{"gene":"DIP2A","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2010,"finding":"DIP2A was identified as a direct binding partner (receptor) of the secreted glycoprotein FSTL1 on the surface of endothelial cells. Co-immunoprecipitation demonstrated physical interaction; siRNA knockdown of DIP2A reduced FSTL1 binding to cells and abolished FSTL1-induced Akt phosphorylation, endothelial cell survival, migration, and differentiation into network structures, as well as the protective effect of FSTL1 against hypoxia/reoxygenation-induced apoptosis in cardiac myocytes.","method":"Co-immunoprecipitation from membrane fraction; siRNA knockdown with functional readouts (Akt phosphorylation, cell survival, migration, tube formation, apoptosis assays)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, multiple orthogonal functional assays (Akt phosphorylation, migration, survival, apoptosis), replicated across two cell types; founding paper replicated by multiple subsequent studies","pmids":["20054002"],"is_preprint":false},{"year":2018,"finding":"In glioblastoma cells, DIP2A cooperates with the HDAC2-DMAP1 complex to enhance H3K9Ac deacetylation, thereby repressing MGMT transcription and increasing temozolomide sensitivity. FSTL1 competitively binds DIP2A to block its nuclear translocation, preventing DIP2A from associating with the HDAC2-DMAP1 complex, increasing H3K9Ac at the MGMT promoter and promoting MGMT expression and temozolomide resistance. DIP2A depletion abolished the effects of FSTL1 on MGMT expression.","method":"Co-immunoprecipitation (DIP2A-HDAC2-DMAP1 complex), subcellular fractionation (nuclear translocation assay), ChIP (H3K9Ac at MGMT promoter), siRNA/overexpression with drug resistance readouts in vitro and in vivo","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP of complex, ChIP for histone mark, subcellular fractionation, rescue experiment (DIP2A depletion abolishes FSTL1 effect), single lab but multiple orthogonal methods","pmids":["30542120"],"is_preprint":false},{"year":2019,"finding":"DIP2A interacts with cortactin via its PXXP motifs binding to the cortactin SH3 domain, maintaining cortactin acetylation levels. Dip2a knockout in mice caused defects in dendritic spine morphogenesis, thin postsynaptic density, and reduced synaptic transmission of pyramidal neurons. Acetylation-mimetic cortactin restored impaired synaptic transmission and ameliorated repetitive behaviors in Dip2a KO mice, establishing DIP2A-regulated cortactin acetylation as the mechanistic link to autism-like phenotypes.","method":"Co-immunoprecipitation (DIP2A-cortactin); domain mapping (PXXP motif - SH3 domain); Dip2a KO mouse with morphological (spine morphology, PSD thickness by EM), electrophysiological (synaptic transmission), and behavioral (autism-like behavior) readouts; acetylation-mimetic cortactin rescue experiment","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP with domain mapping, KO mouse phenotype across multiple orthogonal readouts (structural, electrophysiological, behavioral), plus mechanistic rescue with acetylation-mimetic cortactin","pmids":["31600191"],"is_preprint":false},{"year":2020,"finding":"FSTL1 binding to DIP2A activates Smad2/3 signaling to promote angiogenesis in endothelial cells. This DIP2A-Smad2/3 activation was shown to be independent of TGFβR1, as TGFβR1 inhibition did not block DIP2A-mediated Smad2/3 phosphorylation or VEGF-A expression. In vivo, exercise-induced skeletal muscle FSTL1 promoted cardiac angiogenesis via this pathway following myocardial infarction in rats.","method":"Western blotting (Smad2/3 phosphorylation), TGFβR1 inhibitor treatment, HUVEC tube formation assay, in vivo rat MI model with AAV-FSTL1, immunofluorescence for DIP2A localization","journal":"Journal of sport and health science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibitor dissection of pathway, in vivo and in vitro concordant results, single lab","pmids":["33246164"],"is_preprint":false},{"year":2018,"finding":"DIP2A expression on tumor cells is required for FSTL1-induced immunoresistance. Blocking the FSTL1-DIP2A axis suppressed cancer progression and metastasis in mouse tumor models with increased mesenchymal stromal/stem cells.","method":"In vivo mouse tumor models; DIP2A expression manipulation in tumor cells with readouts of cancer progression, metastasis, and immune function","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo tumor models with DIP2A manipulation, multiple tumor models tested, single lab","pmids":["30110636"],"is_preprint":false},{"year":2021,"finding":"DIP2A knockout in mouse cerebral cortex inhibited superoxide dismutase (SOD) activity, increased reactive oxygen species (ROS) levels, caused irregular mitochondrial morphology, and impaired mitochondrial metabolism with over-consumption of lipids for energy supply. In vitro gain-of-function experiments confirmed a positive role of DIP2A in scavenging ROS upon oxidative stress.","method":"Dip2a KO mouse; SOD activity assay; ROS measurement; electron microscopy (mitochondrial morphology); metabolic profiling; gain-of-function in vitro ROS scavenging assay","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with multiple orthogonal assays plus in vitro gain-of-function confirmation, single lab","pmids":["33781892"],"is_preprint":false},{"year":2019,"finding":"FSTL1 promotes DLBCL cell proliferation and reduces ADCC. Mechanistically, FSTL1 (secreted by cancer-associated fibroblasts) interacts with DIP2A on DLBCL cells and promotes ICAM-1 expression, contributing to cell adhesion-mediated drug resistance.","method":"Co-immunoprecipitation/interaction assay (FSTL1-DIP2A); ICAM-1 expression measurement; siRNA knockdown; cell proliferation and ADCC assays in vitro","journal":"Biomedicine & pharmacotherapy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mechanistic experiments described in abstract but limited methodological detail; single lab, single paper","pmids":["41616470"],"is_preprint":false},{"year":2024,"finding":"DIP2A is abundantly expressed in excitatory neurons of the basolateral amygdala. Deletion of Dip2a specifically in these neurons resulted in hopelessness-like behavior in the tail suspension test. Dip2a deficiency caused abnormal metabolism of tryptophan and thyroxine in the basolateral amygdala and medial prefrontal cortex, and acute restraint stress induced a decrease in 5-hydroxytryptamine in the basolateral amygdala of Dip2a KO mice.","method":"Conditional/cell-type-specific Dip2a KO; targeted neurotransmitter metabolomics; behavioral testing (tail suspension test); immunofluorescence for cell-type localization","journal":"Neural regeneration research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — cell-type-specific KO with behavioral and metabolomics readouts, direct localization; single lab, single paper","pmids":["39104112"],"is_preprint":false}],"current_model":"DIP2A functions as a cell-surface receptor for the secreted glycoprotein FSTL1, mediating downstream Akt and Smad2/3 signaling to promote endothelial cell survival, migration, and angiogenesis; inside the nucleus, DIP2A associates with the HDAC2-DMAP1 complex to deacetylate H3K9Ac and suppress MGMT transcription (an interaction blocked by FSTL1 binding, which sequesters DIP2A in the cytoplasm); in neurons, DIP2A maintains cortactin acetylation via PXXP–SH3 domain interaction, supporting dendritic spine morphogenesis and synaptic transmission, and in mitochondria DIP2A supports SOD-mediated antioxidant defense."},"narrative":{"mechanistic_narrative":"DIP2A is a cell-surface receptor for the secreted glycoprotein FSTL1 that transduces pro-survival and pro-angiogenic signaling while also functioning intracellularly to control protein acetylation states [PMID:20054002, PMID:31600191]. At the endothelial surface, FSTL1 binding to DIP2A drives Akt phosphorylation to support endothelial cell survival, migration, and tube formation, and protects cardiac myocytes against hypoxia/reoxygenation injury [PMID:20054002]; the same axis activates Smad2/3 signaling independently of TGFβR1 to induce VEGF-A and promote angiogenesis, including exercise-induced cardiac angiogenesis after myocardial infarction [PMID:33246164]. In tumor cells, the FSTL1–DIP2A axis mediates immunoresistance and supports cancer progression and metastasis [PMID:30110636]. DIP2A also acts in the nucleus, where it associates with the HDAC2–DMAP1 complex to promote H3K9Ac deacetylation at the MGMT promoter and repress MGMT transcription, sensitizing glioblastoma cells to temozolomide; FSTL1 competitively binds DIP2A to block its nuclear translocation, derepressing MGMT and conferring drug resistance [PMID:30542120]. In neurons, DIP2A binds cortactin through PXXP-motif/SH3-domain contacts to maintain cortactin acetylation, supporting dendritic spine morphogenesis and synaptic transmission, and its loss produces autism-like phenotypes rescuable by acetylation-mimetic cortactin [PMID:31600191]. DIP2A additionally supports mitochondrial integrity and antioxidant defense, sustaining SOD activity and limiting ROS in the cerebral cortex [PMID:33781892].","teleology":[{"year":2010,"claim":"Established the founding molecular identity of DIP2A as the cell-surface receptor through which FSTL1 signals, answering what receptor mediates FSTL1's cytoprotective effects.","evidence":"Co-IP from endothelial membrane fraction plus siRNA knockdown with Akt phosphorylation, survival, migration, tube formation, and apoptosis readouts across endothelial cells and cardiac myocytes","pmids":["20054002"],"confidence":"High","gaps":["No structural basis for the FSTL1-DIP2A interaction","Downstream signaling beyond Akt not delineated in this study"]},{"year":2018,"claim":"Defined a nuclear, chromatin-regulatory role for DIP2A and showed FSTL1 controls its subcellular partitioning, explaining how the FSTL1 axis modulates chemoresistance.","evidence":"Co-IP of DIP2A-HDAC2-DMAP1 complex, subcellular fractionation, ChIP for H3K9Ac at the MGMT promoter, and rescue with DIP2A depletion in glioblastoma models in vitro and in vivo","pmids":["30542120"],"confidence":"High","gaps":["Mechanism of DIP2A nuclear translocation not resolved","Whether DIP2A directly contacts chromatin or acts only through HDAC2-DMAP1 unclear"]},{"year":2018,"claim":"Extended the FSTL1-DIP2A axis to tumor immunoresistance, showing tumor-cell DIP2A is required for FSTL1-driven cancer progression.","evidence":"In vivo mouse tumor models with DIP2A manipulation, readouts of progression, metastasis, and immune function","pmids":["30110636"],"confidence":"Medium","gaps":["Molecular signaling linking DIP2A to immunoresistance not defined","Single lab"]},{"year":2019,"claim":"Identified DIP2A as a regulator of cortactin acetylation via direct domain-level interaction, providing a mechanistic link from DIP2A to synaptic structure and autism-like behavior.","evidence":"Co-IP with PXXP-SH3 domain mapping, Dip2a KO mouse with EM, electrophysiology, behavior, and acetylation-mimetic cortactin rescue","pmids":["31600191"],"confidence":"High","gaps":["How DIP2A maintains cortactin acetylation enzymatically not established","Relationship to the surface-receptor function unclear"]},{"year":2019,"claim":"Generalized the FSTL1-DIP2A interaction to a hematologic malignancy, linking it to ICAM-1 upregulation and adhesion-mediated drug resistance.","evidence":"Interaction assay, siRNA knockdown, ICAM-1 measurement, proliferation and ADCC assays in DLBCL cells","pmids":["41616470"],"confidence":"Low","gaps":["Limited methodological detail in available record","Reciprocal interaction validation not described","Single lab, single paper"]},{"year":2020,"claim":"Resolved a second signaling output of the FSTL1-DIP2A axis, showing Smad2/3 activation occurs independently of TGFβR1 to drive angiogenesis.","evidence":"Smad2/3 phosphorylation Western blotting, TGFβR1 inhibitor dissection, HUVEC tube formation, and in vivo rat MI model with AAV-FSTL1","pmids":["33246164"],"confidence":"Medium","gaps":["How DIP2A couples to Smad2/3 without a TGFβ receptor unknown","Single lab"]},{"year":2021,"claim":"Revealed a mitochondrial/antioxidant function for DIP2A, showing it sustains SOD activity and limits ROS to preserve mitochondrial integrity.","evidence":"Dip2a KO mouse cortex with SOD activity, ROS measurement, EM, metabolic profiling, and in vitro gain-of-function ROS scavenging","pmids":["33781892"],"confidence":"Medium","gaps":["Molecular mechanism connecting DIP2A to SOD activity unknown","Whether mitochondrial role is direct or secondary unresolved"]},{"year":2024,"claim":"Mapped DIP2A to a defined neural circuit, linking its loss to neurotransmitter metabolic dysregulation and depression-like behavior.","evidence":"Cell-type-specific Dip2a KO in basolateral amygdala excitatory neurons, targeted metabolomics, tail suspension test, and immunofluorescence localization","pmids":["39104112"],"confidence":"Medium","gaps":["Causal molecular link between DIP2A and tryptophan/thyroxine metabolism not defined","Single lab, single paper"]},{"year":null,"claim":"How DIP2A's surface-receptor, nuclear chromatin, cortactin-regulatory, and mitochondrial functions are biochemically unified within one protein remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of DIP2A","No defined catalytic activity reconciling its diverse roles","Mechanism of subcellular partitioning between membrane and nucleus incompletely characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[0]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,3]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[1]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[2,7]}],"complexes":["HDAC2-DMAP1 complex"],"partners":["FSTL1","HDAC2","DMAP1","CTTN"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14689","full_name":"Disco-interacting protein 2 homolog A","aliases":[],"length_aa":1571,"mass_kda":170.4,"function":"Catalyzes the de novo synthesis of acetyl-CoA in vitro (By similarity). Promotes acetylation of CTTN, possibly by providing the acetyl donor, ensuring correct dendritic spine morphology and synaptic transmission (By similarity). Binds to follistatin-related protein FSTL1 and may act as a cell surface receptor for FSTL1, contributing to AKT activation and subsequent FSTL1-induced survival and function of endothelial cells and cardiac myocytes (PubMed:20054002)","subcellular_location":"Cell membrane; Mitochondrion; Cell projection, dendritic spine","url":"https://www.uniprot.org/uniprotkb/Q14689/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DIP2A","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/DIP2A","total_profiled":1310},"omim":[{"mim_id":"607711","title":"DISCO-INTERACTING PROTEIN 2 HOMOLOG A; DIP2A","url":"https://www.omim.org/entry/607711"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Nucleoplasm","reliability":"Uncertain"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Actin filaments","reliability":"Additional"},{"location":"Focal adhesion sites","reliability":"Additional"},{"location":"Mitochondria","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/DIP2A"},"hgnc":{"alias_symbol":["Dip2","KIAA0184"],"prev_symbol":["C21orf106"]},"alphafold":{"accession":"Q14689","domains":[{"cath_id":"3.30.300.30","chopping":"816-937","consensus_level":"medium","plddt":87.61,"start":816,"end":937},{"cath_id":"3.30.300.30","chopping":"1463-1570","consensus_level":"high","plddt":89.3768,"start":1463,"end":1570}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14689","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14689-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14689-F1-predicted_aligned_error_v6.png","plddt_mean":78.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DIP2A","jax_strain_url":"https://www.jax.org/strain/search?query=DIP2A"},"sequence":{"accession":"Q14689","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14689.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14689/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14689"}},"corpus_meta":[{"pmid":"20054002","id":"PMC_20054002","title":"DIP2A functions as a FSTL1 receptor.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20054002","citation_count":110,"is_preprint":false},{"pmid":"33246164","id":"PMC_33246164","title":"Dynamic resistance exercise increases skeletal muscle-derived FSTL1 inducing cardiac angiogenesis via DIP2A-Smad2/3 in rats following myocardial infarction.","date":"2020","source":"Journal of sport and health science","url":"https://pubmed.ncbi.nlm.nih.gov/33246164","citation_count":67,"is_preprint":false},{"pmid":"30542120","id":"PMC_30542120","title":"Fstl1/DIP2A/MGMT signaling pathway plays important roles in temozolomide resistance in glioblastoma.","date":"2018","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/30542120","citation_count":47,"is_preprint":false},{"pmid":"31600191","id":"PMC_31600191","title":"Autism candidate gene DIP2A regulates spine morphogenesis via acetylation of cortactin.","date":"2019","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/31600191","citation_count":45,"is_preprint":false},{"pmid":"30110636","id":"PMC_30110636","title":"Blocking the FSTL1-DIP2A Axis Improves Anti-tumor Immunity.","date":"2018","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/30110636","citation_count":37,"is_preprint":false},{"pmid":"26605542","id":"PMC_26605542","title":"Expression Patterns and Potential Biological Roles of Dip2a.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26605542","citation_count":29,"is_preprint":false},{"pmid":"26452339","id":"PMC_26452339","title":"Genetic variant in DIP2A gene is associated with developmental dyslexia in Chinese population.","date":"2015","source":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26452339","citation_count":28,"is_preprint":false},{"pmid":"33781892","id":"PMC_33781892","title":"DIP2A is involved in SOD-mediated antioxidative reactions in murine brain.","date":"2021","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33781892","citation_count":22,"is_preprint":false},{"pmid":"31291246","id":"PMC_31291246","title":"Transcriptome profiling of mouse brain and lung under Dip2a regulation using RNA-sequencing.","date":"2019","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/31291246","citation_count":8,"is_preprint":false},{"pmid":"32361465","id":"PMC_32361465","title":"Generation of Dip2a homozygous knockout murine ES cell line IBMSe001-A-1 via CRISPR/Cas9 technology.","date":"2020","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/32361465","citation_count":6,"is_preprint":false},{"pmid":"34562157","id":"PMC_34562157","title":"A pilot study to investigate the alteration of gut microbial profile in Dip2a knockout mice.","date":"2021","source":"International microbiology : the official journal of the Spanish Society for Microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/34562157","citation_count":5,"is_preprint":false},{"pmid":"37897975","id":"PMC_37897975","title":"Disco interacting protein 2 homolog A (DIP2A): A key component in the regulation of brain disorders.","date":"2023","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/37897975","citation_count":4,"is_preprint":false},{"pmid":"33184751","id":"PMC_33184751","title":"Peri-natal growth retardation rate and fat mass accumulation in mice lacking Dip2A is dependent on the dietary composition.","date":"2020","source":"Transgenic research","url":"https://pubmed.ncbi.nlm.nih.gov/33184751","citation_count":4,"is_preprint":false},{"pmid":"31725791","id":"PMC_31725791","title":"Correction: Transcriptome profiling of mouse brain and lung under Dip2a regulation using RNA-sequencing.","date":"2019","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/31725791","citation_count":1,"is_preprint":false},{"pmid":"41251805","id":"PMC_41251805","title":"The FSTL1-DIP2A axis is a significant biomarker for predicting anti-PD1 therapeutic efficacy in advanced gastric cancer.","date":"2025","source":"Cancer immunology, immunotherapy : CII","url":"https://pubmed.ncbi.nlm.nih.gov/41251805","citation_count":0,"is_preprint":false},{"pmid":"38292475","id":"PMC_38292475","title":"Transcriptomic profiling of Dip2a in the neural differentiation of mouse embryonic stem cells.","date":"2023","source":"Computational and structural biotechnology journal","url":"https://pubmed.ncbi.nlm.nih.gov/38292475","citation_count":0,"is_preprint":false},{"pmid":"39104112","id":"PMC_39104112","title":"Dip2a regulates stress susceptibility in the basolateral amygdala.","date":"2024","source":"Neural regeneration research","url":"https://pubmed.ncbi.nlm.nih.gov/39104112","citation_count":0,"is_preprint":false},{"pmid":"41814799","id":"PMC_41814799","title":"[Baicalin ameliorates obesity-related lung injury by targeting FSTL1/DIP2A signaling pathway].","date":"2026","source":"Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica","url":"https://pubmed.ncbi.nlm.nih.gov/41814799","citation_count":0,"is_preprint":false},{"pmid":"41616470","id":"PMC_41616470","title":"FSTL1 contribute to aggressive clinical behavior in DLBCL may by activating the DIP2A/ICAM-1-mediated adhesion mechanism.","date":"2026","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/41616470","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11542,"output_tokens":2501,"usd":0.03607,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9687,"output_tokens":3083,"usd":0.062755,"stage2_stop_reason":"end_turn"},"total_usd":0.098825,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2010,\n      \"finding\": \"DIP2A was identified as a direct binding partner (receptor) of the secreted glycoprotein FSTL1 on the surface of endothelial cells. Co-immunoprecipitation demonstrated physical interaction; siRNA knockdown of DIP2A reduced FSTL1 binding to cells and abolished FSTL1-induced Akt phosphorylation, endothelial cell survival, migration, and differentiation into network structures, as well as the protective effect of FSTL1 against hypoxia/reoxygenation-induced apoptosis in cardiac myocytes.\",\n      \"method\": \"Co-immunoprecipitation from membrane fraction; siRNA knockdown with functional readouts (Akt phosphorylation, cell survival, migration, tube formation, apoptosis assays)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, multiple orthogonal functional assays (Akt phosphorylation, migration, survival, apoptosis), replicated across two cell types; founding paper replicated by multiple subsequent studies\",\n      \"pmids\": [\"20054002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In glioblastoma cells, DIP2A cooperates with the HDAC2-DMAP1 complex to enhance H3K9Ac deacetylation, thereby repressing MGMT transcription and increasing temozolomide sensitivity. FSTL1 competitively binds DIP2A to block its nuclear translocation, preventing DIP2A from associating with the HDAC2-DMAP1 complex, increasing H3K9Ac at the MGMT promoter and promoting MGMT expression and temozolomide resistance. DIP2A depletion abolished the effects of FSTL1 on MGMT expression.\",\n      \"method\": \"Co-immunoprecipitation (DIP2A-HDAC2-DMAP1 complex), subcellular fractionation (nuclear translocation assay), ChIP (H3K9Ac at MGMT promoter), siRNA/overexpression with drug resistance readouts in vitro and in vivo\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of complex, ChIP for histone mark, subcellular fractionation, rescue experiment (DIP2A depletion abolishes FSTL1 effect), single lab but multiple orthogonal methods\",\n      \"pmids\": [\"30542120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DIP2A interacts with cortactin via its PXXP motifs binding to the cortactin SH3 domain, maintaining cortactin acetylation levels. Dip2a knockout in mice caused defects in dendritic spine morphogenesis, thin postsynaptic density, and reduced synaptic transmission of pyramidal neurons. Acetylation-mimetic cortactin restored impaired synaptic transmission and ameliorated repetitive behaviors in Dip2a KO mice, establishing DIP2A-regulated cortactin acetylation as the mechanistic link to autism-like phenotypes.\",\n      \"method\": \"Co-immunoprecipitation (DIP2A-cortactin); domain mapping (PXXP motif - SH3 domain); Dip2a KO mouse with morphological (spine morphology, PSD thickness by EM), electrophysiological (synaptic transmission), and behavioral (autism-like behavior) readouts; acetylation-mimetic cortactin rescue experiment\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP with domain mapping, KO mouse phenotype across multiple orthogonal readouts (structural, electrophysiological, behavioral), plus mechanistic rescue with acetylation-mimetic cortactin\",\n      \"pmids\": [\"31600191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FSTL1 binding to DIP2A activates Smad2/3 signaling to promote angiogenesis in endothelial cells. This DIP2A-Smad2/3 activation was shown to be independent of TGFβR1, as TGFβR1 inhibition did not block DIP2A-mediated Smad2/3 phosphorylation or VEGF-A expression. In vivo, exercise-induced skeletal muscle FSTL1 promoted cardiac angiogenesis via this pathway following myocardial infarction in rats.\",\n      \"method\": \"Western blotting (Smad2/3 phosphorylation), TGFβR1 inhibitor treatment, HUVEC tube formation assay, in vivo rat MI model with AAV-FSTL1, immunofluorescence for DIP2A localization\",\n      \"journal\": \"Journal of sport and health science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibitor dissection of pathway, in vivo and in vitro concordant results, single lab\",\n      \"pmids\": [\"33246164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DIP2A expression on tumor cells is required for FSTL1-induced immunoresistance. Blocking the FSTL1-DIP2A axis suppressed cancer progression and metastasis in mouse tumor models with increased mesenchymal stromal/stem cells.\",\n      \"method\": \"In vivo mouse tumor models; DIP2A expression manipulation in tumor cells with readouts of cancer progression, metastasis, and immune function\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo tumor models with DIP2A manipulation, multiple tumor models tested, single lab\",\n      \"pmids\": [\"30110636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DIP2A knockout in mouse cerebral cortex inhibited superoxide dismutase (SOD) activity, increased reactive oxygen species (ROS) levels, caused irregular mitochondrial morphology, and impaired mitochondrial metabolism with over-consumption of lipids for energy supply. In vitro gain-of-function experiments confirmed a positive role of DIP2A in scavenging ROS upon oxidative stress.\",\n      \"method\": \"Dip2a KO mouse; SOD activity assay; ROS measurement; electron microscopy (mitochondrial morphology); metabolic profiling; gain-of-function in vitro ROS scavenging assay\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with multiple orthogonal assays plus in vitro gain-of-function confirmation, single lab\",\n      \"pmids\": [\"33781892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FSTL1 promotes DLBCL cell proliferation and reduces ADCC. Mechanistically, FSTL1 (secreted by cancer-associated fibroblasts) interacts with DIP2A on DLBCL cells and promotes ICAM-1 expression, contributing to cell adhesion-mediated drug resistance.\",\n      \"method\": \"Co-immunoprecipitation/interaction assay (FSTL1-DIP2A); ICAM-1 expression measurement; siRNA knockdown; cell proliferation and ADCC assays in vitro\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mechanistic experiments described in abstract but limited methodological detail; single lab, single paper\",\n      \"pmids\": [\"41616470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DIP2A is abundantly expressed in excitatory neurons of the basolateral amygdala. Deletion of Dip2a specifically in these neurons resulted in hopelessness-like behavior in the tail suspension test. Dip2a deficiency caused abnormal metabolism of tryptophan and thyroxine in the basolateral amygdala and medial prefrontal cortex, and acute restraint stress induced a decrease in 5-hydroxytryptamine in the basolateral amygdala of Dip2a KO mice.\",\n      \"method\": \"Conditional/cell-type-specific Dip2a KO; targeted neurotransmitter metabolomics; behavioral testing (tail suspension test); immunofluorescence for cell-type localization\",\n      \"journal\": \"Neural regeneration research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — cell-type-specific KO with behavioral and metabolomics readouts, direct localization; single lab, single paper\",\n      \"pmids\": [\"39104112\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DIP2A functions as a cell-surface receptor for the secreted glycoprotein FSTL1, mediating downstream Akt and Smad2/3 signaling to promote endothelial cell survival, migration, and angiogenesis; inside the nucleus, DIP2A associates with the HDAC2-DMAP1 complex to deacetylate H3K9Ac and suppress MGMT transcription (an interaction blocked by FSTL1 binding, which sequesters DIP2A in the cytoplasm); in neurons, DIP2A maintains cortactin acetylation via PXXP–SH3 domain interaction, supporting dendritic spine morphogenesis and synaptic transmission, and in mitochondria DIP2A supports SOD-mediated antioxidant defense.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DIP2A is a cell-surface receptor for the secreted glycoprotein FSTL1 that transduces pro-survival and pro-angiogenic signaling while also functioning intracellularly to control protein acetylation states [#0, #2]. At the endothelial surface, FSTL1 binding to DIP2A drives Akt phosphorylation to support endothelial cell survival, migration, and tube formation, and protects cardiac myocytes against hypoxia/reoxygenation injury [#0]; the same axis activates Smad2/3 signaling independently of TGFβR1 to induce VEGF-A and promote angiogenesis, including exercise-induced cardiac angiogenesis after myocardial infarction [#3]. In tumor cells, the FSTL1–DIP2A axis mediates immunoresistance and supports cancer progression and metastasis [#4]. DIP2A also acts in the nucleus, where it associates with the HDAC2–DMAP1 complex to promote H3K9Ac deacetylation at the MGMT promoter and repress MGMT transcription, sensitizing glioblastoma cells to temozolomide; FSTL1 competitively binds DIP2A to block its nuclear translocation, derepressing MGMT and conferring drug resistance [#1]. In neurons, DIP2A binds cortactin through PXXP-motif/SH3-domain contacts to maintain cortactin acetylation, supporting dendritic spine morphogenesis and synaptic transmission, and its loss produces autism-like phenotypes rescuable by acetylation-mimetic cortactin [#2]. DIP2A additionally supports mitochondrial integrity and antioxidant defense, sustaining SOD activity and limiting ROS in the cerebral cortex [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established the founding molecular identity of DIP2A as the cell-surface receptor through which FSTL1 signals, answering what receptor mediates FSTL1's cytoprotective effects.\",\n      \"evidence\": \"Co-IP from endothelial membrane fraction plus siRNA knockdown with Akt phosphorylation, survival, migration, tube formation, and apoptosis readouts across endothelial cells and cardiac myocytes\",\n      \"pmids\": [\"20054002\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural basis for the FSTL1-DIP2A interaction\", \"Downstream signaling beyond Akt not delineated in this study\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined a nuclear, chromatin-regulatory role for DIP2A and showed FSTL1 controls its subcellular partitioning, explaining how the FSTL1 axis modulates chemoresistance.\",\n      \"evidence\": \"Co-IP of DIP2A-HDAC2-DMAP1 complex, subcellular fractionation, ChIP for H3K9Ac at the MGMT promoter, and rescue with DIP2A depletion in glioblastoma models in vitro and in vivo\",\n      \"pmids\": [\"30542120\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of DIP2A nuclear translocation not resolved\", \"Whether DIP2A directly contacts chromatin or acts only through HDAC2-DMAP1 unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended the FSTL1-DIP2A axis to tumor immunoresistance, showing tumor-cell DIP2A is required for FSTL1-driven cancer progression.\",\n      \"evidence\": \"In vivo mouse tumor models with DIP2A manipulation, readouts of progression, metastasis, and immune function\",\n      \"pmids\": [\"30110636\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular signaling linking DIP2A to immunoresistance not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified DIP2A as a regulator of cortactin acetylation via direct domain-level interaction, providing a mechanistic link from DIP2A to synaptic structure and autism-like behavior.\",\n      \"evidence\": \"Co-IP with PXXP-SH3 domain mapping, Dip2a KO mouse with EM, electrophysiology, behavior, and acetylation-mimetic cortactin rescue\",\n      \"pmids\": [\"31600191\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How DIP2A maintains cortactin acetylation enzymatically not established\", \"Relationship to the surface-receptor function unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Generalized the FSTL1-DIP2A interaction to a hematologic malignancy, linking it to ICAM-1 upregulation and adhesion-mediated drug resistance.\",\n      \"evidence\": \"Interaction assay, siRNA knockdown, ICAM-1 measurement, proliferation and ADCC assays in DLBCL cells\",\n      \"pmids\": [\"41616470\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Limited methodological detail in available record\", \"Reciprocal interaction validation not described\", \"Single lab, single paper\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved a second signaling output of the FSTL1-DIP2A axis, showing Smad2/3 activation occurs independently of TGFβR1 to drive angiogenesis.\",\n      \"evidence\": \"Smad2/3 phosphorylation Western blotting, TGFβR1 inhibitor dissection, HUVEC tube formation, and in vivo rat MI model with AAV-FSTL1\",\n      \"pmids\": [\"33246164\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How DIP2A couples to Smad2/3 without a TGFβ receptor unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed a mitochondrial/antioxidant function for DIP2A, showing it sustains SOD activity and limits ROS to preserve mitochondrial integrity.\",\n      \"evidence\": \"Dip2a KO mouse cortex with SOD activity, ROS measurement, EM, metabolic profiling, and in vitro gain-of-function ROS scavenging\",\n      \"pmids\": [\"33781892\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism connecting DIP2A to SOD activity unknown\", \"Whether mitochondrial role is direct or secondary unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Mapped DIP2A to a defined neural circuit, linking its loss to neurotransmitter metabolic dysregulation and depression-like behavior.\",\n      \"evidence\": \"Cell-type-specific Dip2a KO in basolateral amygdala excitatory neurons, targeted metabolomics, tail suspension test, and immunofluorescence localization\",\n      \"pmids\": [\"39104112\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal molecular link between DIP2A and tryptophan/thyroxine metabolism not defined\", \"Single lab, single paper\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How DIP2A's surface-receptor, nuclear chromatin, cortactin-regulatory, and mitochondrial functions are biochemically unified within one protein remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of DIP2A\", \"No defined catalytic activity reconciling its diverse roles\", \"Mechanism of subcellular partitioning between membrane and nucleus incompletely characterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [2, 7]}\n    ],\n    \"complexes\": [\"HDAC2-DMAP1 complex\"],\n    \"partners\": [\"FSTL1\", \"HDAC2\", \"DMAP1\", \"CTTN\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}