{"gene":"WDFY2","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2006,"finding":"WDFY2 localizes to a subset of early endosomes residing within 100 nm from the plasma membrane that are positive for transferrin but lack classical markers Rab5 and EEA1; RNAi silencing of WDFY2 in both C. elegans and mammalian cells impairs transferrin endocytosis, establishing a required role in early endocytic processing.","method":"RNAi screen in C. elegans, siRNA knockdown in mammalian cells, quantitative fluorescence microscopy, transferrin uptake assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function with specific endocytic readout replicated across two organisms (C. elegans and mammalian cells) with direct localization data","pmids":["16873553"],"is_preprint":false},{"year":2007,"finding":"FYVE domain variation among FYVE domain-containing proteins, including WDFY2, modulates endosomal binding through differences in oligomerization propensity, membrane bilayer insertion, and electrostatic interactions — properties conferred by residues outside the PtdIns3P head-group recognition site.","method":"In vitro PtdIns3P binding assays, cell-based endosome localization assays with FYVE domain mutants","journal":"Biochemical Society symposium","confidence":"Medium","confidence_rationale":"Tier 1-2 / Weak — biochemical and cell-based assays from a single lab, mechanistic detail on FYVE domain properties but WDFY2-specific mutagenesis data not explicitly described in abstract","pmids":["17233583"],"is_preprint":false},{"year":2010,"finding":"WDFY2-positive early endosomes specifically co-localize with Akt2 but not Akt1; WDFY2 depletion selectively reduces Akt2 protein levels and impairs insulin-stimulated phosphorylation of Akt substrates, glucose transport, and adipogenic gene expression, establishing WDFY2-enriched endosomes as an isoform-specific scaffold for Akt2 signaling downstream of insulin.","method":"Quantitative fluorescence microscopy (co-localization), siRNA knockdown, insulin stimulation assays, phospho-substrate immunoblotting, glucose transport assay, gene expression analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-localization, loss-of-function with multiple orthogonal readouts (protein levels, phosphorylation, glucose transport, gene expression) in a single study","pmids":["20189988"],"is_preprint":false},{"year":2017,"finding":"WDFY2 is identified as an LKB1 regulator downstream of class III PI3K (CIII-PI3K) on endosomes; in Drosophila tissues and human organoids, the endosomal (but not autophagic) function of CIII-PI3K controls epithelial polarity through WDFY2-dependent regulation of LKB1 activity and localization.","method":"Genetic epistasis in Drosophila, human organoid depletion experiments, in vivo co-depletion rescue assays","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis across two model systems (Drosophila and human organoids) with defined pathway placement (CIII-PI3K → WDFY2 → LKB1 → polarity)","pmids":["29084199"],"is_preprint":false},{"year":2018,"finding":"In C. elegans, WDFY-2 levels at periciliary endosomes are controlled by the early endosome maturation factors RABS-5 (Rabenosyn-5) and VPS-45, which regulate periciliary vesicle number and ciliary membrane homeostasis including polycystin-2 (PKD-2) levels.","method":"C. elegans genetics, fluorescence microscopy of endosomal markers, cilia morphology assays","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function in C. elegans with direct imaging of WDFY-2 redistribution, but mechanistic detail specific to WDFY2 function is secondary to the main RABS-5/VPS-45 story","pmids":["29572244"],"is_preprint":false},{"year":2019,"finding":"WDFY2 localizes to endosomal tubules via PtdIns3P binding and interacts with the v-SNARE VAMP3; WDFY2 knockout causes redistribution of VAMP3 into small vesicles near the plasma membrane, leading to increased VAMP3-dependent secretion of MT1-MMP (MMP14), enhanced extracellular matrix degradation, and increased cell invasion.","method":"Co-immunoprecipitation (WDFY2–VAMP3 interaction), WDFY2 knockout cells, live-cell imaging, MT1-MMP secretion assay, extracellular matrix degradation assay, Transwell invasion assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding partner identified by Co-IP, KO with multiple orthogonal readouts (VAMP3 redistribution, MMP secretion, ECM degradation, invasion), VAMP3-dependence confirmed by double manipulation","pmids":["31253801"],"is_preprint":false},{"year":2019,"finding":"WDFY2 deletion causes increased MMP recycling and secretion from endosomes, leading to elevated matrix degradation and cell invasion, consistent with a gatekeeper role for VAMP3-dependent MMP recycling.","method":"WDFY2 knockout, extracellular matrix degradation assay (commentary/summary of PMID:31253801)","journal":"Molecular & cellular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — restatement of findings from the primary paper (PMID:31253801) in a commentary; no new independent experiments","pmids":["31692886"],"is_preprint":false},{"year":2019,"finding":"p63 transcription factor isoforms (ΔN and TA) transcriptionally activate WDFY2 expression through specific p63 response elements in the WDFY2 promoter, validated in TP53-null cells and yeast-based assays, placing WDFY2 downstream of p63 in cancer regulation and limb development networks.","method":"Overexpression of p63 isoforms in TP53-null cells, bioinformatics identification of response elements, yeast-based transcription assay, mammalian reporter assay","journal":"Bioscience reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct transcriptional activation validated by yeast and mammalian reporter assays with identified response elements, single lab","pmids":["31789342"],"is_preprint":false},{"year":2020,"finding":"WDFY2 interacts with the insulin receptor (INSR) via its WD1-4 domain and is required for endosomal localization of INSR after insulin stimulation; this ensures recruitment of IRS1/2 to endosomal INSR, enabling IRS1/2 phosphorylation and downstream Akt2 activation. Wdfy2 knockout mice display systemic insulin resistance with impaired hepatic Akt2 signaling, increased gluconeogenesis, and reduced glycogen accumulation.","method":"Wdfy2 knockout mice, co-immunoprecipitation (WDFY2–INSR interaction, domain mapping), endosomal fractionation, phosphorylation assays (Akt2, FoxO1, GSK-3β), glucose/glycogen metabolic assays, adeno-associated virus rescue in db/db mice","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — KO mouse model with in vivo metabolic phenotype, direct binding partner identified with domain mapping by Co-IP, multiple orthogonal mechanistic readouts, in vivo rescue experiment","pmids":["32641353"],"is_preprint":false},{"year":2025,"finding":"WDFY2 is phosphorylated at serine 84 by the ATM-CHK2 kinase axis in response to DNA double-strand breaks (DSBs); this phosphorylation recruits WDFY2 to DSB sites where it directly interacts with MRE11 and NBS1, bridging the MRE11-RAD50 subcomplex with NBS1 to promote MRN complex formation and DNA end resection required for homologous recombination repair. WDFY2 deficiency or the non-phosphorylatable S84A mutant impairs HR repair and reduces cell survival after DNA damage.","method":"In vitro kinase assay (ATM, CHK2), phosphorylation site mutagenesis (S84A), Co-immunoprecipitation (WDFY2–MRE11, WDFY2–NBS1), laser-induced DSB recruitment assay, HR repair reporter assay, cell survival assay","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct kinase assay identifying writer (ATM-CHK2), active-site mutagenesis (S84A), direct binding partners by Co-IP, functional HR repair assay; single lab but multiple orthogonal methods","pmids":["41196680"],"is_preprint":false},{"year":2025,"finding":"WDFY2 acts as a chaperone that retains VAMP3 at endosomes; phosphorylation of VAMP3 upon LPS-induced dendritic cell activation releases VAMP3 from WDFY2, enabling trafficking of IL-6-positive VAMP3-positive vesicles to the plasma membrane for IL-6 secretion.","method":"Quantitative TIRF microscopy, phosphoproteomic analysis, co-immunoprecipitation (WDFY2–VAMP3), VAMP3 phosphomimetic/phosphodead mutants, IL-6 secretion assay","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying WDFY2–VAMP3 complex with phosphorylation-dependent release, functional secretion assay; single lab, extends prior WDFY2–VAMP3 interaction finding","pmids":["40977280"],"is_preprint":false}],"current_model":"WDFY2 is a PtdIns3P-binding (FYVE domain), WD40 repeat-containing endosomal scaffold protein that (1) defines a subset of early endosomes near the plasma membrane required for endocytosis; (2) promotes isoform-specific Akt2 signaling by recruiting and retaining the insulin receptor and IRS1/2 on endosomes via its WD1-4 domain; (3) gatekeeps VAMP3-dependent recycling of MT1-MMP and IL-6 vesicles from endosomal tubules, suppressing matrix metalloproteinase secretion and cell invasion; (4) acts downstream of CIII-PI3K to regulate LKB1 activity and epithelial polarity; (5) is phosphorylated at S84 by ATM-CHK2 upon DNA damage, whereupon it directly bridges MRE11-RAD50 with NBS1 to assemble the MRN complex at double-strand breaks and promote homologous recombination repair; and (6) is transcriptionally activated by p63 isoforms through defined promoter response elements."},"narrative":{"mechanistic_narrative":"WDFY2 is a PtdIns3P-binding, WD40-repeat endosomal scaffold that defines a distinct subset of early endosomes lying close to the plasma membrane and is required for early endocytic processing of transferrin [PMID:16873553]. From this endosomal platform it organizes isoform-specific insulin signaling: WDFY2-positive endosomes selectively recruit Akt2 over Akt1, and WDFY2 binds the insulin receptor through its WD1-4 domain to retain INSR on endosomes and license IRS1/2 phosphorylation and downstream Akt2 activation; Wdfy2 loss in mice produces systemic insulin resistance with impaired hepatic Akt2 signaling [PMID:20189988, PMID:32641353]. WDFY2 also operates as a gatekeeper of endosomal recycling by binding the v-SNARE VAMP3 and retaining it on endosomal tubules, thereby restraining VAMP3-dependent surface delivery — its loss redistributes VAMP3 to peripheral vesicles, increasing MT1-MMP (MMP14) secretion, matrix degradation and cell invasion [PMID:31253801], and phosphorylation-triggered release of VAMP3 governs IL-6 vesicle secretion during dendritic cell activation [PMID:40977280]. Acting downstream of class III PI3K, WDFY2 regulates LKB1 activity and localization to control epithelial polarity [PMID:29084199]. Beyond its endosomal roles, WDFY2 is phosphorylated at Ser84 by the ATM-CHK2 axis upon DNA double-strand breaks, whereupon it is recruited to break sites and bridges the MRE11-RAD50 subcomplex with NBS1 to assemble the MRN complex and promote end resection and homologous recombination repair [PMID:41196680]. WDFY2 expression is transcriptionally activated by p63 isoforms through defined promoter response elements [PMID:31789342].","teleology":[{"year":2006,"claim":"Established WDFY2 as a marker and functional component of a previously undefined subset of early endosomes, answering whether it has a role in endocytic trafficking.","evidence":"RNAi/siLNA loss-of-function with transferrin uptake assays and localization microscopy across C. elegans and mammalian cells","pmids":["16873553"],"confidence":"High","gaps":["Molecular function on these endosomes not defined","No binding partners identified at this stage","Markers distinguishing this endosome subset beyond transferrin-positive/Rab5-EEA1-negative not fully characterized"]},{"year":2007,"claim":"Clarified that WDFY2's FYVE domain endosome binding depends on properties beyond PtdIns3P head-group recognition, addressing how FYVE proteins achieve differential membrane targeting.","evidence":"In vitro PtdIns3P binding and cell-based localization assays with FYVE domain mutants","pmids":["17233583"],"confidence":"Medium","gaps":["WDFY2-specific mutagenesis data not detailed","Functional consequence of differential binding for WDFY2 not established"]},{"year":2010,"claim":"Defined WDFY2 endosomes as an isoform-selective scaffold for Akt2 in insulin signaling, answering how Akt isoform specificity is achieved spatially.","evidence":"Reciprocal co-localization, siRNA knockdown with insulin stimulation, phospho-substrate immunoblotting, glucose transport and gene expression readouts","pmids":["20189988"],"confidence":"High","gaps":["Direct binding partner linking WDFY2 to Akt2 not yet identified","Mechanism of Akt2 protein-level reduction unclear"]},{"year":2017,"claim":"Placed WDFY2 in a defined signaling cascade (CIII-PI3K → WDFY2 → LKB1) controlling epithelial polarity, answering which downstream effector links endosomal PI3K to polarity.","evidence":"Genetic epistasis in Drosophila and depletion/rescue in human organoids","pmids":["29084199"],"confidence":"High","gaps":["Direct physical interaction between WDFY2 and LKB1 not established","Biochemical mechanism of LKB1 regulation unknown"]},{"year":2018,"claim":"Showed WDFY2 endosomal levels are set by upstream maturation factors and influence ciliary membrane homeostasis, addressing how WDFY2 endosome abundance is regulated.","evidence":"C. elegans genetics with imaging of endosomal markers and cilia morphology","pmids":["29572244"],"confidence":"Medium","gaps":["WDFY2 role secondary to the RABS-5/VPS-45 story","Direct mechanism linking WDFY2 to polycystin-2 levels not defined"]},{"year":2019,"claim":"Identified VAMP3 as a direct WDFY2 partner and established WDFY2 as a gatekeeper restraining MMP recycling and invasion, answering how WDFY2 loss promotes invasive secretion.","evidence":"Co-IP of WDFY2-VAMP3, WDFY2 knockout cells, live-cell imaging, MT1-MMP secretion, ECM degradation and Transwell invasion assays","pmids":["31253801","31692886"],"confidence":"High","gaps":["Structural basis of WDFY2-VAMP3 interaction not resolved","Regulation of the interaction not yet defined"]},{"year":2019,"claim":"Identified p63 isoforms as direct transcriptional activators of WDFY2, answering how WDFY2 expression is controlled in cancer and developmental contexts.","evidence":"p63 isoform overexpression in TP53-null cells, response element bioinformatics, yeast and mammalian reporter assays","pmids":["31789342"],"confidence":"Medium","gaps":["Physiological contexts of p63-driven WDFY2 induction not established","Single lab"]},{"year":2020,"claim":"Resolved the molecular basis of WDFY2's role in insulin signaling by mapping a WD1-4-domain interaction with INSR and demonstrating an in vivo metabolic phenotype, answering how endosomal WDFY2 enables Akt2 activation.","evidence":"Wdfy2 knockout mice, Co-IP with domain mapping, endosomal fractionation, phosphorylation and metabolic assays, AAV rescue in db/db mice","pmids":["32641353"],"confidence":"High","gaps":["Structural details of WD1-4/INSR interface not resolved","How endosomal INSR retention is coupled to IRS1/2 recruitment biochemically not fully defined"]},{"year":2025,"claim":"Extended the WDFY2-VAMP3 axis to immune secretion, showing phosphorylation-dependent release of VAMP3 from WDFY2 controls IL-6 vesicle trafficking, answering how WDFY2-mediated retention is relieved.","evidence":"TIRF microscopy, phosphoproteomics, Co-IP, VAMP3 phosphomimetic/phosphodead mutants, IL-6 secretion assay in LPS-activated dendritic cells","pmids":["40977280"],"confidence":"Medium","gaps":["Kinase responsible for VAMP3 phosphorylation not identified","Single lab extension of prior interaction"]},{"year":2025,"claim":"Revealed a non-endosomal nuclear function: ATM-CHK2-driven Ser84 phosphorylation recruits WDFY2 to break sites to scaffold MRN assembly, answering whether WDFY2 acts directly in DNA repair.","evidence":"In vitro kinase assays, S84A mutagenesis, Co-IP with MRE11 and NBS1, laser-induced DSB recruitment, HR reporter and survival assays","pmids":["41196680"],"confidence":"High","gaps":["Structural basis of the MRE11-RAD50/NBS1 bridging not resolved","How a PtdIns3P-binding endosomal protein accesses nuclear DSB sites not explained","Single lab"]},{"year":null,"claim":"How WDFY2 partitions between its endosomal scaffolding roles and nuclear DNA-repair function, and what controls this functional switch, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No model reconciling cytoplasmic endosomal and nuclear DSB localization","Determinants of context-specific partner selection (INSR vs VAMP3 vs MRN) unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5,8,9,10]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,5]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,2,5]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,8]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[9]}],"complexes":["MRN complex"],"partners":["VAMP3","INSR","MRE11","NBS1","AKT2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96P53","full_name":"WD repeat and FYVE domain-containing protein 2","aliases":["Propeller-FYVE protein","Prof","WD40- and FYVE domain-containing protein 2","Zinc finger FYVE domain-containing protein 22"],"length_aa":400,"mass_kda":45.2,"function":"Acts in an adapter protein-like fashion to mediate the interaction between the kinase PRKCZ and its substrate VAMP2 and increases the PRKCZ-dependent phosphorylation of VAMP2 (PubMed:17313651). Positively regulates adipocyte differentiation, by facilitating the phosphorylation and thus inactivation of the anti-adipogenetic transcription factor FOXO1 by the kinase AKT1 (PubMed:18388859). Plays a role in endosomal control of AKT2 signaling; required for insulin-stimulated AKT2 phosphorylation and glucose uptake and insulin-stimulated phosphorylation of AKT2 substrates (By similarity). Participates in transferrin receptor endocytosis (PubMed:16873553)","subcellular_location":"Endosome; Early endosome; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q96P53/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/WDFY2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/WDFY2","total_profiled":1310},"omim":[{"mim_id":"614240","title":"PH DOMAIN-CONTAINING ENDOCYTIC TRAFFICKING ADAPTOR 2; PHETA2","url":"https://www.omim.org/entry/614240"},{"mim_id":"614239","title":"PH DOMAIN-CONTAINING ENDOCYTIC TRAFFICKING ADAPTOR 1; PHETA1","url":"https://www.omim.org/entry/614239"},{"mim_id":"610418","title":"WD REPEAT- AND FYVE DOMAIN-CONTAINING PROTEIN 2; WDFY2","url":"https://www.omim.org/entry/610418"},{"mim_id":"300535","title":"OCRL INOSITOL POLYPHOSPHATE-5-PHOSPHATASE; OCRL","url":"https://www.omim.org/entry/300535"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/WDFY2"},"hgnc":{"alias_symbol":["ZFYVE22"],"prev_symbol":[]},"alphafold":{"accession":"Q96P53","domains":[{"cath_id":"2.130.10.10","chopping":"16-280_360-395","consensus_level":"medium","plddt":95.956,"start":16,"end":395},{"cath_id":"3.30.40.10","chopping":"299-357","consensus_level":"high","plddt":95.5554,"start":299,"end":357}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96P53","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96P53-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96P53-F1-predicted_aligned_error_v6.png","plddt_mean":94.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=WDFY2","jax_strain_url":"https://www.jax.org/strain/search?query=WDFY2"},"sequence":{"accession":"Q96P53","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96P53.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96P53/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96P53"}},"corpus_meta":[{"pmid":"16873553","id":"PMC_16873553","title":"The WD40 and FYVE domain containing protein 2 defines a class of early endosomes necessary for endocytosis.","date":"2006","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/16873553","citation_count":45,"is_preprint":false},{"pmid":"24675677","id":"PMC_24675677","title":"CDKN2D-WDFY2 is a cancer-specific fusion gene recurrent in high-grade serous ovarian carcinoma.","date":"2014","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24675677","citation_count":41,"is_preprint":false},{"pmid":"30954325","id":"PMC_30954325","title":"Population-based genome-wide association study of cognitive decline in older adults free of dementia: identification of a novel locus for the attention domain.","date":"2019","source":"Neurobiology of aging","url":"https://pubmed.ncbi.nlm.nih.gov/30954325","citation_count":36,"is_preprint":false},{"pmid":"20189988","id":"PMC_20189988","title":"Isoform-specific regulation of Akt signaling by the endosomal protein WDFY2.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20189988","citation_count":35,"is_preprint":false},{"pmid":"31253801","id":"PMC_31253801","title":"WDFY2 restrains matrix metalloproteinase secretion and cell invasion by controlling VAMP3-dependent recycling.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31253801","citation_count":34,"is_preprint":false},{"pmid":"32042757","id":"PMC_32042757","title":"Depletion of MLKL inhibits invasion of radioresistant nasopharyngeal carcinoma cells by suppressing epithelial-mesenchymal transition.","date":"2019","source":"Annals of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32042757","citation_count":28,"is_preprint":false},{"pmid":"29572244","id":"PMC_29572244","title":"Endosome maturation factors Rabenosyn-5/VPS45 and caveolin-1 regulate ciliary membrane and polycystin-2 homeostasis.","date":"2018","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/29572244","citation_count":28,"is_preprint":false},{"pmid":"17233583","id":"PMC_17233583","title":"Evolutionarily conserved structural and functional roles of the FYVE domain.","date":"2007","source":"Biochemical Society symposium","url":"https://pubmed.ncbi.nlm.nih.gov/17233583","citation_count":27,"is_preprint":false},{"pmid":"29084199","id":"PMC_29084199","title":"Class III phosphatidylinositol-3-OH kinase controls epithelial integrity through endosomal LKB1 regulation.","date":"2017","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/29084199","citation_count":25,"is_preprint":false},{"pmid":"30821055","id":"PMC_30821055","title":"Genome-wide DNA methylation investigation of glucocorticoid exposure within buccal samples.","date":"2019","source":"Psychiatry and clinical neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/30821055","citation_count":24,"is_preprint":false},{"pmid":"38509464","id":"PMC_38509464","title":"Elucidation of the genetic determination of body weight and size in Chinese local chicken breeds by large-scale genomic analyses.","date":"2024","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/38509464","citation_count":16,"is_preprint":false},{"pmid":"28653900","id":"PMC_28653900","title":"Overexpression of WDFY2 inhibits prostate cancer cell growth and migration via inactivation of Akt pathway.","date":"2017","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28653900","citation_count":15,"is_preprint":false},{"pmid":"32641353","id":"PMC_32641353","title":"WDFY2 Potentiates Hepatic Insulin Sensitivity and Controls Endosomal Localization of the Insulin Receptor and IRS1/2.","date":"2020","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/32641353","citation_count":11,"is_preprint":false},{"pmid":"29257106","id":"PMC_29257106","title":"A Genome-Wide Association Study and Complex Network Identify Four Core Hub Genes in Bipolar Disorder.","date":"2017","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/29257106","citation_count":11,"is_preprint":false},{"pmid":"31789342","id":"PMC_31789342","title":"P63 modulates the expression of the WDFY2 gene which is implicated in cancer regulation and limb development.","date":"2019","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/31789342","citation_count":7,"is_preprint":false},{"pmid":"36780172","id":"PMC_36780172","title":"Circ_0115118 regulates endometrial functions through the miR-138-1-3p/WDFY2 axis in patients with PCOS†.","date":"2023","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/36780172","citation_count":6,"is_preprint":false},{"pmid":"40016765","id":"PMC_40016765","title":"MicroRNA profiling identifies VHL/HIF-2α dependent miR-2355-5p as a key modulator of clear cell Renal cell carcinoma tumor growth.","date":"2025","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/40016765","citation_count":6,"is_preprint":false},{"pmid":"36971139","id":"PMC_36971139","title":"A pan-cancer analysis of the role of WDFY2 in human tumors.","date":"2023","source":"Biotechnology & genetic engineering reviews","url":"https://pubmed.ncbi.nlm.nih.gov/36971139","citation_count":4,"is_preprint":false},{"pmid":"41196680","id":"PMC_41196680","title":"WDFY2 promotes MRN complex formation required for homologous recombination-mediated DNA repair.","date":"2025","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/41196680","citation_count":1,"is_preprint":false},{"pmid":"31692886","id":"PMC_31692886","title":"Tumor suppression by control of matrix metalloproteinase recycling.","date":"2019","source":"Molecular & cellular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/31692886","citation_count":1,"is_preprint":false},{"pmid":"40977280","id":"PMC_40977280","title":"Phosphorylation of VAMP3 couples IL-6 exocytosis to dendritic cell activation.","date":"2025","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/40977280","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12662,"output_tokens":3263,"usd":0.043465,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10636,"output_tokens":3613,"usd":0.071752,"stage2_stop_reason":"end_turn"},"total_usd":0.115217,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"WDFY2 localizes to a subset of early endosomes residing within 100 nm from the plasma membrane that are positive for transferrin but lack classical markers Rab5 and EEA1; RNAi silencing of WDFY2 in both C. elegans and mammalian cells impairs transferrin endocytosis, establishing a required role in early endocytic processing.\",\n      \"method\": \"RNAi screen in C. elegans, siRNA knockdown in mammalian cells, quantitative fluorescence microscopy, transferrin uptake assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function with specific endocytic readout replicated across two organisms (C. elegans and mammalian cells) with direct localization data\",\n      \"pmids\": [\"16873553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"FYVE domain variation among FYVE domain-containing proteins, including WDFY2, modulates endosomal binding through differences in oligomerization propensity, membrane bilayer insertion, and electrostatic interactions — properties conferred by residues outside the PtdIns3P head-group recognition site.\",\n      \"method\": \"In vitro PtdIns3P binding assays, cell-based endosome localization assays with FYVE domain mutants\",\n      \"journal\": \"Biochemical Society symposium\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Weak — biochemical and cell-based assays from a single lab, mechanistic detail on FYVE domain properties but WDFY2-specific mutagenesis data not explicitly described in abstract\",\n      \"pmids\": [\"17233583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"WDFY2-positive early endosomes specifically co-localize with Akt2 but not Akt1; WDFY2 depletion selectively reduces Akt2 protein levels and impairs insulin-stimulated phosphorylation of Akt substrates, glucose transport, and adipogenic gene expression, establishing WDFY2-enriched endosomes as an isoform-specific scaffold for Akt2 signaling downstream of insulin.\",\n      \"method\": \"Quantitative fluorescence microscopy (co-localization), siRNA knockdown, insulin stimulation assays, phospho-substrate immunoblotting, glucose transport assay, gene expression analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-localization, loss-of-function with multiple orthogonal readouts (protein levels, phosphorylation, glucose transport, gene expression) in a single study\",\n      \"pmids\": [\"20189988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"WDFY2 is identified as an LKB1 regulator downstream of class III PI3K (CIII-PI3K) on endosomes; in Drosophila tissues and human organoids, the endosomal (but not autophagic) function of CIII-PI3K controls epithelial polarity through WDFY2-dependent regulation of LKB1 activity and localization.\",\n      \"method\": \"Genetic epistasis in Drosophila, human organoid depletion experiments, in vivo co-depletion rescue assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis across two model systems (Drosophila and human organoids) with defined pathway placement (CIII-PI3K → WDFY2 → LKB1 → polarity)\",\n      \"pmids\": [\"29084199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In C. elegans, WDFY-2 levels at periciliary endosomes are controlled by the early endosome maturation factors RABS-5 (Rabenosyn-5) and VPS-45, which regulate periciliary vesicle number and ciliary membrane homeostasis including polycystin-2 (PKD-2) levels.\",\n      \"method\": \"C. elegans genetics, fluorescence microscopy of endosomal markers, cilia morphology assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function in C. elegans with direct imaging of WDFY-2 redistribution, but mechanistic detail specific to WDFY2 function is secondary to the main RABS-5/VPS-45 story\",\n      \"pmids\": [\"29572244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"WDFY2 localizes to endosomal tubules via PtdIns3P binding and interacts with the v-SNARE VAMP3; WDFY2 knockout causes redistribution of VAMP3 into small vesicles near the plasma membrane, leading to increased VAMP3-dependent secretion of MT1-MMP (MMP14), enhanced extracellular matrix degradation, and increased cell invasion.\",\n      \"method\": \"Co-immunoprecipitation (WDFY2–VAMP3 interaction), WDFY2 knockout cells, live-cell imaging, MT1-MMP secretion assay, extracellular matrix degradation assay, Transwell invasion assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding partner identified by Co-IP, KO with multiple orthogonal readouts (VAMP3 redistribution, MMP secretion, ECM degradation, invasion), VAMP3-dependence confirmed by double manipulation\",\n      \"pmids\": [\"31253801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"WDFY2 deletion causes increased MMP recycling and secretion from endosomes, leading to elevated matrix degradation and cell invasion, consistent with a gatekeeper role for VAMP3-dependent MMP recycling.\",\n      \"method\": \"WDFY2 knockout, extracellular matrix degradation assay (commentary/summary of PMID:31253801)\",\n      \"journal\": \"Molecular & cellular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — restatement of findings from the primary paper (PMID:31253801) in a commentary; no new independent experiments\",\n      \"pmids\": [\"31692886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"p63 transcription factor isoforms (ΔN and TA) transcriptionally activate WDFY2 expression through specific p63 response elements in the WDFY2 promoter, validated in TP53-null cells and yeast-based assays, placing WDFY2 downstream of p63 in cancer regulation and limb development networks.\",\n      \"method\": \"Overexpression of p63 isoforms in TP53-null cells, bioinformatics identification of response elements, yeast-based transcription assay, mammalian reporter assay\",\n      \"journal\": \"Bioscience reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct transcriptional activation validated by yeast and mammalian reporter assays with identified response elements, single lab\",\n      \"pmids\": [\"31789342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"WDFY2 interacts with the insulin receptor (INSR) via its WD1-4 domain and is required for endosomal localization of INSR after insulin stimulation; this ensures recruitment of IRS1/2 to endosomal INSR, enabling IRS1/2 phosphorylation and downstream Akt2 activation. Wdfy2 knockout mice display systemic insulin resistance with impaired hepatic Akt2 signaling, increased gluconeogenesis, and reduced glycogen accumulation.\",\n      \"method\": \"Wdfy2 knockout mice, co-immunoprecipitation (WDFY2–INSR interaction, domain mapping), endosomal fractionation, phosphorylation assays (Akt2, FoxO1, GSK-3β), glucose/glycogen metabolic assays, adeno-associated virus rescue in db/db mice\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — KO mouse model with in vivo metabolic phenotype, direct binding partner identified with domain mapping by Co-IP, multiple orthogonal mechanistic readouts, in vivo rescue experiment\",\n      \"pmids\": [\"32641353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"WDFY2 is phosphorylated at serine 84 by the ATM-CHK2 kinase axis in response to DNA double-strand breaks (DSBs); this phosphorylation recruits WDFY2 to DSB sites where it directly interacts with MRE11 and NBS1, bridging the MRE11-RAD50 subcomplex with NBS1 to promote MRN complex formation and DNA end resection required for homologous recombination repair. WDFY2 deficiency or the non-phosphorylatable S84A mutant impairs HR repair and reduces cell survival after DNA damage.\",\n      \"method\": \"In vitro kinase assay (ATM, CHK2), phosphorylation site mutagenesis (S84A), Co-immunoprecipitation (WDFY2–MRE11, WDFY2–NBS1), laser-induced DSB recruitment assay, HR repair reporter assay, cell survival assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct kinase assay identifying writer (ATM-CHK2), active-site mutagenesis (S84A), direct binding partners by Co-IP, functional HR repair assay; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"41196680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"WDFY2 acts as a chaperone that retains VAMP3 at endosomes; phosphorylation of VAMP3 upon LPS-induced dendritic cell activation releases VAMP3 from WDFY2, enabling trafficking of IL-6-positive VAMP3-positive vesicles to the plasma membrane for IL-6 secretion.\",\n      \"method\": \"Quantitative TIRF microscopy, phosphoproteomic analysis, co-immunoprecipitation (WDFY2–VAMP3), VAMP3 phosphomimetic/phosphodead mutants, IL-6 secretion assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying WDFY2–VAMP3 complex with phosphorylation-dependent release, functional secretion assay; single lab, extends prior WDFY2–VAMP3 interaction finding\",\n      \"pmids\": [\"40977280\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"WDFY2 is a PtdIns3P-binding (FYVE domain), WD40 repeat-containing endosomal scaffold protein that (1) defines a subset of early endosomes near the plasma membrane required for endocytosis; (2) promotes isoform-specific Akt2 signaling by recruiting and retaining the insulin receptor and IRS1/2 on endosomes via its WD1-4 domain; (3) gatekeeps VAMP3-dependent recycling of MT1-MMP and IL-6 vesicles from endosomal tubules, suppressing matrix metalloproteinase secretion and cell invasion; (4) acts downstream of CIII-PI3K to regulate LKB1 activity and epithelial polarity; (5) is phosphorylated at S84 by ATM-CHK2 upon DNA damage, whereupon it directly bridges MRE11-RAD50 with NBS1 to assemble the MRN complex at double-strand breaks and promote homologous recombination repair; and (6) is transcriptionally activated by p63 isoforms through defined promoter response elements.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"WDFY2 is a PtdIns3P-binding, WD40-repeat endosomal scaffold that defines a distinct subset of early endosomes lying close to the plasma membrane and is required for early endocytic processing of transferrin [#0]. From this endosomal platform it organizes isoform-specific insulin signaling: WDFY2-positive endosomes selectively recruit Akt2 over Akt1, and WDFY2 binds the insulin receptor through its WD1-4 domain to retain INSR on endosomes and license IRS1/2 phosphorylation and downstream Akt2 activation; Wdfy2 loss in mice produces systemic insulin resistance with impaired hepatic Akt2 signaling [#2, #8]. WDFY2 also operates as a gatekeeper of endosomal recycling by binding the v-SNARE VAMP3 and retaining it on endosomal tubules, thereby restraining VAMP3-dependent surface delivery — its loss redistributes VAMP3 to peripheral vesicles, increasing MT1-MMP (MMP14) secretion, matrix degradation and cell invasion [#5], and phosphorylation-triggered release of VAMP3 governs IL-6 vesicle secretion during dendritic cell activation [#10]. Acting downstream of class III PI3K, WDFY2 regulates LKB1 activity and localization to control epithelial polarity [#3]. Beyond its endosomal roles, WDFY2 is phosphorylated at Ser84 by the ATM-CHK2 axis upon DNA double-strand breaks, whereupon it is recruited to break sites and bridges the MRE11-RAD50 subcomplex with NBS1 to assemble the MRN complex and promote end resection and homologous recombination repair [#9]. WDFY2 expression is transcriptionally activated by p63 isoforms through defined promoter response elements [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established WDFY2 as a marker and functional component of a previously undefined subset of early endosomes, answering whether it has a role in endocytic trafficking.\",\n      \"evidence\": \"RNAi/siLNA loss-of-function with transferrin uptake assays and localization microscopy across C. elegans and mammalian cells\",\n      \"pmids\": [\"16873553\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular function on these endosomes not defined\", \"No binding partners identified at this stage\", \"Markers distinguishing this endosome subset beyond transferrin-positive/Rab5-EEA1-negative not fully characterized\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Clarified that WDFY2's FYVE domain endosome binding depends on properties beyond PtdIns3P head-group recognition, addressing how FYVE proteins achieve differential membrane targeting.\",\n      \"evidence\": \"In vitro PtdIns3P binding and cell-based localization assays with FYVE domain mutants\",\n      \"pmids\": [\"17233583\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"WDFY2-specific mutagenesis data not detailed\", \"Functional consequence of differential binding for WDFY2 not established\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined WDFY2 endosomes as an isoform-selective scaffold for Akt2 in insulin signaling, answering how Akt isoform specificity is achieved spatially.\",\n      \"evidence\": \"Reciprocal co-localization, siRNA knockdown with insulin stimulation, phospho-substrate immunoblotting, glucose transport and gene expression readouts\",\n      \"pmids\": [\"20189988\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding partner linking WDFY2 to Akt2 not yet identified\", \"Mechanism of Akt2 protein-level reduction unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed WDFY2 in a defined signaling cascade (CIII-PI3K → WDFY2 → LKB1) controlling epithelial polarity, answering which downstream effector links endosomal PI3K to polarity.\",\n      \"evidence\": \"Genetic epistasis in Drosophila and depletion/rescue in human organoids\",\n      \"pmids\": [\"29084199\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct physical interaction between WDFY2 and LKB1 not established\", \"Biochemical mechanism of LKB1 regulation unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed WDFY2 endosomal levels are set by upstream maturation factors and influence ciliary membrane homeostasis, addressing how WDFY2 endosome abundance is regulated.\",\n      \"evidence\": \"C. elegans genetics with imaging of endosomal markers and cilia morphology\",\n      \"pmids\": [\"29572244\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"WDFY2 role secondary to the RABS-5/VPS-45 story\", \"Direct mechanism linking WDFY2 to polycystin-2 levels not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified VAMP3 as a direct WDFY2 partner and established WDFY2 as a gatekeeper restraining MMP recycling and invasion, answering how WDFY2 loss promotes invasive secretion.\",\n      \"evidence\": \"Co-IP of WDFY2-VAMP3, WDFY2 knockout cells, live-cell imaging, MT1-MMP secretion, ECM degradation and Transwell invasion assays\",\n      \"pmids\": [\"31253801\", \"31692886\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of WDFY2-VAMP3 interaction not resolved\", \"Regulation of the interaction not yet defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified p63 isoforms as direct transcriptional activators of WDFY2, answering how WDFY2 expression is controlled in cancer and developmental contexts.\",\n      \"evidence\": \"p63 isoform overexpression in TP53-null cells, response element bioinformatics, yeast and mammalian reporter assays\",\n      \"pmids\": [\"31789342\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological contexts of p63-driven WDFY2 induction not established\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved the molecular basis of WDFY2's role in insulin signaling by mapping a WD1-4-domain interaction with INSR and demonstrating an in vivo metabolic phenotype, answering how endosomal WDFY2 enables Akt2 activation.\",\n      \"evidence\": \"Wdfy2 knockout mice, Co-IP with domain mapping, endosomal fractionation, phosphorylation and metabolic assays, AAV rescue in db/db mice\",\n      \"pmids\": [\"32641353\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural details of WD1-4/INSR interface not resolved\", \"How endosomal INSR retention is coupled to IRS1/2 recruitment biochemically not fully defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended the WDFY2-VAMP3 axis to immune secretion, showing phosphorylation-dependent release of VAMP3 from WDFY2 controls IL-6 vesicle trafficking, answering how WDFY2-mediated retention is relieved.\",\n      \"evidence\": \"TIRF microscopy, phosphoproteomics, Co-IP, VAMP3 phosphomimetic/phosphodead mutants, IL-6 secretion assay in LPS-activated dendritic cells\",\n      \"pmids\": [\"40977280\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase responsible for VAMP3 phosphorylation not identified\", \"Single lab extension of prior interaction\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed a non-endosomal nuclear function: ATM-CHK2-driven Ser84 phosphorylation recruits WDFY2 to break sites to scaffold MRN assembly, answering whether WDFY2 acts directly in DNA repair.\",\n      \"evidence\": \"In vitro kinase assays, S84A mutagenesis, Co-IP with MRE11 and NBS1, laser-induced DSB recruitment, HR reporter and survival assays\",\n      \"pmids\": [\"41196680\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the MRE11-RAD50/NBS1 bridging not resolved\", \"How a PtdIns3P-binding endosomal protein accesses nuclear DSB sites not explained\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How WDFY2 partitions between its endosomal scaffolding roles and nuclear DNA-repair function, and what controls this functional switch, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No model reconciling cytoplasmic endosomal and nuclear DSB localization\", \"Determinants of context-specific partner selection (INSR vs VAMP3 vs MRN) unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 8, 9, 10]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 2, 5]},\n      {\"term_id\": \"GO:0005769\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 8]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"complexes\": [\"MRN complex\"],\n    \"partners\": [\"VAMP3\", \"INSR\", \"MRE11\", \"NBS1\", \"AKT2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}