{"gene":"AGAP2","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2005,"finding":"AGAP2 directly interacts with the adaptor protein complex AP-1, colocalizes with AP-1, transferrin receptor, and Rab4 on endosomes, and overexpression promotes Rab4-dependent fast recycling of transferrin; this distinguishes AGAP2 from the closely related AGAP1 which associates with AP-3 endosomes.","method":"Co-localization, direct interaction assay, transferrin recycling assay, overexpression","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — reciprocal functional distinction, multiple orthogonal methods, published in peer-reviewed journal with 55 citations","pmids":["16079295"],"is_preprint":false},{"year":2009,"finding":"AGAP2 binds to focal adhesion kinase (FAK) via its pleckstrin homology (PH) domain independently of FAK activation; overexpression of AGAP2 augments FAK activity and promotes focal adhesion dissolution, while knockdown attenuates FAK activity and stabilizes focal adhesions; the focal adhesion dissolution effect is independent of GAP activity but may involve the N-terminal G protein-like domain.","method":"Co-immunoprecipitation, RNA interference knockdown, overexpression, FAK activity assays, focal adhesion imaging","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including domain mutagenesis, KD and OE with defined cellular phenotype","pmids":["19318351"],"is_preprint":false},{"year":2010,"finding":"AGAP2 regulates retrograde transport of cargo (Shiga toxin, cholera toxin, TGN46, mannose 6-phosphate receptor) from early endosomes to the TGN; depletion of AGAP2 causes Shiga toxin to accumulate in transferrin-receptor-positive early endosomes, indicating AGAP2 acts at the very early steps of retrograde sorting; Arf1, but not Arf6, is required for this pathway.","method":"siRNA depletion, intracellular trafficking assays, dominant-negative mutant expression, colocalization imaging","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — multiple cargo proteins tested, genetic epistasis with Arf1, clean KO with specific trafficking phenotype","pmids":["20551179"],"is_preprint":false},{"year":2013,"finding":"AGAP2 forms a complex with β-arrestin1 and β-arrestin2; AGAP2 colocalizes with β-arrestin2 on the plasma membrane and with internalized β2-adrenergic receptors on endosomes; overexpression of AGAP2 slows accumulation of β2-adrenergic receptor in perinuclear recycling endosomes and potentiates ERK phosphorylation; knockdown prevents β2-adrenergic receptor recycling to the plasma membrane.","method":"Co-immunoprecipitation, colocalization, overexpression and knockdown, receptor recycling assay, ERK phosphorylation assay","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods, both KD and OE with defined trafficking and signaling phenotypes","pmids":["23527545"],"is_preprint":false},{"year":2013,"finding":"RACK1 scaffolds AGAP2 to FAK in neuronal cells; the RACK1-AGAP2 complex localizes together in the growth cone of differentiated cells; suppression of AGAP2 by siRNA increases FAK phosphorylation and cell adhesion, resulting in decreased neurite outgrowth.","method":"Immunoprecipitation, mass spectrometry, siRNA knockdown, co-localization in growth cones, FAK phosphorylation assay, neurite outgrowth assay","journal":"Cellular signalling","confidence":"High","confidence_rationale":"Tier 2 — MS-identified interaction confirmed biochemically, multiple orthogonal methods, functional neurite outgrowth phenotype","pmids":["24056044"],"is_preprint":false},{"year":2019,"finding":"In hepatic stellate cells, AGAP2 knockdown partially prevents TGFβ1-induced proliferation, migration, and expression of fibrogenic genes (ACTA2, COL1A2, EDN1, etc.); AGAP2 overexpression enhances collagen-I expression via FAK and MEK1 signaling; TGFβ1 induces AGAP2 promoter activation and protein expression; AGAP2 silencing affects TGFβ receptor 2 (TGFR2) trafficking, blocking its recycling to the membrane.","method":"siRNA knockdown, overexpression, fibrosis gene array, promoter reporter assay, receptor trafficking assay, inhibitor experiments","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including promoter assay, trafficking, and gene expression array; in vitro and in vivo fibrosis model","pmids":["30660615"],"is_preprint":false},{"year":2019,"finding":"SP1 binds the AGAP2 proximal promoter and is required for AGAP2 expression in cancer cells; silencing SP1 decreases AGAP2 protein levels; RARα, RXRα, and the lysine acetyltransferase PCAF are also present at the AGAP2 promoter; all-trans retinoic acid (ATRA) increases AGAP2 protein levels and curcumin reduces ATRA-mediated AGAP2 increase.","method":"Promoter reporter assay, ChIP, siRNA knockdown of SP1, Western blot","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and reporter assay in two cancer cell lines, but single lab","pmids":["30674964"],"is_preprint":false},{"year":2022,"finding":"AGAP2 promotes FcγR-mediated phagocytosis; AGAP2 transiently accumulates at actin-rich phagocytic cups; the GAP domain (but not GAP catalytic activity) is required for recruitment to phagocytic cups and enhancement of engulfment; silencing AGAP2 in neutrophil-like PLB-985 cells reduces phagocytosis; particulate agonists induce AGAP2 phosphorylation in human neutrophils.","method":"Overexpression of deletion/point mutants, phagocytosis assay, colocalization imaging, siRNA knockdown, phosphorylation detection","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 — domain mutagenesis with functional readout, KD phenotype, but single lab","pmids":["36611866"],"is_preprint":false},{"year":2022,"finding":"Demethylzeylasteral (T-96) exerts antifibrotic effects by suppressing AGAP2 expression, inhibiting subsequent phosphorylation of FAK and AKT, and reducing fibrosis-related gene expression in hepatic stellate cells and a CCl4 mouse fibrosis model.","method":"RNA-seq, Western blot, immunofluorescence, immunoprecipitation, in vitro and in vivo fibrosis assays","journal":"Phytomedicine","confidence":"Medium","confidence_rationale":"Tier 2 — RNA-seq plus functional verification, in vitro and in vivo, but mechanistic attribution relies on AGAP2 suppression rather than direct manipulation","pmids":["35905567"],"is_preprint":false},{"year":2026,"finding":"AGAP2 promotes lipid deposition and AML progression by inhibiting the AMPKα/ACC pathway; NR2F2 binds to the AGAP2 promoter and suppresses its transcription; NR2F2 overexpression reduces lipid accumulation, an effect reversed by AGAP2 overexpression.","method":"Promoter binding assay, overexpression and knockdown, mRNA sequencing, KEGG pathway analysis, Filipin III staining, in vivo mouse model","journal":"Cellular oncology (Dordrecht, Netherlands)","confidence":"Medium","confidence_rationale":"Tier 2 — functional rescue experiments linking NR2F2/AGAP2/AMPK axis, in vitro and in vivo, single lab","pmids":["41838329"],"is_preprint":false}],"current_model":"AGAP2 (PIKE-A) is a multi-domain ArfGAP/GTPase that regulates endosomal membrane trafficking (AP-1-dependent recycling, retrograde early endosome-to-TGN transport, β2-adrenergic receptor recycling), focal adhesion dynamics via direct PH-domain binding to FAK and scaffolding through RACK1, FcγR-mediated phagocytosis through its GAP domain, TGFβ receptor trafficking and downstream fibrogenic signaling in hepatic stellate cells, and lipid metabolic reprogramming in AML via inhibition of the AMPKα/ACC pathway; its transcription is driven by SP1 and repressed by NR2F2."},"narrative":{"teleology":[{"year":2005,"claim":"The question of which trafficking compartment AGAP2 operates on was answered by showing it binds AP-1 and localizes to Rab4-positive endosomes, establishing AGAP2 as a regulator of fast endosomal recycling distinct from the AP-3-associated paralog AGAP1.","evidence":"Co-localization, direct interaction assay, and transferrin recycling assay with overexpression in cultured cells","pmids":["16079295"],"confidence":"High","gaps":["The endogenous cargo spectrum regulated by AGAP2-AP-1 interaction is undefined","Whether AGAP2 GAP activity is required for the recycling function was not tested","Rab4 epistasis experiments were not performed"]},{"year":2009,"claim":"The mechanism by which AGAP2 influences cell adhesion was resolved: its PH domain directly binds FAK independently of FAK activation state, and AGAP2 promotes focal adhesion dissolution through a GAP-independent, possibly GLD-dependent mechanism.","evidence":"Co-immunoprecipitation, domain mutants, RNA interference knockdown and overexpression with focal adhesion imaging in HeLa cells","pmids":["19318351"],"confidence":"High","gaps":["The specific contribution of the G protein-like domain to focal adhesion turnover was not fully dissected","In vivo relevance of AGAP2-FAK interaction to cell migration was not demonstrated"]},{"year":2010,"claim":"A previously unrecognized role for AGAP2 in retrograde early-endosome-to-TGN transport was established by showing that AGAP2 depletion traps Shiga toxin, TGN46, and mannose-6-phosphate receptor in early endosomes, and that this pathway requires Arf1 but not Arf6.","evidence":"siRNA depletion, dominant-negative Arf mutants, toxin trafficking and colocalization imaging","pmids":["20551179"],"confidence":"High","gaps":["Whether AGAP2 GAP activity toward Arf1 is catalytically required for retrograde sorting was not directly tested","The coat or adaptor complex partnering with AGAP2 at this step is unknown"]},{"year":2013,"claim":"AGAP2's trafficking role was extended to GPCR biology: it complexes with β-arrestins and controls β2-adrenergic receptor recycling and ERK signaling, linking its endosomal function to receptor-mediated signal transduction.","evidence":"Co-immunoprecipitation with β-arrestins, receptor recycling assay, ERK phosphorylation measurement upon overexpression and knockdown","pmids":["23527545"],"confidence":"High","gaps":["Whether AGAP2 acts on the sorting or tubulation step of receptor recycling is unresolved","Generality to other GPCRs was not tested"]},{"year":2013,"claim":"RACK1 was identified as a scaffold that bridges AGAP2 to FAK in neuronal growth cones, resolving how AGAP2-FAK signaling is spatially organized to control neurite outgrowth.","evidence":"Mass spectrometry, immunoprecipitation, siRNA knockdown with FAK phosphorylation and neurite outgrowth assays in neuronal cells","pmids":["24056044"],"confidence":"High","gaps":["Upstream signals regulating RACK1-AGAP2 assembly are unknown","Whether the RACK1-AGAP2-FAK complex participates in non-neuronal cell migration was not addressed"]},{"year":2019,"claim":"AGAP2 was placed within the hepatic fibrosis signaling network: TGFβ1 transcriptionally induces AGAP2, which in turn sustains TGFβR2 recycling and profibrogenic gene expression through FAK and MEK1, revealing a positive feedback loop.","evidence":"siRNA knockdown and overexpression in hepatic stellate cells, promoter reporter, receptor trafficking assay, in vivo CCl4 fibrosis model","pmids":["30660615"],"confidence":"High","gaps":["Whether AGAP2 directly regulates TGFβR2 sorting or acts indirectly through general recycling machinery is unclear","The promoter elements mediating TGFβ1-induced AGAP2 transcription were not mapped"]},{"year":2019,"claim":"The transcription factor SP1 was identified as a direct driver of AGAP2 expression, with RARα/RXRα and PCAF also occupying the promoter, establishing the first transcriptional regulatory framework for AGAP2.","evidence":"ChIP, promoter reporter assay, SP1 siRNA knockdown, ATRA and curcumin treatments in cancer cell lines","pmids":["30674964"],"confidence":"Medium","gaps":["Single lab study; independent validation needed","Whether SP1 regulation of AGAP2 is cell-type-specific was not assessed","Functional contribution of PCAF-mediated acetylation at the AGAP2 locus is unknown"]},{"year":2022,"claim":"AGAP2 was shown to promote Fcγ receptor–mediated phagocytosis, with the GAP domain—but not its catalytic activity—required for recruitment to phagocytic cups, extending AGAP2 function to innate immunity.","evidence":"Domain deletion and point mutants, phagocytosis assay, siRNA knockdown in PLB-985 neutrophil-like cells, phosphorylation detection in primary neutrophils","pmids":["36611866"],"confidence":"Medium","gaps":["Single lab; independent replication needed","The binding partner recognized by the GAP domain at the phagocytic cup is unidentified","Whether AGAP2 acts upstream or downstream of Arf1 during phagocytosis is unresolved"]},{"year":2022,"claim":"Pharmacological suppression of AGAP2 by demethylzeylasteral phenocopied AGAP2 knockdown in hepatic stellate cells, reducing FAK/AKT phosphorylation and fibrosis, providing orthogonal support for the AGAP2–FAK–fibrosis axis.","evidence":"RNA-seq, Western blot, immunofluorescence, in vitro and in vivo CCl4 fibrosis model","pmids":["35905567"],"confidence":"Medium","gaps":["Mechanistic attribution relies on AGAP2 suppression by a compound that likely has additional targets","Direct rescue with AGAP2 overexpression was not performed"]},{"year":2026,"claim":"AGAP2 was linked to lipid metabolic reprogramming in AML: NR2F2 transcriptionally represses AGAP2, and AGAP2 promotes lipid deposition and leukemia progression by inhibiting the AMPKα/ACC pathway, revealing a non-trafficking metabolic role.","evidence":"Promoter binding assay, overexpression/knockdown rescue experiments, mRNA-seq, Filipin III staining, in vivo AML mouse model","pmids":["41838329"],"confidence":"Medium","gaps":["Single lab; awaits independent confirmation","Mechanism by which AGAP2 inhibits AMPKα is unknown—direct binding or indirect","Whether the lipid metabolic role is unique to AML or generalizable is untested"]},{"year":null,"claim":"A structural understanding of how AGAP2's individual domains (GLD, PH, ArfGAP, ankyrin repeats) cooperate to partition its distinct trafficking, adhesion, phagocytic, and metabolic functions remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of full-length AGAP2 or multi-domain constructs exists","Allosteric regulation between the GLD and GAP domains has not been characterized","Physiological Arf substrate specificity in each functional context is undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[2,7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,4,9]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3,4]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,2,3]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,7]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,4]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,2,3,5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,3,4,5,9]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[9]}],"complexes":[],"partners":["FAK","RACK1","AP1B1","ARRB1","ARRB2","ARF1","SP1","NR2F2"],"other_free_text":[]},"mechanistic_narrative":"AGAP2 is a multi-domain ArfGAP protein that functions as a central regulator of endosomal membrane trafficking and focal adhesion dynamics. It interacts with AP-1 on Rab4-positive endosomes to promote fast recycling of transferrin receptor [PMID:16079295], mediates Arf1-dependent retrograde transport from early endosomes to the TGN [PMID:20551179], and controls β2-adrenergic receptor recycling through a complex with β-arrestins [PMID:23527545]. AGAP2 binds FAK via its PH domain to drive focal adhesion turnover independently of its GAP activity, while the scaffolding protein RACK1 bridges AGAP2 to FAK in neuronal growth cones to regulate neurite outgrowth [PMID:19318351, PMID:24056044]. Beyond trafficking, AGAP2 sustains TGFβ receptor recycling and profibrogenic signaling in hepatic stellate cells [PMID:30660615], promotes Fcγ receptor–mediated phagocytosis through GAP-domain–dependent recruitment to phagocytic cups [PMID:36611866], and drives lipid metabolic reprogramming in AML by inhibiting the AMPKα/ACC pathway under transcriptional repression by NR2F2 [PMID:41838329]."},"prefetch_data":{"uniprot":{"accession":"Q99490","full_name":"Arf-GAP with GTPase, ANK repeat and PH domain-containing protein 2","aliases":["Centaurin-gamma-1","Cnt-g1","GTP-binding and GTPase-activating protein 2","GGAP2","Phosphatidylinositol 3-kinase enhancer","PIKE"],"length_aa":1192,"mass_kda":124.6,"function":"GTPase-activating protein (GAP) for ARF1 and ARF5, which also shows strong GTPase activity. Isoform 1 participates in the prevention of neuronal apoptosis by enhancing PI3 kinase activity. It aids the coupling of metabotropic glutamate receptor 1 (GRM1) to cytoplasmic PI3 kinase by interacting with Homer scaffolding proteins, and also seems to mediate anti-apoptotic effects of NGF by activating nuclear PI3 kinase. Isoform 2 does not stimulate PI3 kinase but may protect cells from apoptosis by stimulating Akt. It also regulates the adapter protein 1 (AP-1)-dependent trafficking of proteins in the endosomal system. It seems to be oncogenic. It is overexpressed in cancer cells, prevents apoptosis and promotes cancer cell invasion","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q99490/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/AGAP2","classification":"Not Classified","n_dependent_lines":200,"n_total_lines":1208,"dependency_fraction":0.16556291390728478},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/AGAP2","total_profiled":1310},"omim":[{"mim_id":"619642","title":"TRANSMEMBRANE p24 TRAFFICKING PROTEIN 2; TMED2","url":"https://www.omim.org/entry/619642"},{"mim_id":"605476","title":"ARF GTPase-ACTIVATING PROTEIN WITH GTPase DOMAIN, ANKYRIN REPEAT, AND PLECKSTRIN HOMOLOGY DOMAIN 2; AGAP2","url":"https://www.omim.org/entry/605476"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"},{"location":"Midbody ring","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":181.6}],"url":"https://www.proteinatlas.org/search/AGAP2"},"hgnc":{"alias_symbol":[],"prev_symbol":["CENTG1"]},"alphafold":{"accession":"Q99490","domains":[{"cath_id":"3.40.50.300","chopping":"407-578","consensus_level":"high","plddt":89.7059,"start":407,"end":578},{"cath_id":"2.30.29.30","chopping":"680-738_876-918","consensus_level":"high","plddt":85.5672,"start":680,"end":918},{"cath_id":"1.10.220.150","chopping":"928-1147","consensus_level":"medium","plddt":91.5535,"start":928,"end":1147}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99490","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q99490-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q99490-F1-predicted_aligned_error_v6.png","plddt_mean":58.59},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=AGAP2","jax_strain_url":"https://www.jax.org/strain/search?query=AGAP2"},"sequence":{"accession":"Q99490","fasta_url":"https://rest.uniprot.org/uniprotkb/Q99490.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q99490/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99490"}},"corpus_meta":[{"pmid":"27195672","id":"PMC_27195672","title":"Upregulated long non-coding RNA AGAP2-AS1 represses LATS2 and KLF2 expression through interacting with EZH2 and LSD1 in non-small-cell lung cancer cells.","date":"2016","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/27195672","citation_count":149,"is_preprint":false},{"pmid":"30157918","id":"PMC_30157918","title":"SP1-induced lncRNA AGAP2-AS1 expression promotes chemoresistance of breast cancer by epigenetic regulation of MyD88.","date":"2018","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/30157918","citation_count":136,"is_preprint":false},{"pmid":"28209205","id":"PMC_28209205","title":"Long noncoding AGAP2-AS1 is activated by SP1 and promotes cell proliferation and invasion in gastric cancer.","date":"2017","source":"Journal of hematology & oncology","url":"https://pubmed.ncbi.nlm.nih.gov/28209205","citation_count":116,"is_preprint":false},{"pmid":"31088485","id":"PMC_31088485","title":"Long non-coding RNA AGAP2-AS1, functioning as a competitive endogenous RNA, upregulates ANXA11 expression by sponging miR-16-5p and promotes proliferation and metastasis in hepatocellular carcinoma.","date":"2019","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/31088485","citation_count":110,"is_preprint":false},{"pmid":"31386624","id":"PMC_31386624","title":"Exosomes derived from microRNA-199a-overexpressing mesenchymal stem cells inhibit glioma progression by down-regulating AGAP2.","date":"2019","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/31386624","citation_count":107,"is_preprint":false},{"pmid":"30814490","id":"PMC_30814490","title":"RREB1-induced upregulation of the lncRNA AGAP2-AS1 regulates the proliferation and migration of pancreatic cancer partly through suppressing ANKRD1 and ANGPTL4.","date":"2019","source":"Cell death & 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colocalizes with AP-1, transferrin receptor, and Rab4 on endosomes, and overexpression promotes Rab4-dependent fast recycling of transferrin; this distinguishes AGAP2 from the closely related AGAP1 which associates with AP-3 endosomes.\",\n      \"method\": \"Co-localization, direct interaction assay, transferrin recycling assay, overexpression\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal functional distinction, multiple orthogonal methods, published in peer-reviewed journal with 55 citations\",\n      \"pmids\": [\"16079295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"AGAP2 binds to focal adhesion kinase (FAK) via its pleckstrin homology (PH) domain independently of FAK activation; overexpression of AGAP2 augments FAK activity and promotes focal adhesion dissolution, while knockdown attenuates FAK activity and stabilizes focal adhesions; the focal adhesion dissolution effect is independent of GAP activity but may involve the N-terminal G protein-like domain.\",\n      \"method\": \"Co-immunoprecipitation, RNA interference knockdown, overexpression, FAK activity assays, focal adhesion imaging\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including domain mutagenesis, KD and OE with defined cellular phenotype\",\n      \"pmids\": [\"19318351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"AGAP2 regulates retrograde transport of cargo (Shiga toxin, cholera toxin, TGN46, mannose 6-phosphate receptor) from early endosomes to the TGN; depletion of AGAP2 causes Shiga toxin to accumulate in transferrin-receptor-positive early endosomes, indicating AGAP2 acts at the very early steps of retrograde sorting; Arf1, but not Arf6, is required for this pathway.\",\n      \"method\": \"siRNA depletion, intracellular trafficking assays, dominant-negative mutant expression, colocalization imaging\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple cargo proteins tested, genetic epistasis with Arf1, clean KO with specific trafficking phenotype\",\n      \"pmids\": [\"20551179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"AGAP2 forms a complex with β-arrestin1 and β-arrestin2; AGAP2 colocalizes with β-arrestin2 on the plasma membrane and with internalized β2-adrenergic receptors on endosomes; overexpression of AGAP2 slows accumulation of β2-adrenergic receptor in perinuclear recycling endosomes and potentiates ERK phosphorylation; knockdown prevents β2-adrenergic receptor recycling to the plasma membrane.\",\n      \"method\": \"Co-immunoprecipitation, colocalization, overexpression and knockdown, receptor recycling assay, ERK phosphorylation assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, both KD and OE with defined trafficking and signaling phenotypes\",\n      \"pmids\": [\"23527545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RACK1 scaffolds AGAP2 to FAK in neuronal cells; the RACK1-AGAP2 complex localizes together in the growth cone of differentiated cells; suppression of AGAP2 by siRNA increases FAK phosphorylation and cell adhesion, resulting in decreased neurite outgrowth.\",\n      \"method\": \"Immunoprecipitation, mass spectrometry, siRNA knockdown, co-localization in growth cones, FAK phosphorylation assay, neurite outgrowth assay\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — MS-identified interaction confirmed biochemically, multiple orthogonal methods, functional neurite outgrowth phenotype\",\n      \"pmids\": [\"24056044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In hepatic stellate cells, AGAP2 knockdown partially prevents TGFβ1-induced proliferation, migration, and expression of fibrogenic genes (ACTA2, COL1A2, EDN1, etc.); AGAP2 overexpression enhances collagen-I expression via FAK and MEK1 signaling; TGFβ1 induces AGAP2 promoter activation and protein expression; AGAP2 silencing affects TGFβ receptor 2 (TGFR2) trafficking, blocking its recycling to the membrane.\",\n      \"method\": \"siRNA knockdown, overexpression, fibrosis gene array, promoter reporter assay, receptor trafficking assay, inhibitor experiments\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including promoter assay, trafficking, and gene expression array; in vitro and in vivo fibrosis model\",\n      \"pmids\": [\"30660615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SP1 binds the AGAP2 proximal promoter and is required for AGAP2 expression in cancer cells; silencing SP1 decreases AGAP2 protein levels; RARα, RXRα, and the lysine acetyltransferase PCAF are also present at the AGAP2 promoter; all-trans retinoic acid (ATRA) increases AGAP2 protein levels and curcumin reduces ATRA-mediated AGAP2 increase.\",\n      \"method\": \"Promoter reporter assay, ChIP, siRNA knockdown of SP1, Western blot\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and reporter assay in two cancer cell lines, but single lab\",\n      \"pmids\": [\"30674964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"AGAP2 promotes FcγR-mediated phagocytosis; AGAP2 transiently accumulates at actin-rich phagocytic cups; the GAP domain (but not GAP catalytic activity) is required for recruitment to phagocytic cups and enhancement of engulfment; silencing AGAP2 in neutrophil-like PLB-985 cells reduces phagocytosis; particulate agonists induce AGAP2 phosphorylation in human neutrophils.\",\n      \"method\": \"Overexpression of deletion/point mutants, phagocytosis assay, colocalization imaging, siRNA knockdown, phosphorylation detection\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain mutagenesis with functional readout, KD phenotype, but single lab\",\n      \"pmids\": [\"36611866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Demethylzeylasteral (T-96) exerts antifibrotic effects by suppressing AGAP2 expression, inhibiting subsequent phosphorylation of FAK and AKT, and reducing fibrosis-related gene expression in hepatic stellate cells and a CCl4 mouse fibrosis model.\",\n      \"method\": \"RNA-seq, Western blot, immunofluorescence, immunoprecipitation, in vitro and in vivo fibrosis assays\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RNA-seq plus functional verification, in vitro and in vivo, but mechanistic attribution relies on AGAP2 suppression rather than direct manipulation\",\n      \"pmids\": [\"35905567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"AGAP2 promotes lipid deposition and AML progression by inhibiting the AMPKα/ACC pathway; NR2F2 binds to the AGAP2 promoter and suppresses its transcription; NR2F2 overexpression reduces lipid accumulation, an effect reversed by AGAP2 overexpression.\",\n      \"method\": \"Promoter binding assay, overexpression and knockdown, mRNA sequencing, KEGG pathway analysis, Filipin III staining, in vivo mouse model\",\n      \"journal\": \"Cellular oncology (Dordrecht, Netherlands)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional rescue experiments linking NR2F2/AGAP2/AMPK axis, in vitro and in vivo, single lab\",\n      \"pmids\": [\"41838329\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"AGAP2 (PIKE-A) is a multi-domain ArfGAP/GTPase that regulates endosomal membrane trafficking (AP-1-dependent recycling, retrograde early endosome-to-TGN transport, β2-adrenergic receptor recycling), focal adhesion dynamics via direct PH-domain binding to FAK and scaffolding through RACK1, FcγR-mediated phagocytosis through its GAP domain, TGFβ receptor trafficking and downstream fibrogenic signaling in hepatic stellate cells, and lipid metabolic reprogramming in AML via inhibition of the AMPKα/ACC pathway; its transcription is driven by SP1 and repressed by NR2F2.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"AGAP2 is a multi-domain ArfGAP protein that functions as a central regulator of endosomal membrane trafficking and focal adhesion dynamics. It interacts with AP-1 on Rab4-positive endosomes to promote fast recycling of transferrin receptor [PMID:16079295], mediates Arf1-dependent retrograde transport from early endosomes to the TGN [PMID:20551179], and controls β2-adrenergic receptor recycling through a complex with β-arrestins [PMID:23527545]. AGAP2 binds FAK via its PH domain to drive focal adhesion turnover independently of its GAP activity, while the scaffolding protein RACK1 bridges AGAP2 to FAK in neuronal growth cones to regulate neurite outgrowth [PMID:19318351, PMID:24056044]. Beyond trafficking, AGAP2 sustains TGFβ receptor recycling and profibrogenic signaling in hepatic stellate cells [PMID:30660615], promotes Fcγ receptor–mediated phagocytosis through GAP-domain–dependent recruitment to phagocytic cups [PMID:36611866], and drives lipid metabolic reprogramming in AML by inhibiting the AMPKα/ACC pathway under transcriptional repression by NR2F2 [PMID:41838329].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"The question of which trafficking compartment AGAP2 operates on was answered by showing it binds AP-1 and localizes to Rab4-positive endosomes, establishing AGAP2 as a regulator of fast endosomal recycling distinct from the AP-3-associated paralog AGAP1.\",\n      \"evidence\": \"Co-localization, direct interaction assay, and transferrin recycling assay with overexpression in cultured cells\",\n      \"pmids\": [\"16079295\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The endogenous cargo spectrum regulated by AGAP2-AP-1 interaction is undefined\",\n        \"Whether AGAP2 GAP activity is required for the recycling function was not tested\",\n        \"Rab4 epistasis experiments were not performed\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"The mechanism by which AGAP2 influences cell adhesion was resolved: its PH domain directly binds FAK independently of FAK activation state, and AGAP2 promotes focal adhesion dissolution through a GAP-independent, possibly GLD-dependent mechanism.\",\n      \"evidence\": \"Co-immunoprecipitation, domain mutants, RNA interference knockdown and overexpression with focal adhesion imaging in HeLa cells\",\n      \"pmids\": [\"19318351\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The specific contribution of the G protein-like domain to focal adhesion turnover was not fully dissected\",\n        \"In vivo relevance of AGAP2-FAK interaction to cell migration was not demonstrated\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"A previously unrecognized role for AGAP2 in retrograde early-endosome-to-TGN transport was established by showing that AGAP2 depletion traps Shiga toxin, TGN46, and mannose-6-phosphate receptor in early endosomes, and that this pathway requires Arf1 but not Arf6.\",\n      \"evidence\": \"siRNA depletion, dominant-negative Arf mutants, toxin trafficking and colocalization imaging\",\n      \"pmids\": [\"20551179\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether AGAP2 GAP activity toward Arf1 is catalytically required for retrograde sorting was not directly tested\",\n        \"The coat or adaptor complex partnering with AGAP2 at this step is unknown\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"AGAP2's trafficking role was extended to GPCR biology: it complexes with β-arrestins and controls β2-adrenergic receptor recycling and ERK signaling, linking its endosomal function to receptor-mediated signal transduction.\",\n      \"evidence\": \"Co-immunoprecipitation with β-arrestins, receptor recycling assay, ERK phosphorylation measurement upon overexpression and knockdown\",\n      \"pmids\": [\"23527545\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether AGAP2 acts on the sorting or tubulation step of receptor recycling is unresolved\",\n        \"Generality to other GPCRs was not tested\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"RACK1 was identified as a scaffold that bridges AGAP2 to FAK in neuronal growth cones, resolving how AGAP2-FAK signaling is spatially organized to control neurite outgrowth.\",\n      \"evidence\": \"Mass spectrometry, immunoprecipitation, siRNA knockdown with FAK phosphorylation and neurite outgrowth assays in neuronal cells\",\n      \"pmids\": [\"24056044\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Upstream signals regulating RACK1-AGAP2 assembly are unknown\",\n        \"Whether the RACK1-AGAP2-FAK complex participates in non-neuronal cell migration was not addressed\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"AGAP2 was placed within the hepatic fibrosis signaling network: TGFβ1 transcriptionally induces AGAP2, which in turn sustains TGFβR2 recycling and profibrogenic gene expression through FAK and MEK1, revealing a positive feedback loop.\",\n      \"evidence\": \"siRNA knockdown and overexpression in hepatic stellate cells, promoter reporter, receptor trafficking assay, in vivo CCl4 fibrosis model\",\n      \"pmids\": [\"30660615\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether AGAP2 directly regulates TGFβR2 sorting or acts indirectly through general recycling machinery is unclear\",\n        \"The promoter elements mediating TGFβ1-induced AGAP2 transcription were not mapped\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The transcription factor SP1 was identified as a direct driver of AGAP2 expression, with RARα/RXRα and PCAF also occupying the promoter, establishing the first transcriptional regulatory framework for AGAP2.\",\n      \"evidence\": \"ChIP, promoter reporter assay, SP1 siRNA knockdown, ATRA and curcumin treatments in cancer cell lines\",\n      \"pmids\": [\"30674964\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab study; independent validation needed\",\n        \"Whether SP1 regulation of AGAP2 is cell-type-specific was not assessed\",\n        \"Functional contribution of PCAF-mediated acetylation at the AGAP2 locus is unknown\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"AGAP2 was shown to promote Fcγ receptor–mediated phagocytosis, with the GAP domain—but not its catalytic activity—required for recruitment to phagocytic cups, extending AGAP2 function to innate immunity.\",\n      \"evidence\": \"Domain deletion and point mutants, phagocytosis assay, siRNA knockdown in PLB-985 neutrophil-like cells, phosphorylation detection in primary neutrophils\",\n      \"pmids\": [\"36611866\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab; independent replication needed\",\n        \"The binding partner recognized by the GAP domain at the phagocytic cup is unidentified\",\n        \"Whether AGAP2 acts upstream or downstream of Arf1 during phagocytosis is unresolved\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Pharmacological suppression of AGAP2 by demethylzeylasteral phenocopied AGAP2 knockdown in hepatic stellate cells, reducing FAK/AKT phosphorylation and fibrosis, providing orthogonal support for the AGAP2–FAK–fibrosis axis.\",\n      \"evidence\": \"RNA-seq, Western blot, immunofluorescence, in vitro and in vivo CCl4 fibrosis model\",\n      \"pmids\": [\"35905567\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanistic attribution relies on AGAP2 suppression by a compound that likely has additional targets\",\n        \"Direct rescue with AGAP2 overexpression was not performed\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"AGAP2 was linked to lipid metabolic reprogramming in AML: NR2F2 transcriptionally represses AGAP2, and AGAP2 promotes lipid deposition and leukemia progression by inhibiting the AMPKα/ACC pathway, revealing a non-trafficking metabolic role.\",\n      \"evidence\": \"Promoter binding assay, overexpression/knockdown rescue experiments, mRNA-seq, Filipin III staining, in vivo AML mouse model\",\n      \"pmids\": [\"41838329\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab; awaits independent confirmation\",\n        \"Mechanism by which AGAP2 inhibits AMPKα is unknown—direct binding or indirect\",\n        \"Whether the lipid metabolic role is unique to AML or generalizable is untested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A structural understanding of how AGAP2's individual domains (GLD, PH, ArfGAP, ankyrin repeats) cooperate to partition its distinct trafficking, adhesion, phagocytic, and metabolic functions remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution structure of full-length AGAP2 or multi-domain constructs exists\",\n        \"Allosteric regulation between the GLD and GAP domains has not been characterized\",\n        \"Physiological Arf substrate specificity in each functional context is undefined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [2, 7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 4, 9]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 7]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 2, 3, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 3, 4, 5, 9]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"FAK\",\n      \"RACK1\",\n      \"AP1B1\",\n      \"ARRB1\",\n      \"ARRB2\",\n      \"ARF1\",\n      \"SP1\",\n      \"NR2F2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}