{"gene":"ACAP3","run_date":"2026-06-09T22:02:38","timeline":{"discoveries":[{"year":2016,"finding":"ACAP3 functions as a GTPase-activating protein (GAP) specific to Arf6 in mouse hippocampal neurons. Knockdown of ACAP3 abrogated neurite outgrowth, which was rescued by wild-type ACAP3 but not by a GAP-inactive mutant. ACAP3 knockdown significantly increased GTP-bound Arf6 levels, confirming its role as an Arf6 GAP. Cycling between active and inactive forms of Arf6, regulated by ACAP3 together with a guanine-nucleotide-exchange factor, is required for neurite outgrowth.","method":"Primary hippocampal neuron knockdown, rescue with wild-type vs. GAP-inactive mutant, Arf6-GTP pulldown assay, Arf6 fast-cycle mutant rescue experiment, HEK-293T GAP activity assay","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods: in vitro GAP activity assay, active-site mutagenesis rescue, GTP-bound Arf6 measurement, and fast-cycle mutant complementation all converge on the same conclusion","pmids":["27330119"],"is_preprint":false},{"year":2017,"finding":"ACAP3 is required for neuronal migration in the developing mouse cerebral cortex in vivo. In utero knockdown of ACAP3 significantly impaired cortical neuron migration and the associated morphological changes; rescue with wild-type ACAP3 restored migration, but a GAP-inactive mutant did not, indicating the mechanism depends on Arf6 GAP activity.","method":"In utero electroporation-based knockdown in mouse cortex, rescue with wild-type vs. GAP-inactive mutant ACAP3, histological analysis of cortical layering","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean in vivo loss-of-function with defined cellular phenotype, replicated rescue including active-site mutant control, single lab","pmids":["28919417"],"is_preprint":false},{"year":2024,"finding":"HDAC2 negatively regulates ACAP3 expression in papillary thyroid carcinoma (PTC) cells. ACAP3 overexpression suppressed viability, proliferation, migration, and invasion, and promoted apoptosis of PTC cells, modulating AKT and p53 signalling (decreased p-AKT/AKT ratio, increased p-p53/p53 ratio, altered Bcl-2/Bax and E-cadherin/N-cadherin expression); HDAC2 overexpression reversed the tumour-suppressive effects of ACAP3.","method":"qRT-PCR, cell counting kit-8, transwell, wound-healing, flow cytometry assays, Western blot, Pearson correlation analysis, rescue (oe-ACAP3 + oe-HDAC2) experiment","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — multiple functional assays and rescue experiment in cell lines, single lab, no direct biochemical demonstration of HDAC2 binding/deacetylating ACAP3 promoter","pmids":["39098591"],"is_preprint":false},{"year":2026,"finding":"Myc mediates epigenetic silencing of ACAP3 via DNA hypermethylation and deacetylation in lung adenocarcinoma (LUAD). ACAP3 inhibits EGFR signalling by impairing EGFR recycling and accelerating lysosome-mediated EGFR degradation in a GAP activity-dependent manner, thereby suppressing LUAD cell proliferation in vitro and in vivo.","method":"Reduced representation bisulfite sequencing (RRBS), in vitro and in vivo proliferation assays, EGFR recycling and lysosomal degradation assays, GAP-activity-deficient mutant comparison","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (epigenome profiling, functional assays, GAP mutant), single lab, abstract-level detail only","pmids":["41520057"],"is_preprint":false},{"year":2010,"finding":"The intronic minisatellite UPS29 of the ACAP3 (CENTB5) gene possesses enhancer-like activity in neuronal-type cells (rat astrocytes) but not uniformly across cell types, as demonstrated by reporter gene (EGFP) transient transfection assays in HeLa, F9, and rat astrocyte cultures.","method":"Transient transfection of EGFP reporter constructs containing different UPS29 alleles in HeLa, mouse F9 embryonal carcinoma cells, and rat astrocytes","journal":"Tsitologiia","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single reporter assay in cell lines, single lab, no direct demonstration of effect on endogenous ACAP3 protein","pmids":["21105360"],"is_preprint":false}],"current_model":"ACAP3 is a GTPase-activating protein (GAP) selective for the small GTPase Arf6; it promotes neurite outgrowth and cortical neuronal migration in vivo by cycling Arf6 between its GTP- and GDP-bound states, and in cancer cells it suppresses EGFR signalling by impairing receptor recycling and promoting lysosomal EGFR degradation in a GAP-activity-dependent manner, while its own expression is negatively regulated epigenetically by Myc-driven DNA methylation and by HDAC2."},"narrative":{"mechanistic_narrative":"ACAP3 is a GTPase-activating protein (GAP) selective for the small GTPase Arf6 that governs cell morphological dynamics in both neural development and epithelial cancers [PMID:27330119]. In neurons, ACAP3 drives neurite outgrowth by cycling Arf6 between its GTP- and GDP-bound states; loss of ACAP3 raises GTP-bound Arf6 and abolishes outgrowth, a defect rescued by wild-type but not GAP-inactive ACAP3 [PMID:27330119], and the same GAP-dependent activity is required for cortical neuronal migration in vivo [PMID:28919417]. In cancer cells, ACAP3 acts as a tumour suppressor: in lung adenocarcinoma it inhibits EGFR signalling by impairing EGFR recycling and accelerating lysosome-mediated EGFR degradation in a GAP-activity-dependent manner, suppressing proliferation [PMID:41520057], and in papillary thyroid carcinoma it suppresses viability, migration, and invasion while promoting apoptosis through modulation of AKT and p53 signalling [PMID:39098591]. ACAP3 expression is held down epigenetically, via Myc-driven DNA hypermethylation and deacetylation in lung adenocarcinoma [PMID:41520057] and via HDAC2 in papillary thyroid carcinoma [PMID:39098591].","teleology":[{"year":2016,"claim":"Established ACAP3 as an Arf6-specific GAP whose nucleotide-cycling activity is mechanistically required for neurite outgrowth, defining its core molecular function.","evidence":"Primary hippocampal neuron knockdown with wild-type vs. GAP-inactive rescue, Arf6-GTP pulldown, fast-cycle mutant complementation, and HEK-293T GAP assay","pmids":["27330119"],"confidence":"High","gaps":["Does not identify the cognate Arf6 GEF that partners ACAP3 in cycling","Downstream effectors linking Arf6 cycling to outgrowth not defined"]},{"year":2017,"claim":"Extended ACAP3's GAP function from cultured neurons to in vivo brain development, showing it is required for cortical neuronal migration through the same Arf6 GAP activity.","evidence":"In utero electroporation knockdown in mouse cortex with wild-type vs. GAP-inactive rescue and histological layering analysis","pmids":["28919417"],"confidence":"High","gaps":["Molecular link between Arf6 cycling and migration machinery unresolved","Single lab, single phenotypic readout"]},{"year":2024,"claim":"Identified ACAP3 as a tumour suppressor negatively regulated by HDAC2 in papillary thyroid carcinoma, linking its expression to AKT and p53 signalling control of proliferation and apoptosis.","evidence":"Functional assays (proliferation, migration, invasion, apoptosis), Western blot, and oe-ACAP3 + oe-HDAC2 rescue in PTC cell lines","pmids":["39098591"],"confidence":"Medium","gaps":["No direct demonstration that HDAC2 binds or deacetylates the ACAP3 promoter","Whether tumour suppression requires Arf6 GAP activity not tested in this system","Cell-line only, no in vivo validation"]},{"year":2026,"claim":"Connected ACAP3's GAP activity to EGFR trafficking control in lung adenocarcinoma and showed Myc enforces its epigenetic silencing, defining a receptor-recycling mechanism for tumour suppression.","evidence":"RRBS epigenome profiling, EGFR recycling and lysosomal degradation assays, GAP-deficient mutant comparison, in vitro and in vivo proliferation assays","pmids":["41520057"],"confidence":"Medium","gaps":["Abstract-level detail only","Direct biochemical link between Arf6 and EGFR sorting endosomes not shown","Whether Myc acts directly on the ACAP3 locus unresolved"]},{"year":null,"claim":"How ACAP3-controlled Arf6 cycling is mechanistically coupled to its distinct outputs — neurite outgrowth, neuronal migration, and EGFR sorting — and what GEF and effector partners operate in each context remain open.","evidence":"","pmids":[],"confidence":"Low","gaps":["Cognate Arf6 GEF unidentified","No structural model of the ACAP3-Arf6 interaction","Unified mechanism across neural and cancer contexts not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1]}],"localization":[],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1]}],"complexes":[],"partners":["ARF6","EGFR"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96P50","full_name":"Arf-GAP with coiled-coil, ANK repeat and PH domain-containing protein 3","aliases":["Centaurin-beta-5","Cnt-b5"],"length_aa":834,"mass_kda":92.5,"function":"GTPase-activating protein for the ADP ribosylation factor family","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q96P50/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ACAP3","classification":"Not Classified","n_dependent_lines":20,"n_total_lines":1208,"dependency_fraction":0.016556291390728478},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000131584","cell_line_id":"CID000675","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"big_aggregates","grade":2},{"compartment":"mitochondria","grade":2}],"interactors":[{"gene":"ACAP2","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000675","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Golgi apparatus","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":155.0}],"url":"https://www.proteinatlas.org/search/ACAP3"},"hgnc":{"alias_symbol":["KIAA1716"],"prev_symbol":["CENTB5"]},"alphafold":{"accession":"Q96P50","domains":[{"cath_id":"1.20.1270.60","chopping":"6-247","consensus_level":"high","plddt":94.368,"start":6,"end":247},{"cath_id":"2.30.29.30","chopping":"270-368","consensus_level":"high","plddt":86.264,"start":270,"end":368},{"cath_id":"1.10.220.150","chopping":"416-514","consensus_level":"high","plddt":89.7595,"start":416,"end":514}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96P50","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96P50-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96P50-F1-predicted_aligned_error_v6.png","plddt_mean":75.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ACAP3","jax_strain_url":"https://www.jax.org/strain/search?query=ACAP3"},"sequence":{"accession":"Q96P50","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96P50.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96P50/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96P50"}},"corpus_meta":[{"pmid":"33540684","id":"PMC_33540684","title":"Analysis of m6A RNA Methylation-Related Genes in Liver Hepatocellular Carcinoma and Their Correlation with Survival.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33540684","citation_count":53,"is_preprint":false},{"pmid":"37464898","id":"PMC_37464898","title":"Aging Differentially Affects Axonal Autophagosome Formation and Maturation.","date":"2023","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/37464898","citation_count":24,"is_preprint":false},{"pmid":"29491472","id":"PMC_29491472","title":"Integrative functional analysis of super enhancer SNPs for coronary artery disease.","date":"2018","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29491472","citation_count":22,"is_preprint":false},{"pmid":"27330119","id":"PMC_27330119","title":"ACAP3 regulates neurite outgrowth through its GAP activity specific to Arf6 in mouse hippocampal neurons.","date":"2016","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/27330119","citation_count":17,"is_preprint":false},{"pmid":"38723630","id":"PMC_38723630","title":"Cis- and trans-eQTL TWASs of breast and ovarian cancer identify more than 100 susceptibility genes in the BCAC and OCAC consortia.","date":"2024","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38723630","citation_count":10,"is_preprint":false},{"pmid":"28919417","id":"PMC_28919417","title":"ACAP3, the GTPase-activating protein specific to the small GTPase Arf6, regulates neuronal migration in the developing cerebral cortex.","date":"2017","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/28919417","citation_count":9,"is_preprint":false},{"pmid":"38093298","id":"PMC_38093298","title":"Identification and validation of eight lysosomes-related genes signatures and correlation with immune cell infiltration in lung adenocarcinoma.","date":"2023","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/38093298","citation_count":9,"is_preprint":false},{"pmid":"33276684","id":"PMC_33276684","title":"Length Polymorphism and Methylation Status of UPS29 Minisatellite of the ACAP3 Gene as Molecular Biomarker of Epilepsy. Sex Differences in Seizure Types and Symptoms.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33276684","citation_count":7,"is_preprint":false},{"pmid":"39098591","id":"PMC_39098591","title":"ACAP3 negatively regulated by HDAC2 inhibits the malignant development of papillary thyroid carcinoma cells.","date":"2024","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/39098591","citation_count":2,"is_preprint":false},{"pmid":"23657595","id":"PMC_23657595","title":"The expression and phylogenetic analysis of four AP3-like paralogs in the stamens, carpels, and single-whorl perianth of the paleoherb Asarum caudigerum.","date":"2013","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/23657595","citation_count":2,"is_preprint":false},{"pmid":"38014246","id":"PMC_38014246","title":"Cis- and trans-eQTL TWAS of breast and ovarian cancer identify more than 100 risk associated genes in the BCAC and OCAC consortia.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/38014246","citation_count":2,"is_preprint":false},{"pmid":"21105360","id":"PMC_21105360","title":"[Human intra-intronic minisatellite UPS29 associated with neurological diseases regulates reporter gene EGFP expression depending on cell type].","date":"2010","source":"Tsitologiia","url":"https://pubmed.ncbi.nlm.nih.gov/21105360","citation_count":1,"is_preprint":false},{"pmid":"41520057","id":"PMC_41520057","title":"Myc-mediated epigenetic silencing of ACAP3 promotes lung adenocarcinoma proliferation via regulating EGFR dynamics.","date":"2026","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/41520057","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9009,"output_tokens":1605,"usd":0.025551,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8332,"output_tokens":1893,"usd":0.044492,"stage2_stop_reason":"end_turn"},"total_usd":0.070043,"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\": 2016,\n      \"finding\": \"ACAP3 functions as a GTPase-activating protein (GAP) specific to Arf6 in mouse hippocampal neurons. Knockdown of ACAP3 abrogated neurite outgrowth, which was rescued by wild-type ACAP3 but not by a GAP-inactive mutant. ACAP3 knockdown significantly increased GTP-bound Arf6 levels, confirming its role as an Arf6 GAP. Cycling between active and inactive forms of Arf6, regulated by ACAP3 together with a guanine-nucleotide-exchange factor, is required for neurite outgrowth.\",\n      \"method\": \"Primary hippocampal neuron knockdown, rescue with wild-type vs. GAP-inactive mutant, Arf6-GTP pulldown assay, Arf6 fast-cycle mutant rescue experiment, HEK-293T GAP activity assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods: in vitro GAP activity assay, active-site mutagenesis rescue, GTP-bound Arf6 measurement, and fast-cycle mutant complementation all converge on the same conclusion\",\n      \"pmids\": [\"27330119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ACAP3 is required for neuronal migration in the developing mouse cerebral cortex in vivo. In utero knockdown of ACAP3 significantly impaired cortical neuron migration and the associated morphological changes; rescue with wild-type ACAP3 restored migration, but a GAP-inactive mutant did not, indicating the mechanism depends on Arf6 GAP activity.\",\n      \"method\": \"In utero electroporation-based knockdown in mouse cortex, rescue with wild-type vs. GAP-inactive mutant ACAP3, histological analysis of cortical layering\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean in vivo loss-of-function with defined cellular phenotype, replicated rescue including active-site mutant control, single lab\",\n      \"pmids\": [\"28919417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HDAC2 negatively regulates ACAP3 expression in papillary thyroid carcinoma (PTC) cells. ACAP3 overexpression suppressed viability, proliferation, migration, and invasion, and promoted apoptosis of PTC cells, modulating AKT and p53 signalling (decreased p-AKT/AKT ratio, increased p-p53/p53 ratio, altered Bcl-2/Bax and E-cadherin/N-cadherin expression); HDAC2 overexpression reversed the tumour-suppressive effects of ACAP3.\",\n      \"method\": \"qRT-PCR, cell counting kit-8, transwell, wound-healing, flow cytometry assays, Western blot, Pearson correlation analysis, rescue (oe-ACAP3 + oe-HDAC2) experiment\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — multiple functional assays and rescue experiment in cell lines, single lab, no direct biochemical demonstration of HDAC2 binding/deacetylating ACAP3 promoter\",\n      \"pmids\": [\"39098591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Myc mediates epigenetic silencing of ACAP3 via DNA hypermethylation and deacetylation in lung adenocarcinoma (LUAD). ACAP3 inhibits EGFR signalling by impairing EGFR recycling and accelerating lysosome-mediated EGFR degradation in a GAP activity-dependent manner, thereby suppressing LUAD cell proliferation in vitro and in vivo.\",\n      \"method\": \"Reduced representation bisulfite sequencing (RRBS), in vitro and in vivo proliferation assays, EGFR recycling and lysosomal degradation assays, GAP-activity-deficient mutant comparison\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (epigenome profiling, functional assays, GAP mutant), single lab, abstract-level detail only\",\n      \"pmids\": [\"41520057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The intronic minisatellite UPS29 of the ACAP3 (CENTB5) gene possesses enhancer-like activity in neuronal-type cells (rat astrocytes) but not uniformly across cell types, as demonstrated by reporter gene (EGFP) transient transfection assays in HeLa, F9, and rat astrocyte cultures.\",\n      \"method\": \"Transient transfection of EGFP reporter constructs containing different UPS29 alleles in HeLa, mouse F9 embryonal carcinoma cells, and rat astrocytes\",\n      \"journal\": \"Tsitologiia\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single reporter assay in cell lines, single lab, no direct demonstration of effect on endogenous ACAP3 protein\",\n      \"pmids\": [\"21105360\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ACAP3 is a GTPase-activating protein (GAP) selective for the small GTPase Arf6; it promotes neurite outgrowth and cortical neuronal migration in vivo by cycling Arf6 between its GTP- and GDP-bound states, and in cancer cells it suppresses EGFR signalling by impairing receptor recycling and promoting lysosomal EGFR degradation in a GAP-activity-dependent manner, while its own expression is negatively regulated epigenetically by Myc-driven DNA methylation and by HDAC2.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ACAP3 is a GTPase-activating protein (GAP) selective for the small GTPase Arf6 that governs cell morphological dynamics in both neural development and epithelial cancers [#0]. In neurons, ACAP3 drives neurite outgrowth by cycling Arf6 between its GTP- and GDP-bound states; loss of ACAP3 raises GTP-bound Arf6 and abolishes outgrowth, a defect rescued by wild-type but not GAP-inactive ACAP3 [#0], and the same GAP-dependent activity is required for cortical neuronal migration in vivo [#1]. In cancer cells, ACAP3 acts as a tumour suppressor: in lung adenocarcinoma it inhibits EGFR signalling by impairing EGFR recycling and accelerating lysosome-mediated EGFR degradation in a GAP-activity-dependent manner, suppressing proliferation [#3], and in papillary thyroid carcinoma it suppresses viability, migration, and invasion while promoting apoptosis through modulation of AKT and p53 signalling [#2]. ACAP3 expression is held down epigenetically, via Myc-driven DNA hypermethylation and deacetylation in lung adenocarcinoma [#3] and via HDAC2 in papillary thyroid carcinoma [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Established ACAP3 as an Arf6-specific GAP whose nucleotide-cycling activity is mechanistically required for neurite outgrowth, defining its core molecular function.\",\n      \"evidence\": \"Primary hippocampal neuron knockdown with wild-type vs. GAP-inactive rescue, Arf6-GTP pulldown, fast-cycle mutant complementation, and HEK-293T GAP assay\",\n      \"pmids\": [\"27330119\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not identify the cognate Arf6 GEF that partners ACAP3 in cycling\", \"Downstream effectors linking Arf6 cycling to outgrowth not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended ACAP3's GAP function from cultured neurons to in vivo brain development, showing it is required for cortical neuronal migration through the same Arf6 GAP activity.\",\n      \"evidence\": \"In utero electroporation knockdown in mouse cortex with wild-type vs. GAP-inactive rescue and histological layering analysis\",\n      \"pmids\": [\"28919417\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between Arf6 cycling and migration machinery unresolved\", \"Single lab, single phenotypic readout\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified ACAP3 as a tumour suppressor negatively regulated by HDAC2 in papillary thyroid carcinoma, linking its expression to AKT and p53 signalling control of proliferation and apoptosis.\",\n      \"evidence\": \"Functional assays (proliferation, migration, invasion, apoptosis), Western blot, and oe-ACAP3 + oe-HDAC2 rescue in PTC cell lines\",\n      \"pmids\": [\"39098591\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct demonstration that HDAC2 binds or deacetylates the ACAP3 promoter\", \"Whether tumour suppression requires Arf6 GAP activity not tested in this system\", \"Cell-line only, no in vivo validation\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Connected ACAP3's GAP activity to EGFR trafficking control in lung adenocarcinoma and showed Myc enforces its epigenetic silencing, defining a receptor-recycling mechanism for tumour suppression.\",\n      \"evidence\": \"RRBS epigenome profiling, EGFR recycling and lysosomal degradation assays, GAP-deficient mutant comparison, in vitro and in vivo proliferation assays\",\n      \"pmids\": [\"41520057\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Abstract-level detail only\", \"Direct biochemical link between Arf6 and EGFR sorting endosomes not shown\", \"Whether Myc acts directly on the ACAP3 locus unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ACAP3-controlled Arf6 cycling is mechanistically coupled to its distinct outputs — neurite outgrowth, neuronal migration, and EGFR sorting — and what GEF and effector partners operate in each context remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Cognate Arf6 GEF unidentified\", \"No structural model of the ACAP3-Arf6 interaction\", \"Unified mechanism across neural and cancer contexts not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ARF6\", \"EGFR\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}