{"gene":"AGAP1","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2002,"finding":"AGAP1 is a phosphoinositide-dependent ArfGAP with activity toward Arf1>Arf5>Arf6; phosphatidylinositol 4,5-bisphosphate and phosphatidic acid synergistically stimulate its GAP activity; the PH domain is necessary for activity; and the GTP-binding protein-like (GLD) domain affects lipid dependence of GAP activity.","method":"In vitro GAP activity assays with lipid vesicles, domain deletion mutants","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstituted enzymatic assay with mutagenesis, replicated in domain deletion studies","pmids":["12388557"],"is_preprint":false},{"year":2002,"finding":"Overexpressed AGAP1 localizes to endocytic punctate structures containing transferrin and Rab4 (endosomal markers), redistributes AP-1 from trans-Golgi to these structures, and inhibits PDGF-induced ruffle formation while also inducing loss of actin stress fibers.","method":"Overexpression with immunofluorescence and transferrin uptake assays in cultured cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization experiment with functional consequence, single lab","pmids":["12388557"],"is_preprint":false},{"year":2003,"finding":"AGAP1 directly associates with the AP-3 adaptor protein complex via its PH domain binding to the delta and sigma3 subunits of AP-3; AGAP1 overexpression changes cellular distribution of AP-3 and increases LAMP1 trafficking via the plasma membrane, while reduced AGAP1 expression renders AP-3 resistant to brefeldin A.","method":"Co-immunoprecipitation, colocalization, siRNA knockdown, overexpression with trafficking assays","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 — reciprocal binding confirmed, multiple orthogonal methods (Co-IP, knockdown, overexpression, trafficking assay), replicated by subsequent studies","pmids":["12967569"],"is_preprint":false},{"year":2004,"finding":"AGAP1 interacts with Arf1 through the N-terminal amino acids 2–17 of Arf1, and lysines 15 and 16 of Arf1 are critical for productive interaction with AGAP1; peptides from amino acids 2–17 of Arf1 directly bind AGAP1 and inhibit its GAP activity.","method":"In vitro GAP activity assays with Arf1 deletion/point mutants, antibody sequestration, direct peptide binding","journal":"Cellular signalling","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstituted assay with defined Arf1 mutants, direct binding confirmed","pmids":["15212764"],"is_preprint":false},{"year":2004,"finding":"AGAP1 physically interacts with both the alpha1 and beta1 subunits of soluble guanylyl cyclase (sGC) via its C-terminal portion, and tyrosine phosphorylation of AGAP1 by Src-like kinases potently increases this interaction.","method":"Co-immunoprecipitation in vitro and in vivo, tyrosine phosphorylation assay with Src kinase","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP in vitro and in vivo with phosphorylation modulation, single lab","pmids":["15381706"],"is_preprint":false},{"year":2005,"finding":"AGAP1 specifically associates with AP-3 (not AP-1) endosomes, distinguishing it from the closely related AGAP2 which specifically interacts with AP-1; this specificity underlies differential regulation of AP-3 versus AP-1 trafficking compartments.","method":"Co-immunoprecipitation, colocalization, overexpression trafficking assays comparing AGAP1 and AGAP2","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods, replicates and extends prior AP-3 finding with comparative analysis","pmids":["16079295"],"is_preprint":false},{"year":2010,"finding":"AGAP1 directly and specifically interacts with the M5 muscarinic receptor and mediates binding of AP-3 to M5; this AGAP1-M5 interaction is required for AP-3-dependent endocytic recycling of M5 in neurons; disruption of this interaction in vivo reduces presynaptic M5-mediated dopamine release potentiation in the striatum.","method":"Co-immunoprecipitation, receptor recycling assays in neurons, in vivo pharmacological and genetic disruption with dopamine release measurements","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — direct binding shown, loss-of-function in vivo with defined physiological readout, multiple orthogonal methods","pmids":["20664521"],"is_preprint":false},{"year":2012,"finding":"The GLD domain of AGAP1 functions as a protein-binding site that allosterically regulates ArfGAP catalytic activity; RhoA binds to the GLD domain via its C-terminus (nucleotide-independently) and increases AGAP1 GAP activity specifically toward Arf1; Rac1 and Cdc42 were identified as potential binding partners but Cdc42 C-terminal peptide did not bind or activate AGAP1.","method":"Two-hybrid screen, co-immunoprecipitation, in vitro GAP activity assays with RhoA and peptides, deletion mutants","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstituted allosteric activation with defined peptides, two-hybrid plus Co-IP confirmation","pmids":["22453919"],"is_preprint":false},{"year":2016,"finding":"AGAP1 localizes to axons, dendrites, dendritic spines, and synapses in neurons, colocalizing preferentially with early and recycling endosome markers; overexpression and knockdown of AGAP1 alter neuronal endosomal trafficking and dendritic spine morphology; AGAP1 protein and mRNA levels are selectively reduced in DTNBP1 (dysbindin) null mice, placing AGAP1 downstream of dysbindin.","method":"Immunofluorescence in neurons, overexpression and siRNA knockdown with morphological readouts, comparison in DTNBP1 null mouse tissue","journal":"Frontiers in cellular neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization with functional consequence, genetic epistasis via null mouse, single lab","pmids":["27713690"],"is_preprint":false},{"year":2016,"finding":"AGAP1 directly interacts with the kinesin-13 family member Kif2A via its GLD and PH domains binding the Kif2A motor domain; Kif2A increases AGAP1 GAP activity, and the GLD-PH domains of AGAP1 increase Kif2A ATPase activity; the Kif2A·AGAP1 complex functionally contributes to cytoskeleton remodeling during cell migration and spreading.","method":"Pulldown, in vitro GAP activity assay, in vitro ATPase assay, knockdown rescue experiments with mutants in cell migration/spreading assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro biochemical reconstitution of mutual activation, domain mapping, rescue with binding-deficient mutant","pmids":["27531749"],"is_preprint":false},{"year":2019,"finding":"AGAP1 binds to the C-terminus of FilGAP (a Rac-specific GAP) via its N-terminal GLD-containing region; AGAP1 controls subcellular localization of FilGAP to intracellular vesicles, and depletion of AGAP1 causes FilGAP to accumulate at focal adhesions, leading to suppressed cell spreading and increased cancer cell invasion that is reversed by co-depletion of FilGAP.","method":"Co-immunoprecipitation, colocalization, siRNA knockdown, cell spreading and invasion assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP with domain mapping, knockdown with epistatic rescue, functional cellular readouts","pmids":["31785816"],"is_preprint":false},{"year":2021,"finding":"The crystal structure of the AGAP1 GLD domain (residues 70–235) was determined at 3.0 Å resolution; the domain contains conserved G1–G5 loops consistent with NTPase fold, supporting its role as a protein-binding regulatory domain rather than a nucleotide-hydrolyzing domain.","method":"X-ray crystallography","journal":"Acta crystallographica. Section F, Structural biology communications","confidence":"Medium","confidence_rationale":"Tier 1 — crystal structure, but functional validation limited to structural inference","pmids":["33830075"],"is_preprint":false},{"year":2023,"finding":"AGAP1 promotes exosome formation in cancer cells; the mutant p53-G245S interacts with hnRNPA2B1 to increase AGAP1 mRNA stability and protein translation, and elevated AGAP1 enhances exosome formation to promote cancer cell proliferation and metastasis.","method":"Whole-genome sequencing, RNA stability assays, co-immunoprecipitation, AGAP1 inhibitor (QS11) treatment, functional proliferation/migration assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods linking pathway, but exosome mechanism for AGAP1 is novel and single-lab","pmids":["37030635"],"is_preprint":false},{"year":2023,"finding":"Loss of the Drosophila AGAP1 ortholog CenG1a results in reduced axon terminal size, increased neuronal endosome abundance, elevated autophagy, basal elevation of eIF2α phosphorylation, and inability to further activate the integrated stress response upon cytotoxic stress, placing AGAP1 function in endolysosomal trafficking upstream of the integrated stress response pathway.","method":"Drosophila loss-of-function genetics, immunofluorescence, phospho-eIF2α western blot, survival assays with environmental stressors","journal":"Disease models & mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 — genetic loss-of-function in orthologous model with multiple cellular readouts and pathway placement","pmids":["37470098"],"is_preprint":false}],"current_model":"AGAP1 is a phosphoinositide-dependent ArfGAP (acting preferentially on Arf1) whose PH domain confers lipid-stimulated catalytic activity, whose GLD domain serves as an allosteric protein-binding site regulated by RhoA and Kif2A, and which specifically associates with the AP-3 adaptor complex to control endosomal-lysosomal trafficking, dendritic spine morphology, GPCR recycling (M5 muscarinic receptor), FilGAP localization, and actin cytoskeleton remodeling; its activity is also modulated by tyrosine phosphorylation via Src-like kinases, which enhances its interaction with soluble guanylyl cyclase."},"narrative":{"teleology":[{"year":2002,"claim":"Establishing AGAP1 as a lipid-regulated ArfGAP resolved how phosphoinositide and phosphatidic acid signals are integrated to control Arf1 GTP hydrolysis, and identified the PH and GLD domains as critical regulatory elements.","evidence":"In vitro GAP assays with lipid vesicles and domain deletion mutants","pmids":["12388557"],"confidence":"High","gaps":["Structural basis for synergistic lipid activation unknown","In vivo substrates beyond Arf1 not tested in endogenous settings"]},{"year":2003,"claim":"Demonstrating that AGAP1 specifically binds the AP-3 adaptor complex and controls LAMP1 trafficking established AGAP1 as a key regulator of the endosomal–lysosomal sorting pathway, distinct from AP-1-associated ArfGAPs.","evidence":"Co-immunoprecipitation of AGAP1 PH domain with AP-3 δ/σ3 subunits, siRNA knockdown, LAMP1 trafficking assays, and comparative analysis with AGAP2","pmids":["12967569","16079295"],"confidence":"High","gaps":["Structural determinants of AP-3 selectivity versus AP-1 not defined at atomic level","Cargo repertoire beyond LAMP1 not systematically assessed"]},{"year":2004,"claim":"Mapping the Arf1 N-terminal helix (residues 2–17) as the AGAP1 interaction site and identifying critical lysines resolved how AGAP1 recognizes its primary substrate.","evidence":"In vitro GAP assays with Arf1 deletion/point mutants and peptide competition","pmids":["15212764"],"confidence":"High","gaps":["No co-crystal structure of AGAP1–Arf1 complex","Whether the same interface is used in membrane-bound context is untested"]},{"year":2004,"claim":"Discovery that Src-mediated tyrosine phosphorylation of AGAP1 enhances its interaction with soluble guanylyl cyclase opened a link between Arf signaling and NO/cGMP pathways.","evidence":"Co-immunoprecipitation in vitro and in vivo with Src kinase phosphorylation assay","pmids":["15381706"],"confidence":"Medium","gaps":["Functional consequence of sGC–AGAP1 interaction on cGMP production not shown","Phosphorylation sites on AGAP1 not mapped","Not independently replicated"]},{"year":2010,"claim":"Showing that AGAP1 bridges the M5 muscarinic receptor to AP-3 for endocytic recycling, and that this pathway modulates dopamine release in vivo, provided the first receptor-specific physiological role for AGAP1 in the nervous system.","evidence":"Co-IP of AGAP1–M5, receptor recycling assays in neurons, in vivo striatal dopamine release measurements upon pathway disruption","pmids":["20664521"],"confidence":"High","gaps":["Whether other GPCRs use AGAP1/AP-3 for recycling is unknown","Mechanism by which AGAP1 recognizes M5 cytoplasmic domain not mapped"]},{"year":2012,"claim":"Identification of the GLD domain as an allosteric protein-binding module activated by RhoA resolved how Rho-family GTPase signals converge on Arf1 inactivation through AGAP1.","evidence":"Two-hybrid screen, Co-IP, in vitro GAP assays with RhoA C-terminal peptides and GLD deletion mutants","pmids":["22453919"],"confidence":"High","gaps":["Nucleotide-independence of RhoA binding is unusual and mechanistic basis is unclear","Cdc42 and Rac1 binding specificity not fully resolved"]},{"year":2016,"claim":"Demonstrating mutual enzymatic activation between AGAP1 and the kinesin Kif2A established a direct link between Arf signaling and microtubule dynamics during cell migration.","evidence":"In vitro GAP and ATPase assays, domain-mapping pulldowns, knockdown rescue with binding-deficient mutants in migration/spreading assays","pmids":["27531749"],"confidence":"High","gaps":["In vivo relevance of Kif2A–AGAP1 complex in neurons not tested","Structural basis of mutual activation unknown"]},{"year":2016,"claim":"Localization of AGAP1 to dendritic spines and demonstration that its levels depend on dysbindin placed AGAP1 within a neuronal endosomal network relevant to schizophrenia-associated biology.","evidence":"Immunofluorescence in neurons, overexpression/knockdown morphological analysis, DTNBP1 null mouse comparison","pmids":["27713690"],"confidence":"Medium","gaps":["Direct transcriptional or post-translational mechanism by which dysbindin regulates AGAP1 not defined","Causal role of AGAP1 reduction in schizophrenia-related phenotypes not established"]},{"year":2019,"claim":"Showing that AGAP1 controls FilGAP localization to intracellular vesicles and that AGAP1 loss redirects FilGAP to focal adhesions revealed a new mechanism by which AGAP1 indirectly regulates Rac-dependent cell spreading and invasion.","evidence":"Co-IP, colocalization, siRNA knockdown with epistatic rescue, cell spreading/invasion assays","pmids":["31785816"],"confidence":"Medium","gaps":["Whether AGAP1 GAP activity is required for FilGAP relocalization or only scaffolding is unclear","Single-lab finding not yet independently replicated"]},{"year":2021,"claim":"The crystal structure of the GLD domain confirmed a conserved NTPase fold with G1–G5 loops, supporting the model that the GLD serves as a regulatory protein-interaction domain rather than an active GTPase.","evidence":"X-ray crystallography at 3.0 Å resolution","pmids":["33830075"],"confidence":"Medium","gaps":["No co-structure with RhoA or Kif2A to reveal allosteric mechanism","Whether GLD binds nucleotide in vivo is unresolved"]},{"year":2023,"claim":"Two studies expanded AGAP1's functional scope: in cancer, mutant p53 stabilizes AGAP1 mRNA to promote exosome-mediated proliferation and metastasis; in Drosophila, loss of the AGAP1 ortholog CenG1a disrupts endolysosomal trafficking and constitutively activates the integrated stress response.","evidence":"RNA stability assays and proliferation/migration assays in cancer cells; Drosophila loss-of-function genetics with phospho-eIF2α readouts","pmids":["37030635","37470098"],"confidence":"Medium","gaps":["Mechanism by which AGAP1 promotes exosome biogenesis is undefined","Whether ISR dysregulation upon AGAP1 loss is conserved in mammals is untested","Single-lab findings for each"]},{"year":null,"claim":"Key open questions include the structural basis of AGAP1's allosteric regulation by the GLD domain, whether AGAP1 functions as a scaffold independent of its GAP activity in vivo, the full cargo repertoire of AGAP1/AP-3 trafficking, and whether AGAP1 dysfunction directly contributes to neuropsychiatric or cancer pathology in humans.","evidence":"","pmids":[],"confidence":"Low","gaps":["No full-length AGAP1 structure or AGAP1–partner co-structure available","No genetic disease association established by human family studies","Systematic identification of AGAP1-dependent cargoes not performed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,3,7,9]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,6,10]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[1,2,5,8]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[1,10]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[2,5,6,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,7,9]}],"complexes":["AP-3 adaptor complex"],"partners":["ARF1","AP3D1","AP3S1","RHOA","KIF2A","CHRM5","FILGAP","GUCY1A1"],"other_free_text":[]},"mechanistic_narrative":"AGAP1 is a phosphoinositide-dependent Arf GTPase-activating protein that couples lipid-regulated Arf1 inactivation to endosomal sorting, cytoskeletal remodeling, and neuronal membrane trafficking. Its catalytic ArfGAP activity toward Arf1 is stimulated by PI(4,5)P₂ and phosphatidic acid via its PH domain, and allosterically enhanced by RhoA and the kinesin-13 family member Kif2A binding to its GLD domain [PMID:12388557, PMID:22453919, PMID:27531749]. AGAP1 selectively associates with the AP-3 adaptor complex through PH-domain contacts with the δ and σ3 subunits, and this interaction is required for AP-3-dependent endosomal–lysosomal trafficking, including recycling of the M5 muscarinic receptor and regulation of dendritic spine morphology in neurons [PMID:12967569, PMID:20664521, PMID:27713690]. AGAP1 also controls subcellular localization of the Rac-GAP FilGAP to intracellular vesicles, promotes exosome biogenesis in cancer cells, and functions upstream of the integrated stress response through its role in endolysosomal trafficking, as demonstrated by loss-of-function studies in Drosophila [PMID:31785816, PMID:37030635, PMID:37470098]."},"prefetch_data":{"uniprot":{"accession":"Q9UPQ3","full_name":"Arf-GAP with GTPase, ANK repeat and PH domain-containing protein 1","aliases":["Centaurin-gamma-2","Cnt-g2","GTP-binding and GTPase-activating protein 1","GGAP1"],"length_aa":857,"mass_kda":94.5,"function":"GTPase-activating protein for ARF1 and, to a lesser extent, ARF5. Directly and specifically regulates the adapter protein 3 (AP-3)-dependent trafficking of proteins in the endosomal-lysosomal system","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9UPQ3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/AGAP1","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000157985","cell_line_id":"CID000650","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"cell_contact","grade":2},{"compartment":"membrane","grade":2}],"interactors":[{"gene":"AGAP3","stoichiometry":10.0},{"gene":"TANC1","stoichiometry":0.2},{"gene":"CLNS1A","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000650","total_profiled":1310},"omim":[{"mim_id":"621159","title":"ARF GTPase-ACTIVATING PROTEIN WITH GTPase DOMAIN, ANKYRIN REPEAT, AND PLECKSTRIN HOMOLOGY DOMAIN 11, NONCODING; AGAP11","url":"https://www.omim.org/entry/621159"},{"mim_id":"621158","title":"ARF GTPase-ACTIVATING PROTEIN WITH GTPase DOMAIN, ANKYRIN REPEAT, AND PLECKSTRIN HOMOLOGY DOMAIN 9; AGAP9","url":"https://www.omim.org/entry/621158"},{"mim_id":"621157","title":"ARF GTPase-ACTIVATING PROTEIN WITH GTPase DOMAIN, ANKYRIN REPEAT, AND PLECKSTRIN HOMOLOGY DOMAIN 6; AGAP6","url":"https://www.omim.org/entry/621157"},{"mim_id":"621156","title":"ARF GTPase-ACTIVATING PROTEIN WITH GTPase DOMAIN, ANKYRIN REPEAT, AND PLECKSTRIN HOMOLOGY DOMAIN 5; AGAP5","url":"https://www.omim.org/entry/621156"},{"mim_id":"621155","title":"ARF GTPase-ACTIVATING PROTEIN WITH GTPase DOMAIN, ANKYRIN REPEAT, AND PLECKSTRIN HOMOLOGY DOMAIN 4; AGAP4","url":"https://www.omim.org/entry/621155"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"retina","ntpm":43.5}],"url":"https://www.proteinatlas.org/search/AGAP1"},"hgnc":{"alias_symbol":["KIAA1099","GGAP1"],"prev_symbol":["CENTG2"]},"alphafold":{"accession":"Q9UPQ3","domains":[{"cath_id":"3.40.50.300","chopping":"71-239","consensus_level":"high","plddt":90.5609,"start":71,"end":239},{"cath_id":"2.30.29.30","chopping":"347-408_555-598","consensus_level":"medium","plddt":84.8924,"start":347,"end":598},{"cath_id":"1.10.220.150","chopping":"619-718","consensus_level":"high","plddt":95.0388,"start":619,"end":718},{"cath_id":"1.25.40.20","chopping":"733-830","consensus_level":"high","plddt":92.0343,"start":733,"end":830},{"cath_id":"1.10.287","chopping":"2-64","consensus_level":"medium","plddt":78.0013,"start":2,"end":64}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UPQ3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UPQ3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UPQ3-F1-predicted_aligned_error_v6.png","plddt_mean":71.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=AGAP1","jax_strain_url":"https://www.jax.org/strain/search?query=AGAP1"},"sequence":{"accession":"Q9UPQ3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UPQ3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UPQ3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UPQ3"}},"corpus_meta":[{"pmid":"12388557","id":"PMC_12388557","title":"AGAP1, an endosome-associated, phosphoinositide-dependent ADP-ribosylation factor GTPase-activating protein that affects actin cytoskeleton.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12388557","citation_count":93,"is_preprint":false},{"pmid":"12967569","id":"PMC_12967569","title":"Specific regulation of the adaptor protein complex AP-3 by the Arf GAP AGAP1.","date":"2003","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/12967569","citation_count":76,"is_preprint":false},{"pmid":"20664521","id":"PMC_20664521","title":"AGAP1/AP-3-dependent endocytic recycling of M5 muscarinic receptors promotes dopamine release.","date":"2010","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/20664521","citation_count":64,"is_preprint":false},{"pmid":"15892143","id":"PMC_15892143","title":"Evaluation of the chromosome 2q37.3 gene CENTG2 as an autism susceptibility gene.","date":"2005","source":"American journal of medical genetics. 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A proteomics approach towards Ca<sup>2+</sup>dependent and independent proteome changes in response to oxidative stress in <i>A. thaliana</i>","date":"2025-04-01","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.31.645912","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.05.21.595193","title":"Parkinson’s disease-associated alterations in DNA methylation and hydroxymethylation in human brain","date":"2024-05-22","source":"bioRxiv","url":"https://doi.org/10.1101/2024.05.21.595193","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12011,"output_tokens":3319,"usd":0.042909},"stage2":{"model":"claude-opus-4-6","input_tokens":6726,"output_tokens":2918,"usd":0.15987},"total_usd":0.202779,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"AGAP1 is a phosphoinositide-dependent ArfGAP with activity toward Arf1>Arf5>Arf6; phosphatidylinositol 4,5-bisphosphate and phosphatidic acid synergistically stimulate its GAP activity; the PH domain is necessary for activity; and the GTP-binding protein-like (GLD) domain affects lipid dependence of GAP activity.\",\n      \"method\": \"In vitro GAP activity assays with lipid vesicles, domain deletion mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstituted enzymatic assay with mutagenesis, replicated in domain deletion studies\",\n      \"pmids\": [\"12388557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Overexpressed AGAP1 localizes to endocytic punctate structures containing transferrin and Rab4 (endosomal markers), redistributes AP-1 from trans-Golgi to these structures, and inhibits PDGF-induced ruffle formation while also inducing loss of actin stress fibers.\",\n      \"method\": \"Overexpression with immunofluorescence and transferrin uptake assays in cultured cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment with functional consequence, single lab\",\n      \"pmids\": [\"12388557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"AGAP1 directly associates with the AP-3 adaptor protein complex via its PH domain binding to the delta and sigma3 subunits of AP-3; AGAP1 overexpression changes cellular distribution of AP-3 and increases LAMP1 trafficking via the plasma membrane, while reduced AGAP1 expression renders AP-3 resistant to brefeldin A.\",\n      \"method\": \"Co-immunoprecipitation, colocalization, siRNA knockdown, overexpression with trafficking assays\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal binding confirmed, multiple orthogonal methods (Co-IP, knockdown, overexpression, trafficking assay), replicated by subsequent studies\",\n      \"pmids\": [\"12967569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"AGAP1 interacts with Arf1 through the N-terminal amino acids 2–17 of Arf1, and lysines 15 and 16 of Arf1 are critical for productive interaction with AGAP1; peptides from amino acids 2–17 of Arf1 directly bind AGAP1 and inhibit its GAP activity.\",\n      \"method\": \"In vitro GAP activity assays with Arf1 deletion/point mutants, antibody sequestration, direct peptide binding\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstituted assay with defined Arf1 mutants, direct binding confirmed\",\n      \"pmids\": [\"15212764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"AGAP1 physically interacts with both the alpha1 and beta1 subunits of soluble guanylyl cyclase (sGC) via its C-terminal portion, and tyrosine phosphorylation of AGAP1 by Src-like kinases potently increases this interaction.\",\n      \"method\": \"Co-immunoprecipitation in vitro and in vivo, tyrosine phosphorylation assay with Src kinase\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP in vitro and in vivo with phosphorylation modulation, single lab\",\n      \"pmids\": [\"15381706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"AGAP1 specifically associates with AP-3 (not AP-1) endosomes, distinguishing it from the closely related AGAP2 which specifically interacts with AP-1; this specificity underlies differential regulation of AP-3 versus AP-1 trafficking compartments.\",\n      \"method\": \"Co-immunoprecipitation, colocalization, overexpression trafficking assays comparing AGAP1 and AGAP2\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, replicates and extends prior AP-3 finding with comparative analysis\",\n      \"pmids\": [\"16079295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"AGAP1 directly and specifically interacts with the M5 muscarinic receptor and mediates binding of AP-3 to M5; this AGAP1-M5 interaction is required for AP-3-dependent endocytic recycling of M5 in neurons; disruption of this interaction in vivo reduces presynaptic M5-mediated dopamine release potentiation in the striatum.\",\n      \"method\": \"Co-immunoprecipitation, receptor recycling assays in neurons, in vivo pharmacological and genetic disruption with dopamine release measurements\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct binding shown, loss-of-function in vivo with defined physiological readout, multiple orthogonal methods\",\n      \"pmids\": [\"20664521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The GLD domain of AGAP1 functions as a protein-binding site that allosterically regulates ArfGAP catalytic activity; RhoA binds to the GLD domain via its C-terminus (nucleotide-independently) and increases AGAP1 GAP activity specifically toward Arf1; Rac1 and Cdc42 were identified as potential binding partners but Cdc42 C-terminal peptide did not bind or activate AGAP1.\",\n      \"method\": \"Two-hybrid screen, co-immunoprecipitation, in vitro GAP activity assays with RhoA and peptides, deletion mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstituted allosteric activation with defined peptides, two-hybrid plus Co-IP confirmation\",\n      \"pmids\": [\"22453919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"AGAP1 localizes to axons, dendrites, dendritic spines, and synapses in neurons, colocalizing preferentially with early and recycling endosome markers; overexpression and knockdown of AGAP1 alter neuronal endosomal trafficking and dendritic spine morphology; AGAP1 protein and mRNA levels are selectively reduced in DTNBP1 (dysbindin) null mice, placing AGAP1 downstream of dysbindin.\",\n      \"method\": \"Immunofluorescence in neurons, overexpression and siRNA knockdown with morphological readouts, comparison in DTNBP1 null mouse tissue\",\n      \"journal\": \"Frontiers in cellular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization with functional consequence, genetic epistasis via null mouse, single lab\",\n      \"pmids\": [\"27713690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"AGAP1 directly interacts with the kinesin-13 family member Kif2A via its GLD and PH domains binding the Kif2A motor domain; Kif2A increases AGAP1 GAP activity, and the GLD-PH domains of AGAP1 increase Kif2A ATPase activity; the Kif2A·AGAP1 complex functionally contributes to cytoskeleton remodeling during cell migration and spreading.\",\n      \"method\": \"Pulldown, in vitro GAP activity assay, in vitro ATPase assay, knockdown rescue experiments with mutants in cell migration/spreading assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro biochemical reconstitution of mutual activation, domain mapping, rescue with binding-deficient mutant\",\n      \"pmids\": [\"27531749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"AGAP1 binds to the C-terminus of FilGAP (a Rac-specific GAP) via its N-terminal GLD-containing region; AGAP1 controls subcellular localization of FilGAP to intracellular vesicles, and depletion of AGAP1 causes FilGAP to accumulate at focal adhesions, leading to suppressed cell spreading and increased cancer cell invasion that is reversed by co-depletion of FilGAP.\",\n      \"method\": \"Co-immunoprecipitation, colocalization, siRNA knockdown, cell spreading and invasion assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with domain mapping, knockdown with epistatic rescue, functional cellular readouts\",\n      \"pmids\": [\"31785816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The crystal structure of the AGAP1 GLD domain (residues 70–235) was determined at 3.0 Å resolution; the domain contains conserved G1–G5 loops consistent with NTPase fold, supporting its role as a protein-binding regulatory domain rather than a nucleotide-hydrolyzing domain.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"Acta crystallographica. Section F, Structural biology communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure, but functional validation limited to structural inference\",\n      \"pmids\": [\"33830075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"AGAP1 promotes exosome formation in cancer cells; the mutant p53-G245S interacts with hnRNPA2B1 to increase AGAP1 mRNA stability and protein translation, and elevated AGAP1 enhances exosome formation to promote cancer cell proliferation and metastasis.\",\n      \"method\": \"Whole-genome sequencing, RNA stability assays, co-immunoprecipitation, AGAP1 inhibitor (QS11) treatment, functional proliferation/migration assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods linking pathway, but exosome mechanism for AGAP1 is novel and single-lab\",\n      \"pmids\": [\"37030635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Loss of the Drosophila AGAP1 ortholog CenG1a results in reduced axon terminal size, increased neuronal endosome abundance, elevated autophagy, basal elevation of eIF2α phosphorylation, and inability to further activate the integrated stress response upon cytotoxic stress, placing AGAP1 function in endolysosomal trafficking upstream of the integrated stress response pathway.\",\n      \"method\": \"Drosophila loss-of-function genetics, immunofluorescence, phospho-eIF2α western blot, survival assays with environmental stressors\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function in orthologous model with multiple cellular readouts and pathway placement\",\n      \"pmids\": [\"37470098\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"AGAP1 is a phosphoinositide-dependent ArfGAP (acting preferentially on Arf1) whose PH domain confers lipid-stimulated catalytic activity, whose GLD domain serves as an allosteric protein-binding site regulated by RhoA and Kif2A, and which specifically associates with the AP-3 adaptor complex to control endosomal-lysosomal trafficking, dendritic spine morphology, GPCR recycling (M5 muscarinic receptor), FilGAP localization, and actin cytoskeleton remodeling; its activity is also modulated by tyrosine phosphorylation via Src-like kinases, which enhances its interaction with soluble guanylyl cyclase.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"AGAP1 is a phosphoinositide-dependent Arf GTPase-activating protein that couples lipid-regulated Arf1 inactivation to endosomal sorting, cytoskeletal remodeling, and neuronal membrane trafficking. Its catalytic ArfGAP activity toward Arf1 is stimulated by PI(4,5)P₂ and phosphatidic acid via its PH domain, and allosterically enhanced by RhoA and the kinesin-13 family member Kif2A binding to its GLD domain [PMID:12388557, PMID:22453919, PMID:27531749]. AGAP1 selectively associates with the AP-3 adaptor complex through PH-domain contacts with the δ and σ3 subunits, and this interaction is required for AP-3-dependent endosomal–lysosomal trafficking, including recycling of the M5 muscarinic receptor and regulation of dendritic spine morphology in neurons [PMID:12967569, PMID:20664521, PMID:27713690]. AGAP1 also controls subcellular localization of the Rac-GAP FilGAP to intracellular vesicles, promotes exosome biogenesis in cancer cells, and functions upstream of the integrated stress response through its role in endolysosomal trafficking, as demonstrated by loss-of-function studies in Drosophila [PMID:31785816, PMID:37030635, PMID:37470098].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Establishing AGAP1 as a lipid-regulated ArfGAP resolved how phosphoinositide and phosphatidic acid signals are integrated to control Arf1 GTP hydrolysis, and identified the PH and GLD domains as critical regulatory elements.\",\n      \"evidence\": \"In vitro GAP assays with lipid vesicles and domain deletion mutants\",\n      \"pmids\": [\"12388557\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for synergistic lipid activation unknown\", \"In vivo substrates beyond Arf1 not tested in endogenous settings\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrating that AGAP1 specifically binds the AP-3 adaptor complex and controls LAMP1 trafficking established AGAP1 as a key regulator of the endosomal–lysosomal sorting pathway, distinct from AP-1-associated ArfGAPs.\",\n      \"evidence\": \"Co-immunoprecipitation of AGAP1 PH domain with AP-3 δ/σ3 subunits, siRNA knockdown, LAMP1 trafficking assays, and comparative analysis with AGAP2\",\n      \"pmids\": [\"12967569\", \"16079295\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural determinants of AP-3 selectivity versus AP-1 not defined at atomic level\", \"Cargo repertoire beyond LAMP1 not systematically assessed\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Mapping the Arf1 N-terminal helix (residues 2–17) as the AGAP1 interaction site and identifying critical lysines resolved how AGAP1 recognizes its primary substrate.\",\n      \"evidence\": \"In vitro GAP assays with Arf1 deletion/point mutants and peptide competition\",\n      \"pmids\": [\"15212764\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No co-crystal structure of AGAP1–Arf1 complex\", \"Whether the same interface is used in membrane-bound context is untested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Discovery that Src-mediated tyrosine phosphorylation of AGAP1 enhances its interaction with soluble guanylyl cyclase opened a link between Arf signaling and NO/cGMP pathways.\",\n      \"evidence\": \"Co-immunoprecipitation in vitro and in vivo with Src kinase phosphorylation assay\",\n      \"pmids\": [\"15381706\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of sGC–AGAP1 interaction on cGMP production not shown\", \"Phosphorylation sites on AGAP1 not mapped\", \"Not independently replicated\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showing that AGAP1 bridges the M5 muscarinic receptor to AP-3 for endocytic recycling, and that this pathway modulates dopamine release in vivo, provided the first receptor-specific physiological role for AGAP1 in the nervous system.\",\n      \"evidence\": \"Co-IP of AGAP1–M5, receptor recycling assays in neurons, in vivo striatal dopamine release measurements upon pathway disruption\",\n      \"pmids\": [\"20664521\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other GPCRs use AGAP1/AP-3 for recycling is unknown\", \"Mechanism by which AGAP1 recognizes M5 cytoplasmic domain not mapped\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of the GLD domain as an allosteric protein-binding module activated by RhoA resolved how Rho-family GTPase signals converge on Arf1 inactivation through AGAP1.\",\n      \"evidence\": \"Two-hybrid screen, Co-IP, in vitro GAP assays with RhoA C-terminal peptides and GLD deletion mutants\",\n      \"pmids\": [\"22453919\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Nucleotide-independence of RhoA binding is unusual and mechanistic basis is unclear\", \"Cdc42 and Rac1 binding specificity not fully resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrating mutual enzymatic activation between AGAP1 and the kinesin Kif2A established a direct link between Arf signaling and microtubule dynamics during cell migration.\",\n      \"evidence\": \"In vitro GAP and ATPase assays, domain-mapping pulldowns, knockdown rescue with binding-deficient mutants in migration/spreading assays\",\n      \"pmids\": [\"27531749\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of Kif2A–AGAP1 complex in neurons not tested\", \"Structural basis of mutual activation unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Localization of AGAP1 to dendritic spines and demonstration that its levels depend on dysbindin placed AGAP1 within a neuronal endosomal network relevant to schizophrenia-associated biology.\",\n      \"evidence\": \"Immunofluorescence in neurons, overexpression/knockdown morphological analysis, DTNBP1 null mouse comparison\",\n      \"pmids\": [\"27713690\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcriptional or post-translational mechanism by which dysbindin regulates AGAP1 not defined\", \"Causal role of AGAP1 reduction in schizophrenia-related phenotypes not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showing that AGAP1 controls FilGAP localization to intracellular vesicles and that AGAP1 loss redirects FilGAP to focal adhesions revealed a new mechanism by which AGAP1 indirectly regulates Rac-dependent cell spreading and invasion.\",\n      \"evidence\": \"Co-IP, colocalization, siRNA knockdown with epistatic rescue, cell spreading/invasion assays\",\n      \"pmids\": [\"31785816\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether AGAP1 GAP activity is required for FilGAP relocalization or only scaffolding is unclear\", \"Single-lab finding not yet independently replicated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The crystal structure of the GLD domain confirmed a conserved NTPase fold with G1–G5 loops, supporting the model that the GLD serves as a regulatory protein-interaction domain rather than an active GTPase.\",\n      \"evidence\": \"X-ray crystallography at 3.0 Å resolution\",\n      \"pmids\": [\"33830075\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No co-structure with RhoA or Kif2A to reveal allosteric mechanism\", \"Whether GLD binds nucleotide in vivo is unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Two studies expanded AGAP1's functional scope: in cancer, mutant p53 stabilizes AGAP1 mRNA to promote exosome-mediated proliferation and metastasis; in Drosophila, loss of the AGAP1 ortholog CenG1a disrupts endolysosomal trafficking and constitutively activates the integrated stress response.\",\n      \"evidence\": \"RNA stability assays and proliferation/migration assays in cancer cells; Drosophila loss-of-function genetics with phospho-eIF2α readouts\",\n      \"pmids\": [\"37030635\", \"37470098\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which AGAP1 promotes exosome biogenesis is undefined\", \"Whether ISR dysregulation upon AGAP1 loss is conserved in mammals is untested\", \"Single-lab findings for each\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include the structural basis of AGAP1's allosteric regulation by the GLD domain, whether AGAP1 functions as a scaffold independent of its GAP activity in vivo, the full cargo repertoire of AGAP1/AP-3 trafficking, and whether AGAP1 dysfunction directly contributes to neuropsychiatric or cancer pathology in humans.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No full-length AGAP1 structure or AGAP1–partner co-structure available\", \"No genetic disease association established by human family studies\", \"Systematic identification of AGAP1-dependent cargoes not performed\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 3, 7, 9]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 6, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [1, 2, 5, 8]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [1, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [2, 5, 6, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 7, 9]}\n    ],\n    \"complexes\": [\n      \"AP-3 adaptor complex\"\n    ],\n    \"partners\": [\n      \"ARF1\",\n      \"AP3D1\",\n      \"AP3S1\",\n      \"RHOA\",\n      \"KIF2A\",\n      \"CHRM5\",\n      \"FILGAP\",\n      \"GUCY1A1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}