912455","id":"PMC_34912455","title":"ARHGAP11A Promotes the Malignant Progression of Gastric Cancer by Regulating the Stability of Actin Filaments through TPM1.","date":"2021","source":"Journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34912455","citation_count":11,"is_preprint":false},{"pmid":"39389782","id":"PMC_39389782","title":"The hGIDGID4 E3 ubiquitin ligase complex targets ARHGAP11A to regulate cell migration.","date":"2024","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/39389782","citation_count":10,"is_preprint":false},{"pmid":"37302068","id":"PMC_37302068","title":"ArhGAP11A mediates amyloid-β generation and neuropathology in an Alzheimer's disease-like mouse model.","date":"2023","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/37302068","citation_count":8,"is_preprint":false},{"pmid":"34487020","id":"PMC_34487020","title":"LINC01207 promotes the progression of non-small cell lung cancer via regulating ARHGAP11A by sponging miR-525-5p.","date":"2022","source":"Cancer biomarkers : section A of Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/34487020","citation_count":8,"is_preprint":false},{"pmid":"35754342","id":"PMC_35754342","title":"MicroRNA-30c-2-3p represses malignant progression of gastric adenocarcinoma cells via targeting ARHGAP11A.","date":"2022","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/35754342","citation_count":5,"is_preprint":false},{"pmid":"37841592","id":"PMC_37841592","title":"A Haspin-ARHGAP11A axis regulates epithelial morphogenesis through Rho-ROCK dependent modulation of LIMK1-Cofilin.","date":"2023","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/37841592","citation_count":4,"is_preprint":false},{"pmid":"39482272","id":"PMC_39482272","title":"Machine learning models reveal ARHGAP11A's impact on lymph node metastasis and stemness in NSCLC.","date":"2024","source":"BioFactors (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/39482272","citation_count":3,"is_preprint":false},{"pmid":"35495761","id":"PMC_35495761","title":"Involvement of MiRNA-211-5p and Arhgap11a Interaction During Osteogenic Differentiation of MC3T3-E1 Cells.","date":"2022","source":"Frontiers in surgery","url":"https://pubmed.ncbi.nlm.nih.gov/35495761","citation_count":2,"is_preprint":false},{"pmid":"41307995","id":"PMC_41307995","title":"ARHGAP11A maintains cortical progenitor identity through RHOA-ROCK signaling during human brain development.","date":"2025","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/41307995","citation_count":1,"is_preprint":false},{"pmid":"38046902","id":"PMC_38046902","title":"Protooncogenic Role of ARHGAP11A and ARHGAP11B in Invasive Ductal Carcinoma: Two Promising Breast Cancer Biomarkers.","date":"2023","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/38046902","citation_count":1,"is_preprint":false},{"pmid":"40104729","id":"PMC_40104729","title":"Specific effects of hypoxia-immune core gene ARHGAP11A on lung adenocarcinoma.","date":"2025","source":"Translational cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/40104729","citation_count":1,"is_preprint":false},{"pmid":"42168117","id":"PMC_42168117","title":"Hsa-Let-7c-3p Inhibits Retinoblastoma Cell Growth and Metastasis and Induces Pyroptosis by Targeting ARHGAP11A.","date":"2026","source":"APMIS : acta pathologica, microbiologica, et immunologica Scandinavica","url":"https://pubmed.ncbi.nlm.nih.gov/42168117","citation_count":0,"is_preprint":false},{"pmid":"41674985","id":"PMC_41674985","title":"ARHGAP11A affects lung adenocarcinoma (LUAD) and pancreatic adenocarcinoma (PAAD) progression by regulating FAM83A.","date":"2026","source":"Translational cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/41674985","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11039,"output_tokens":2559,"usd":0.035751,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9761,"output_tokens":3410,"usd":0.067028,"stage2_stop_reason":"end_turn"},"total_usd":0.102779,"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\": 2018,\n      \"finding\": \"ARHGAP11A directly interacts with Rac1B independent of its Rho GTPase-activating activity, and this interaction mediates HCC malignant phenotypes including proliferation, invasion, migration and EMT; Rac1B blockade interrupts ARHGAP11A-elicited malignancy.\",\n      \"method\": \"Co-immunoprecipitation, knockdown/overexpression in HCC cell lines, in vivo xenograft models\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction shown, single lab, multiple orthogonal cellular assays including in vivo rescue\",\n      \"pmids\": [\"30545369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ARHGAP11A acts as an oncoprotein (rather than a tumor suppressor) in basal-like breast cancer, functioning as a RHOA GAP with oncogenic properties in a context-dependent manner distinct from the tumor-suppressive DLC1 RHOA GAP.\",\n      \"method\": \"Functional cell-based assays, expression analysis in cancer subtypes; commentary summarizing experimental findings\",\n      \"journal\": \"Small GTPases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional characterization described across cancer subtypes, single lab, mechanistic context provided but abstract-level detail limited\",\n      \"pmids\": [\"27657701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Arhgap11a mRNA is specifically localized to the basal endfeet of radial glial cells (RGCs) via its 5' UTR, and locally translated there; this local translation of ARHGAP11A is essential for RGC basal endfeet morphology and for correct positioning of interneurons at the basement membrane, acting through local Rho signaling.\",\n      \"method\": \"In situ hybridization (mRNA localization), live imaging, 5' UTR reporter constructs, mRNA transport inhibition, loss-of-function in mouse and human cortical tissue\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (localization, functional UTR constructs, transport inhibition, KO phenotype rescue) in two species\",\n      \"pmids\": [\"36924763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ARHGAP11A interacts with TPM1 (tropomyosin 1) to regulate actin filament stability, thereby promoting gastric cancer cell migration and invasion.\",\n      \"method\": \"Co-immunoprecipitation, ARHGAP11A knockout in vitro and in vivo, actin stability assays\",\n      \"journal\": \"Journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO with defined cellular phenotype and co-IP binding partner identified, single lab\",\n      \"pmids\": [\"34912455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The hGID/GID4 E3 ubiquitin ligase complex binds and ubiquitinates ARHGAP11A, targeting it for proteasomal degradation. GID4 depletion or inhibition of its substrate-binding pocket stabilizes ARHGAP11A at the cell periphery, where it inactivates RhoA and impairs directed cell migration.\",\n      \"method\": \"BioID2 proximity biotinylation, biochemical ubiquitination assays, GID4 depletion/inhibitor (PFI-7), cell motility assays, localization imaging\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods: proximity proteomics, biochemical ubiquitination assay, pharmacological and genetic perturbation, localization and functional readouts in single rigorous study\",\n      \"pmids\": [\"39389782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ArhGAP11A promotes amyloid-β generation in neurons by sustaining expression of APP, PS1, and BACE1 through the RhoA/ROCK/Erk signaling pathway; reducing ArhGAP11A decreases Aβ production, plaque deposition, neuroinflammation, and cognitive deficits in APP/PS1 mice. Aβ oligomers enhance ArhGAP11A expression via E2F1 activation, forming a feed-forward loop.\",\n      \"method\": \"Neuronal-specific knockdown in APP/PS1 mice, Western blot for pathway components, behavioral assays, E2F1 reporter assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function with defined molecular pathway, single lab, multiple readouts\",\n      \"pmids\": [\"37302068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"During mitosis, Haspin kinase regulates Rho-ROCK activity through ARHGAP11A, and ROCK in turn activates LIMK1 and stabilizes the actin cytoskeleton to support spindle orientation. This Haspin-ARHGAP11A-Rho-ROCK-LIMK1-Cofilin axis is required for proper epithelial morphogenesis in 3D cultures.\",\n      \"method\": \"Epistasis/genetic pathway analysis, kinase inhibition, 3D cell culture morphogenesis assays, phospho-LIMK1/Cofilin readouts\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with pharmacological rescue, defined pathway order, single lab\",\n      \"pmids\": [\"37841592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ARHGAP11A maintains apical progenitor identity and ventricular zone integrity in human cortical organoids through the RHOA-ROCK-actin axis; CRISPR-Cas9 knockout of ARHGAP11A randomizes mitotic cleavage-plane orientation, causes premature AP delamination and AP depletion, and reduces glial numbers; pharmacological inhibition of RHOA or ROCK rescues these defects.\",\n      \"method\": \"CRISPR-Cas9 knockout in human forebrain organoids, cleavage-plane orientation measurements, pharmacological rescue with RHOA/ROCK inhibitors\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — CRISPR KO in human organoids with defined mechanistic pathway, pharmacological rescue with two independent inhibitors, multiple cellular phenotype readouts\",\n      \"pmids\": [\"41307995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"miR-211-5p targets the Arhgap11a 3' UTR (validated by dual-luciferase assay) and upregulates Arhgap11a expression in MC3T3-E1 osteoblast cells; this miR-211-5p/Arhgap11a interaction promotes osteogenic differentiation.\",\n      \"method\": \"Dual-luciferase reporter assay, miRNA mimic/inhibitor overexpression, RT-qPCR\",\n      \"journal\": \"Frontiers in surgery\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, luciferase validation but paradoxical miRNA-upregulation relationship not fully mechanistically resolved\",\n      \"pmids\": [\"35495761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Knockdown of ARHGAP11A in lung adenocarcinoma cells reduces FAM83A and LDHA expression, implicating ARHGAP11A upstream of FAM83A in regulating glycolysis, cell cycle progression, proliferation, apoptosis resistance, migration, and mitochondrial membrane potential.\",\n      \"method\": \"siRNA knockdown, Western blot, RT-qPCR, CCK-8, flow cytometry, glycolysis assays\",\n      \"journal\": \"Translational cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single knockdown approach, no direct binding or mechanistic reconstitution shown\",\n      \"pmids\": [\"41674985\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ARHGAP11A is a RhoGAP that inactivates RhoA (and interacts with Rac1B in a GAP-independent manner) and is regulated spatiotemporally: its mRNA is transported to and locally translated in radial glial cell basal endfeet via the 5' UTR, where it controls cortical progenitor morphology and neuronal positioning through Rho signaling; during mitosis, Haspin kinase channels signals through ARHGAP11A to regulate the Rho-ROCK-LIMK1-Cofilin axis for spindle orientation; in cortical progenitors, ARHGAP11A maintains apical progenitor identity and ventricular zone integrity via the RHOA-ROCK-actin axis; the hGID/GID4 E3 ligase ubiquitinates ARHGAP11A for proteasomal degradation, and its levels at the cell periphery control RhoA inactivation and directed cell migration; additional context-dependent interactions include TPM1 binding for actin stability and an upstream role in neuronal APP/PS1/BACE1 expression through RhoA/ROCK/Erk.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ARHGAP11A is a Rho GTPase-activating protein that inactivates RhoA and controls actin cytoskeletal dynamics in contexts ranging from cortical neurogenesis to mitotic spindle orientation and directed cell migration [#4, #7]. In developing cortex its mRNA is delivered to the basal endfeet of radial glial cells through its 5' UTR and locally translated, where it shapes endfoot morphology and positions interneurons at the basement membrane via local Rho signaling [#2], while in apical progenitors it sustains progenitor identity and ventricular zone integrity through the RHOA-ROCK-actin axis, with its loss randomizing mitotic cleavage-plane orientation and depleting progenitors—defects rescued by RHOA or ROCK inhibition [#7]. The same RhoA-ROCK output is deployed in mitosis, where Haspin kinase channels signals through ARHGAP11A to engage ROCK-LIMK1-Cofilin and stabilize actin for proper spindle orientation and epithelial morphogenesis [#6]. ARHGAP11A protein levels are restricted by the hGID/GID4 E3 ubiquitin ligase, which ubiquitinates it for proteasomal degradation; relieving this degradation stabilizes ARHGAP11A at the cell periphery, where it inactivates RhoA and impairs directed migration [#4]. Beyond canonical GAP activity it engages additional partners—Rac1B in a GAP-independent manner to drive carcinoma malignancy [#0] and TPM1 to regulate actin filament stability [#3]—and acts as a context-dependent oncoprotein in basal-like breast cancer [#1].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Established that ARHGAP11A, despite being a RhoA GAP, functions as a context-dependent oncoprotein rather than a tumor suppressor, distinguishing it from canonical tumor-suppressive RhoA GAPs.\",\n      \"evidence\": \"Functional cell-based and expression assays across breast cancer subtypes\",\n      \"pmids\": [\"27657701\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of oncogenic versus tumor-suppressive context not resolved\", \"No direct substrate or partner mapping in this study\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed ARHGAP11A can act independently of its GAP activity, binding Rac1B to drive carcinoma malignancy, revealing a non-canonical effector mode.\",\n      \"evidence\": \"Co-IP, knockdown/overexpression in HCC lines, xenograft rescue\",\n      \"pmids\": [\"30545369\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of GAP-independent Rac1B binding unknown\", \"Single lab; not extended to other tumor types\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified TPM1 as a physical partner linking ARHGAP11A to actin filament stability, connecting it to cytoskeletal regulation in cancer cell motility.\",\n      \"evidence\": \"Co-IP, knockout in vitro/in vivo, actin stability assays in gastric cancer\",\n      \"pmids\": [\"34912455\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TPM1 binding depends on GAP activity not resolved\", \"Single binding partner; reciprocal validation limited\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Reported post-transcriptional regulation by miR-211-5p targeting the Arhgap11a 3' UTR during osteoblast differentiation.\",\n      \"evidence\": \"Dual-luciferase reporter, miRNA mimic/inhibitor, RT-qPCR in MC3T3-E1 cells\",\n      \"pmids\": [\"35495761\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Paradoxical miRNA-driven upregulation not mechanistically explained\", \"Single lab; no functional link to Rho signaling demonstrated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated spatial control of ARHGAP11A through 5' UTR-dependent mRNA localization and local translation in radial glial basal endfeet, establishing it as a locally synthesized regulator of cortical progenitor morphology and neuronal positioning.\",\n      \"evidence\": \"In situ hybridization, 5' UTR reporters, transport inhibition, loss-of-function in mouse and human tissue\",\n      \"pmids\": [\"36924763\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the transport machinery recognizing the 5' UTR unknown\", \"Local Rho effectors at endfeet not enumerated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed ARHGAP11A within a mitotic Haspin-Rho-ROCK-LIMK1-Cofilin axis required for spindle orientation and 3D epithelial morphogenesis, linking it to cell-cycle cytoskeletal control.\",\n      \"evidence\": \"Genetic epistasis, kinase inhibition, 3D morphogenesis assays, phospho-LIMK1/Cofilin readouts\",\n      \"pmids\": [\"37841592\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical link between Haspin and ARHGAP11A not shown\", \"How ARHGAP11A is positioned at the spindle unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected ARHGAP11A to amyloid-β pathology via a RhoA/ROCK/Erk pathway sustaining APP/PS1/BACE1, embedded in an E2F1-driven feed-forward loop.\",\n      \"evidence\": \"Neuronal knockdown in APP/PS1 mice, Western blot, behavior, E2F1 reporter assays\",\n      \"pmids\": [\"37302068\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether GAP activity is required for the APP-axis effect not tested\", \"Direct molecular target downstream of ARHGAP11A unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified the hGID/GID4 E3 ligase as the degradative regulator of ARHGAP11A, showing that its abundance at the cell periphery sets the level of RhoA inactivation and directed migration.\",\n      \"evidence\": \"BioID2 proximity proteomics, ubiquitination assays, GID4 depletion/PFI-7 inhibitor, motility and localization imaging\",\n      \"pmids\": [\"39389782\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Degron sequence recognized by GID4 not mapped\", \"Upstream signals controlling GID4-mediated turnover unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed in human cortical organoids that ARHGAP11A maintains apical progenitor identity and cleavage-plane orientation through the RHOA-ROCK-actin axis, with pharmacological RHOA/ROCK inhibition rescuing knockout defects.\",\n      \"evidence\": \"CRISPR-Cas9 KO in forebrain organoids, cleavage-plane measurements, RHOA/ROCK inhibitor rescue\",\n      \"pmids\": [\"41307995\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ARHGAP11A spatially restricts RhoA at the apical surface unknown\", \"Relationship to its basal-endfoot local-translation role not integrated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated ARHGAP11A upstream of FAM83A/LDHA in lung adenocarcinoma glycolysis and proliferation, extending its oncogenic reach to metabolic reprogramming.\",\n      \"evidence\": \"siRNA knockdown, Western blot, CCK-8, flow cytometry, glycolysis assays\",\n      \"pmids\": [\"41674985\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct binding or mechanistic link to FAM83A shown\", \"Single knockdown approach; not reconstituted\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ARHGAP11A's GAP-dependent and GAP-independent activities, its spatially localized translation, and its degradative control are integrated into a unified regulatory logic across neurogenesis, mitosis, and cancer remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the GAP domain or its effector interfaces in the corpus\", \"Determinants selecting RhoA inactivation versus Rac1B/TPM1 binding unknown\", \"Integration of basal local translation with apical RHOA-ROCK control not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 7, 6]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [3, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 6, 7]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 7]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RAC1B\", \"TPM1\", \"GID4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":5,"faith_total":5,"faith_pct":100.0}}