{"gene":"DIP2A","run_date":"2026-04-28T17:46:02","timeline":{"discoveries":[{"year":2010,"finding":"DIP2A functions as a cell-surface receptor for FSTL1 on endothelial cells and cardiac myocytes, directly binding FSTL1 and mediating its pro-survival, pro-migration, and Akt-phosphorylating effects; knockdown of DIP2A by siRNA reduced FSTL1 binding to cells and abolished FSTL1-induced Akt phosphorylation and cytoprotection.","method":"Co-immunoprecipitation, siRNA knockdown, membrane fractionation, cell-based binding assay, Akt phosphorylation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, siRNA KD with multiple functional readouts, replicated in two cell types","pmids":["20054002"],"is_preprint":false},{"year":2010,"finding":"DIP2A acts as a cell-surface receptor that mediates FRP/FSTL1-induced FOS down-regulation; overexpression of DIP2A augmented FRP-suppression of FOS expression, knockdown of Dip2a led to Fos up-regulation unaffected by exogenous FRP, and Biacore analysis confirmed direct physical binding of FRP to DIP2A.","method":"Yeast two-hybrid, Biacore surface plasmon resonance binding assay, overexpression, siRNA knockdown, FOS expression assay","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro binding kinetics (Biacore), functional overexpression and knockdown with defined molecular readout","pmids":["20860622"],"is_preprint":false},{"year":2018,"finding":"DIP2A cooperates with the HDAC2-DMAP1 complex to enhance H3K9 acetylation deacetylation, thereby repressing MGMT transcription; FSTL1 competitively binds DIP2A to block its nuclear translocation, preventing DIP2A from joining the HDAC2-DMAP1 complex and resulting in elevated H3K9Ac at the MGMT promoter and increased MGMT expression and temozolomide resistance.","method":"Co-immunoprecipitation, nuclear fractionation, H3K9Ac ChIP, siRNA knockdown, overexpression, in vivo xenograft","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (Co-IP, ChIP, fractionation, KD/OE with mechanistic readout), strong mechanistic chain","pmids":["30542120"],"is_preprint":false},{"year":2019,"finding":"DIP2A interacts with cortactin via its PXXP motifs binding the cortactin SH3 domain, and this interaction is required to maintain cortactin acetylation; Dip2a knockout mice show reduced acetylated cortactin, impaired spine morphogenesis with thin PSD, and reduced synaptic transmission, all rescued by acetylation-mimetic cortactin.","method":"Co-immunoprecipitation, Dip2a knockout mouse, domain mutagenesis (PXXP motifs), electrophysiology (synaptic transmission), acetylation assay, behavioral testing","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 1-2 — domain mutagenesis, KO mouse with specific cellular and behavioral phenotypes, rescue experiment with acetylation-mimetic","pmids":["31600191"],"is_preprint":false},{"year":2019,"finding":"DIP2A is a cytoplasmic protein preferentially localized to mitochondria, and possesses acetyl-CoA synthetase activity demonstrated in vitro; overexpression of DIP2A in HEK293 cells increased intracellular acetyl-CoA levels, consistent with this enzymatic function.","method":"Subcellular fractionation, in vitro acetyl-CoA synthetase assay, overexpression in HEK293 cells with acetyl-CoA measurement","journal":"Cell biology international","confidence":"Medium","confidence_rationale":"Tier 1-2 — in vitro enzymatic assay plus cellular gain-of-function, single lab","pmids":["30672040"],"is_preprint":false},{"year":2018,"finding":"C. elegans DIP-2 (ortholog of DIP2A) maintains mature neuronal morphology and inhibits axon regeneration cell-autonomously; loss-of-function causes progressive ectopic neurite sprouting and enhanced axon regrowth, requiring intact adenylate-forming domains (AFDs) but not the DMAP1-binding domain; DIP-2 acts in parallel to DLK-1 MAP kinase and EFA-6 pathways.","method":"C. elegans loss-of-function genetics, domain mutagenesis (AFD and DMAP1-binding domains), epistasis analysis with dlk-1 and efa-6 mutants, in vivo neuronal imaging","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis, domain mutagenesis, cell-autonomy established, replicated across neuron types","pmids":["30396999"],"is_preprint":false},{"year":2020,"finding":"FSTL1 stimulates DIP2A-mediated Smad2/3 phosphorylation to promote cardiac angiogenesis; FSTL1 binds DIP2A to directly activate Smad2/3 independently of TGFβR1, and TGFβR1 inhibitor treatment does not impair DIP2A-Smad2/3 signaling or VEGF-A upregulation.","method":"Western blotting for phospho-Smad2/3, TGFβR1 inhibitor treatment, HUVEC tubule formation assay, immunofluorescence for DIP2A localization, AAV-FSTL1 in vivo model","journal":"Journal of sport and health science","confidence":"Medium","confidence_rationale":"Tier 2-3 — pharmacological inhibitor dissection plus in vivo model, single lab, moderate mechanistic depth","pmids":["33246164"],"is_preprint":false},{"year":2021,"finding":"DIP2A is involved in SOD-mediated antioxidative reactions in murine brain; Dip2a knockout inhibited SOD activity and increased ROS levels in the cerebral cortex, caused irregular mitochondrial morphology, and impaired mitochondrial metabolism with over-reliance on lipid oxidation for energy.","method":"Dip2a knockout mouse, SOD activity assay, ROS measurement, electron microscopy for mitochondrial morphology, metabolic profiling","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse with specific enzymatic and organellar readouts, supported by in vitro gain-of-function, single lab","pmids":["33781892"],"is_preprint":false},{"year":2022,"finding":"DIP2 (yeast/fly/mouse ortholog of DIP2A) is a homeostatic regulator of specific diacylglycerol (DAG) subspecies; its fatty acyl-AMP ligase-like (adenylate-forming) domains are essential for redirecting specific DAG subspecies to triacylglycerol storage, preventing toxic DAG accumulation and ER stress; DIP2 associates with vacuoles via mitochondria-vacuole contact sites to modulate DAG-dependent vacuole membrane fusion and osmoadaptation.","method":"Yeast and Drosophila genetics, lipidomics, genetic screens, in vitro biochemical assay of adenylate-forming domains, fluorescence microscopy for contact-site localization","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 — lipidomics plus domain mutagenesis plus multiple model organisms, reconstitution approach, strong mechanistic chain","pmids":["35766356"],"is_preprint":false},{"year":2025,"finding":"C. elegans DIP-2 (ortholog of DIP2A) genetically counterbalances phospholipid synthesis for axon maintenance and regeneration; loss of dip-2 suppresses axon regrowth defects caused by loss of phospholipid synthesis enzymes CEPT-2 or EPT-1, placing DIP-2 in opposition to the Kennedy pathway of de novo phospholipid synthesis.","method":"C. elegans double-mutant epistasis (genetic suppression), axon regrowth assay after laser axotomy, neuronal imaging","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis with defined pathway, preprint, single lab","pmids":["39974891"],"is_preprint":true},{"year":2024,"finding":"C. elegans DIP-2 acts in a functional network with SAX-2 to maintain neuronal morphology by suppressing extracellular vesicle (EV) release; combined loss of DIP-2 and SAX-2 causes severe neuronal morphology defects and increased EV release, suppressible by gain-of-function in the Dopey family protein PAD-1 or the phospholipid flippase TAT-5/ATP9A.","method":"C. elegans double-mutant genetics, suppressor screen, EV quantification, live fluorescence imaging, domain analysis of PAD-1","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — suppressor screen with orthogonal EV readout and genetic epistasis, preprint, single lab","pmids":["bio_10.1101_2024.05.07.591898"],"is_preprint":true},{"year":2018,"finding":"DIP2A expression in tumor cells is required for FSTL1-induced immunoresistance; blocking the FSTL1-DIP2A axis in mouse tumor models suppressed cancer progression and metastasis while increasing anti-tumor immunity.","method":"Mouse tumor models (in vivo), DIP2A expression manipulation in tumor cells, immune cell profiling","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo tumor model with mechanistic axis (receptor requirement established), single lab","pmids":["30110636"],"is_preprint":false}],"current_model":"DIP2A is a multifunctional conserved protein that acts as a cell-surface receptor for FSTL1 (activating Akt and Smad2/3 signaling), serves as a nuclear co-repressor in complex with HDAC2-DMAP1 to deacetylate H3K9 and suppress MGMT transcription (a function blocked by FSTL1-induced cytoplasmic sequestration), maintains dendritic spine morphology by binding cortactin via PXXP motifs to sustain cortactin acetylation, localizes to mitochondria where it exerts acetyl-CoA synthetase activity and supports SOD-mediated antioxidant defense, and—through its conserved adenylate-forming domains—regulates specific diacylglycerol subspecies homeostasis to prevent ER stress and maintain membrane integrity, with C. elegans DIP-2 additionally acting cell-autonomously to suppress ectopic neurite sprouting and axon regeneration in opposition to phospholipid synthesis pathways."},"narrative":{"teleology":[{"year":2010,"claim":"The identity of the cell-surface receptor mediating FSTL1 signaling was unknown; demonstration that DIP2A directly binds FSTL1 and is required for FSTL1-induced Akt phosphorylation and cytoprotection established DIP2A as a transmembrane receptor activating pro-survival signaling.","evidence":"Co-IP, siRNA knockdown of DIP2A in endothelial cells and cardiomyocytes, membrane fractionation, Biacore binding kinetics","pmids":["20054002","20860622"],"confidence":"High","gaps":["No structural basis for FSTL1-DIP2A interaction","Mechanism by which DIP2A transduces signal to Akt is undefined","Whether DIP2A acts as receptor in non-cardiovascular cell types not established"]},{"year":2018,"claim":"How DIP2A influences gene expression was unclear; showing that DIP2A cooperates with HDAC2-DMAP1 to deacetylate H3K9 at the MGMT promoter, and that FSTL1 blocks this by sequestering DIP2A cytoplasmically, revealed a nuclear co-repressor function modulated by extracellular ligand availability.","evidence":"Co-IP, H3K9Ac ChIP, nuclear fractionation, siRNA/overexpression, xenograft model in glioma cells","pmids":["30542120"],"confidence":"High","gaps":["Genome-wide targets of DIP2A-HDAC2-DMAP1 repression unknown","Whether DIP2A directly contacts chromatin or is recruited via DMAP1 not resolved"]},{"year":2018,"claim":"The neuronal function of DIP2A's conserved adenylate-forming domains was uncharacterized; C. elegans genetics showed that DIP-2 cell-autonomously suppresses ectopic neurite sprouting and axon regeneration through its AFDs but independently of its DMAP1-binding domain, separating its lipid-metabolic and chromatin functions.","evidence":"C. elegans loss-of-function genetics, domain mutagenesis, epistasis with dlk-1 and efa-6, in vivo neuronal imaging","pmids":["30396999"],"confidence":"High","gaps":["Enzymatic substrate of the AFDs in neurons not identified","Downstream effectors linking AFD activity to neurite suppression unknown"]},{"year":2018,"claim":"Whether the FSTL1-DIP2A axis functions in immune evasion was unexplored; tumor model experiments showed DIP2A expression in cancer cells is required for FSTL1-induced immunoresistance and metastasis.","evidence":"Mouse tumor models with DIP2A manipulation, immune cell profiling","pmids":["30110636"],"confidence":"Medium","gaps":["Downstream signaling pathway mediating immune suppression via DIP2A not delineated","Whether DIP2A-dependent immune effects are Akt- or Smad-mediated not tested"]},{"year":2019,"claim":"The synaptic role of DIP2A was unknown; Dip2a knockout mice revealed that DIP2A binds cortactin via PXXP-SH3 interactions to sustain cortactin acetylation, and loss causes thin postsynaptic densities, impaired spine morphogenesis, and reduced synaptic transmission, rescued by acetylation-mimetic cortactin.","evidence":"Dip2a knockout mouse, Co-IP, PXXP domain mutagenesis, electrophysiology, behavioral testing, acetylation assay with rescue","pmids":["31600191"],"confidence":"High","gaps":["Acetyltransferase that modifies cortactin downstream of DIP2A not identified","Whether cortactin mechanism is conserved beyond rodents unknown"]},{"year":2019,"claim":"Whether DIP2A possesses intrinsic enzymatic activity was unclear; in vitro assays demonstrated acetyl-CoA synthetase activity, and overexpression increased cellular acetyl-CoA, linking DIP2A to metabolic acetyl-CoA generation at mitochondria.","evidence":"In vitro acetyl-CoA synthetase assay, subcellular fractionation, overexpression in HEK293 cells","pmids":["30672040"],"confidence":"Medium","gaps":["Kinetic parameters and physiological substrate specificity not defined","Contribution relative to canonical ACS enzymes not established","Single-lab observation"]},{"year":2020,"claim":"Whether DIP2A signals through pathways beyond Akt was unknown; FSTL1-DIP2A was shown to phosphorylate Smad2/3 independently of TGFβR1, promoting VEGF-A upregulation and cardiac angiogenesis.","evidence":"Phospho-Smad2/3 western blot, TGFβR1 inhibitor dissection, HUVEC tubule assay, AAV-FSTL1 in vivo","pmids":["33246164"],"confidence":"Medium","gaps":["Mechanism by which DIP2A activates Smad2/3 without TGFβR1 not defined","Single lab, limited cell type"]},{"year":2021,"claim":"The mitochondrial role of DIP2A beyond acetyl-CoA synthesis was uncharacterized; Dip2a knockout mice showed impaired SOD activity, elevated ROS, abnormal mitochondrial morphology, and metabolic reliance on lipid oxidation, establishing DIP2A as a regulator of mitochondrial antioxidant defense.","evidence":"Dip2a knockout mouse brain, SOD activity assay, ROS measurement, electron microscopy, metabolic profiling","pmids":["33781892"],"confidence":"Medium","gaps":["Whether DIP2A directly activates SOD or acts indirectly via acetyl-CoA/lipid metabolism unresolved","Single lab, correlation between acetyl-CoA and SOD activity not formally tested"]},{"year":2022,"claim":"The biochemical function of DIP2's adenylate-forming domains was unresolved; cross-species lipidomics and reconstitution showed DIP2 acts as a DAG-species-selective enzyme redirecting specific diacylglycerols to triacylglycerol storage, preventing toxic DAG accumulation and ER stress, and localizes to mitochondria-vacuole contact sites to modulate membrane fusion.","evidence":"Yeast and Drosophila genetics, lipidomics, in vitro biochemical assay of AFDs, fluorescence microscopy","pmids":["35766356"],"confidence":"High","gaps":["Exact catalytic mechanism of AFD-mediated DAG-to-TAG conversion not fully reconstituted","Whether mammalian DIP2A performs identical lipid channeling not directly tested in mammalian systems"]},{"year":null,"claim":"How DIP2A's multiple activities — receptor signaling, chromatin repression, cortactin regulation, acetyl-CoA synthesis, and DAG homeostasis — are coordinated across subcellular compartments remains unresolved, and no structural model of full-length DIP2A exists.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of DIP2A or its domains","Relative contribution of receptor vs. enzymatic functions in vivo not dissected","Whether human genetic variants in DIP2A cause a Mendelian disorder not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,6]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,5]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[4,7]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,6]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[2]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[4,8]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[3,5]}],"complexes":["HDAC2-DMAP1"],"partners":["FSTL1","HDAC2","DMAP1","CTTN","SAX2"],"other_free_text":[]},"mechanistic_narrative":"DIP2A is a conserved, multifunctional protein whose adenylate-forming domains regulate diacylglycerol subspecies homeostasis and lipid metabolism, while also serving as a cell-surface receptor for FSTL1 to activate Akt and Smad2/3 signaling independently of TGFβR1 [PMID:20054002, PMID:33246164]. In the nucleus, DIP2A partners with the HDAC2-DMAP1 complex to deacetylate H3K9 and repress MGMT transcription, a function antagonized by FSTL1-mediated cytoplasmic sequestration [PMID:30542120]. DIP2A maintains dendritic spine morphology by binding cortactin through PXXP motifs and sustaining cortactin acetylation, while its mitochondrial pool supports SOD-mediated antioxidant defense and acetyl-CoA production [PMID:31600191, PMID:33781892]. The conserved adenylate-forming domains are essential for redirecting specific diacylglycerol species to triacylglycerol storage to prevent ER stress and, in neurons, for cell-autonomous suppression of ectopic neurite sprouting and axon regeneration in opposition to phospholipid synthesis pathways [PMID:35766356, PMID:30396999]."},"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":"20860622","id":"PMC_20860622","title":"DIP2 disco-interacting protein 2 homolog A (Drosophila) is a candidate receptor for follistatin-related protein/follistatin-like 1--analysis of their binding with TGF-β superfamily proteins.","date":"2010","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/20860622","citation_count":67,"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":65,"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":45,"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":44,"is_preprint":false},{"pmid":"12137943","id":"PMC_12137943","title":"Cloning, genomic organization and expression pattern of a novel Drosophila gene, the disco-interacting protein 2 (dip2), and its murine homolog.","date":"2002","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/12137943","citation_count":37,"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":35,"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":"30396999","id":"PMC_30396999","title":"DIP-2 suppresses ectopic neurite sprouting and axonal regeneration in mature neurons.","date":"2018","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/30396999","citation_count":24,"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":"11432957","id":"PMC_11432957","title":"Arabidopsis coactivator ALY-like proteins, DIP1 and DIP2, interact physically with the DNA-binding domain of the Zn-finger poly(ADP-ribose) polymerase.","date":"2001","source":"Journal of 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& pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/41616470","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":"39974891","id":"PMC_39974891","title":"Context-specific interaction of the lipid regulator DIP-2 with phospholipid synthesis in axon regeneration and maintenance.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/39974891","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.05.07.591898","title":"Dopey-dependent regulation of extracellular vesicles maintains neuronal morphology","date":"2024-05-08","source":"bioRxiv","url":"https://doi.org/10.1101/2024.05.07.591898","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14484,"output_tokens":3166,"usd":0.045471},"stage2":{"model":"claude-opus-4-6","input_tokens":6527,"output_tokens":2894,"usd":0.157477},"total_usd":0.202948,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2010,\n      \"finding\": \"DIP2A functions as a cell-surface receptor for FSTL1 on endothelial cells and cardiac myocytes, directly binding FSTL1 and mediating its pro-survival, pro-migration, and Akt-phosphorylating effects; knockdown of DIP2A by siRNA reduced FSTL1 binding to cells and abolished FSTL1-induced Akt phosphorylation and cytoprotection.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, membrane fractionation, cell-based binding assay, Akt phosphorylation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, siRNA KD with multiple functional readouts, replicated in two cell types\",\n      \"pmids\": [\"20054002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"DIP2A acts as a cell-surface receptor that mediates FRP/FSTL1-induced FOS down-regulation; overexpression of DIP2A augmented FRP-suppression of FOS expression, knockdown of Dip2a led to Fos up-regulation unaffected by exogenous FRP, and Biacore analysis confirmed direct physical binding of FRP to DIP2A.\",\n      \"method\": \"Yeast two-hybrid, Biacore surface plasmon resonance binding assay, overexpression, siRNA knockdown, FOS expression assay\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro binding kinetics (Biacore), functional overexpression and knockdown with defined molecular readout\",\n      \"pmids\": [\"20860622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DIP2A cooperates with the HDAC2-DMAP1 complex to enhance H3K9 acetylation deacetylation, thereby repressing MGMT transcription; FSTL1 competitively binds DIP2A to block its nuclear translocation, preventing DIP2A from joining the HDAC2-DMAP1 complex and resulting in elevated H3K9Ac at the MGMT promoter and increased MGMT expression and temozolomide resistance.\",\n      \"method\": \"Co-immunoprecipitation, nuclear fractionation, H3K9Ac ChIP, siRNA knockdown, overexpression, in vivo xenograft\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Co-IP, ChIP, fractionation, KD/OE with mechanistic readout), strong mechanistic chain\",\n      \"pmids\": [\"30542120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DIP2A interacts with cortactin via its PXXP motifs binding the cortactin SH3 domain, and this interaction is required to maintain cortactin acetylation; Dip2a knockout mice show reduced acetylated cortactin, impaired spine morphogenesis with thin PSD, and reduced synaptic transmission, all rescued by acetylation-mimetic cortactin.\",\n      \"method\": \"Co-immunoprecipitation, Dip2a knockout mouse, domain mutagenesis (PXXP motifs), electrophysiology (synaptic transmission), acetylation assay, behavioral testing\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — domain mutagenesis, KO mouse with specific cellular and behavioral phenotypes, rescue experiment with acetylation-mimetic\",\n      \"pmids\": [\"31600191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DIP2A is a cytoplasmic protein preferentially localized to mitochondria, and possesses acetyl-CoA synthetase activity demonstrated in vitro; overexpression of DIP2A in HEK293 cells increased intracellular acetyl-CoA levels, consistent with this enzymatic function.\",\n      \"method\": \"Subcellular fractionation, in vitro acetyl-CoA synthetase assay, overexpression in HEK293 cells with acetyl-CoA measurement\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro enzymatic assay plus cellular gain-of-function, single lab\",\n      \"pmids\": [\"30672040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"C. elegans DIP-2 (ortholog of DIP2A) maintains mature neuronal morphology and inhibits axon regeneration cell-autonomously; loss-of-function causes progressive ectopic neurite sprouting and enhanced axon regrowth, requiring intact adenylate-forming domains (AFDs) but not the DMAP1-binding domain; DIP-2 acts in parallel to DLK-1 MAP kinase and EFA-6 pathways.\",\n      \"method\": \"C. elegans loss-of-function genetics, domain mutagenesis (AFD and DMAP1-binding domains), epistasis analysis with dlk-1 and efa-6 mutants, in vivo neuronal imaging\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis, domain mutagenesis, cell-autonomy established, replicated across neuron types\",\n      \"pmids\": [\"30396999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FSTL1 stimulates DIP2A-mediated Smad2/3 phosphorylation to promote cardiac angiogenesis; FSTL1 binds DIP2A to directly activate Smad2/3 independently of TGFβR1, and TGFβR1 inhibitor treatment does not impair DIP2A-Smad2/3 signaling or VEGF-A upregulation.\",\n      \"method\": \"Western blotting for phospho-Smad2/3, TGFβR1 inhibitor treatment, HUVEC tubule formation assay, immunofluorescence for DIP2A localization, AAV-FSTL1 in vivo model\",\n      \"journal\": \"Journal of sport and health science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — pharmacological inhibitor dissection plus in vivo model, single lab, moderate mechanistic depth\",\n      \"pmids\": [\"33246164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DIP2A is involved in SOD-mediated antioxidative reactions in murine brain; Dip2a knockout inhibited SOD activity and increased ROS levels in the cerebral cortex, caused irregular mitochondrial morphology, and impaired mitochondrial metabolism with over-reliance on lipid oxidation for energy.\",\n      \"method\": \"Dip2a knockout mouse, SOD activity assay, ROS measurement, electron microscopy for mitochondrial morphology, metabolic profiling\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with specific enzymatic and organellar readouts, supported by in vitro gain-of-function, single lab\",\n      \"pmids\": [\"33781892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DIP2 (yeast/fly/mouse ortholog of DIP2A) is a homeostatic regulator of specific diacylglycerol (DAG) subspecies; its fatty acyl-AMP ligase-like (adenylate-forming) domains are essential for redirecting specific DAG subspecies to triacylglycerol storage, preventing toxic DAG accumulation and ER stress; DIP2 associates with vacuoles via mitochondria-vacuole contact sites to modulate DAG-dependent vacuole membrane fusion and osmoadaptation.\",\n      \"method\": \"Yeast and Drosophila genetics, lipidomics, genetic screens, in vitro biochemical assay of adenylate-forming domains, fluorescence microscopy for contact-site localization\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — lipidomics plus domain mutagenesis plus multiple model organisms, reconstitution approach, strong mechanistic chain\",\n      \"pmids\": [\"35766356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"C. elegans DIP-2 (ortholog of DIP2A) genetically counterbalances phospholipid synthesis for axon maintenance and regeneration; loss of dip-2 suppresses axon regrowth defects caused by loss of phospholipid synthesis enzymes CEPT-2 or EPT-1, placing DIP-2 in opposition to the Kennedy pathway of de novo phospholipid synthesis.\",\n      \"method\": \"C. elegans double-mutant epistasis (genetic suppression), axon regrowth assay after laser axotomy, neuronal imaging\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with defined pathway, preprint, single lab\",\n      \"pmids\": [\"39974891\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"C. elegans DIP-2 acts in a functional network with SAX-2 to maintain neuronal morphology by suppressing extracellular vesicle (EV) release; combined loss of DIP-2 and SAX-2 causes severe neuronal morphology defects and increased EV release, suppressible by gain-of-function in the Dopey family protein PAD-1 or the phospholipid flippase TAT-5/ATP9A.\",\n      \"method\": \"C. elegans double-mutant genetics, suppressor screen, EV quantification, live fluorescence imaging, domain analysis of PAD-1\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — suppressor screen with orthogonal EV readout and genetic epistasis, preprint, single lab\",\n      \"pmids\": [\"bio_10.1101_2024.05.07.591898\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DIP2A expression in tumor cells is required for FSTL1-induced immunoresistance; blocking the FSTL1-DIP2A axis in mouse tumor models suppressed cancer progression and metastasis while increasing anti-tumor immunity.\",\n      \"method\": \"Mouse tumor models (in vivo), DIP2A expression manipulation in tumor cells, immune cell profiling\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo tumor model with mechanistic axis (receptor requirement established), single lab\",\n      \"pmids\": [\"30110636\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DIP2A is a multifunctional conserved protein that acts as a cell-surface receptor for FSTL1 (activating Akt and Smad2/3 signaling), serves as a nuclear co-repressor in complex with HDAC2-DMAP1 to deacetylate H3K9 and suppress MGMT transcription (a function blocked by FSTL1-induced cytoplasmic sequestration), maintains dendritic spine morphology by binding cortactin via PXXP motifs to sustain cortactin acetylation, localizes to mitochondria where it exerts acetyl-CoA synthetase activity and supports SOD-mediated antioxidant defense, and—through its conserved adenylate-forming domains—regulates specific diacylglycerol subspecies homeostasis to prevent ER stress and maintain membrane integrity, with C. elegans DIP-2 additionally acting cell-autonomously to suppress ectopic neurite sprouting and axon regeneration in opposition to phospholipid synthesis pathways.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"DIP2A is a conserved, multifunctional protein whose adenylate-forming domains regulate diacylglycerol subspecies homeostasis and lipid metabolism, while also serving as a cell-surface receptor for FSTL1 to activate Akt and Smad2/3 signaling independently of TGFβR1 [PMID:20054002, PMID:33246164]. In the nucleus, DIP2A partners with the HDAC2-DMAP1 complex to deacetylate H3K9 and repress MGMT transcription, a function antagonized by FSTL1-mediated cytoplasmic sequestration [PMID:30542120]. DIP2A maintains dendritic spine morphology by binding cortactin through PXXP motifs and sustaining cortactin acetylation, while its mitochondrial pool supports SOD-mediated antioxidant defense and acetyl-CoA production [PMID:31600191, PMID:33781892]. The conserved adenylate-forming domains are essential for redirecting specific diacylglycerol species to triacylglycerol storage to prevent ER stress and, in neurons, for cell-autonomous suppression of ectopic neurite sprouting and axon regeneration in opposition to phospholipid synthesis pathways [PMID:35766356, PMID:30396999].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"The identity of the cell-surface receptor mediating FSTL1 signaling was unknown; demonstration that DIP2A directly binds FSTL1 and is required for FSTL1-induced Akt phosphorylation and cytoprotection established DIP2A as a transmembrane receptor activating pro-survival signaling.\",\n      \"evidence\": \"Co-IP, siRNA knockdown of DIP2A in endothelial cells and cardiomyocytes, membrane fractionation, Biacore binding kinetics\",\n      \"pmids\": [\"20054002\", \"20860622\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural basis for FSTL1-DIP2A interaction\",\n        \"Mechanism by which DIP2A transduces signal to Akt is undefined\",\n        \"Whether DIP2A acts as receptor in non-cardiovascular cell types not established\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"How DIP2A influences gene expression was unclear; showing that DIP2A cooperates with HDAC2-DMAP1 to deacetylate H3K9 at the MGMT promoter, and that FSTL1 blocks this by sequestering DIP2A cytoplasmically, revealed a nuclear co-repressor function modulated by extracellular ligand availability.\",\n      \"evidence\": \"Co-IP, H3K9Ac ChIP, nuclear fractionation, siRNA/overexpression, xenograft model in glioma cells\",\n      \"pmids\": [\"30542120\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Genome-wide targets of DIP2A-HDAC2-DMAP1 repression unknown\",\n        \"Whether DIP2A directly contacts chromatin or is recruited via DMAP1 not resolved\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The neuronal function of DIP2A's conserved adenylate-forming domains was uncharacterized; C. elegans genetics showed that DIP-2 cell-autonomously suppresses ectopic neurite sprouting and axon regeneration through its AFDs but independently of its DMAP1-binding domain, separating its lipid-metabolic and chromatin functions.\",\n      \"evidence\": \"C. elegans loss-of-function genetics, domain mutagenesis, epistasis with dlk-1 and efa-6, in vivo neuronal imaging\",\n      \"pmids\": [\"30396999\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Enzymatic substrate of the AFDs in neurons not identified\",\n        \"Downstream effectors linking AFD activity to neurite suppression unknown\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Whether the FSTL1-DIP2A axis functions in immune evasion was unexplored; tumor model experiments showed DIP2A expression in cancer cells is required for FSTL1-induced immunoresistance and metastasis.\",\n      \"evidence\": \"Mouse tumor models with DIP2A manipulation, immune cell profiling\",\n      \"pmids\": [\"30110636\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Downstream signaling pathway mediating immune suppression via DIP2A not delineated\",\n        \"Whether DIP2A-dependent immune effects are Akt- or Smad-mediated not tested\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The synaptic role of DIP2A was unknown; Dip2a knockout mice revealed that DIP2A binds cortactin via PXXP-SH3 interactions to sustain cortactin acetylation, and loss causes thin postsynaptic densities, impaired spine morphogenesis, and reduced synaptic transmission, rescued by acetylation-mimetic cortactin.\",\n      \"evidence\": \"Dip2a knockout mouse, Co-IP, PXXP domain mutagenesis, electrophysiology, behavioral testing, acetylation assay with rescue\",\n      \"pmids\": [\"31600191\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Acetyltransferase that modifies cortactin downstream of DIP2A not identified\",\n        \"Whether cortactin mechanism is conserved beyond rodents unknown\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Whether DIP2A possesses intrinsic enzymatic activity was unclear; in vitro assays demonstrated acetyl-CoA synthetase activity, and overexpression increased cellular acetyl-CoA, linking DIP2A to metabolic acetyl-CoA generation at mitochondria.\",\n      \"evidence\": \"In vitro acetyl-CoA synthetase assay, subcellular fractionation, overexpression in HEK293 cells\",\n      \"pmids\": [\"30672040\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Kinetic parameters and physiological substrate specificity not defined\",\n        \"Contribution relative to canonical ACS enzymes not established\",\n        \"Single-lab observation\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Whether DIP2A signals through pathways beyond Akt was unknown; FSTL1-DIP2A was shown to phosphorylate Smad2/3 independently of TGFβR1, promoting VEGF-A upregulation and cardiac angiogenesis.\",\n      \"evidence\": \"Phospho-Smad2/3 western blot, TGFβR1 inhibitor dissection, HUVEC tubule assay, AAV-FSTL1 in vivo\",\n      \"pmids\": [\"33246164\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which DIP2A activates Smad2/3 without TGFβR1 not defined\",\n        \"Single lab, limited cell type\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The mitochondrial role of DIP2A beyond acetyl-CoA synthesis was uncharacterized; Dip2a knockout mice showed impaired SOD activity, elevated ROS, abnormal mitochondrial morphology, and metabolic reliance on lipid oxidation, establishing DIP2A as a regulator of mitochondrial antioxidant defense.\",\n      \"evidence\": \"Dip2a knockout mouse brain, SOD activity assay, ROS measurement, electron microscopy, metabolic profiling\",\n      \"pmids\": [\"33781892\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether DIP2A directly activates SOD or acts indirectly via acetyl-CoA/lipid metabolism unresolved\",\n        \"Single lab, correlation between acetyl-CoA and SOD activity not formally tested\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The biochemical function of DIP2's adenylate-forming domains was unresolved; cross-species lipidomics and reconstitution showed DIP2 acts as a DAG-species-selective enzyme redirecting specific diacylglycerols to triacylglycerol storage, preventing toxic DAG accumulation and ER stress, and localizes to mitochondria-vacuole contact sites to modulate membrane fusion.\",\n      \"evidence\": \"Yeast and Drosophila genetics, lipidomics, in vitro biochemical assay of AFDs, fluorescence microscopy\",\n      \"pmids\": [\"35766356\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Exact catalytic mechanism of AFD-mediated DAG-to-TAG conversion not fully reconstituted\",\n        \"Whether mammalian DIP2A performs identical lipid channeling not directly tested in mammalian systems\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How DIP2A's multiple activities — receptor signaling, chromatin repression, cortactin regulation, acetyl-CoA synthesis, and DAG homeostasis — are coordinated across subcellular compartments remains unresolved, and no structural model of full-length DIP2A exists.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution structure of DIP2A or its domains\",\n        \"Relative contribution of receptor vs. enzymatic functions in vivo not dissected\",\n        \"Whether human genetic variants in DIP2A cause a Mendelian disorder not established\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 6]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [4, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 6]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [4, 8]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [3, 5]}\n    ],\n    \"complexes\": [\n      \"HDAC2-DMAP1\"\n    ],\n    \"partners\": [\n      \"FSTL1\",\n      \"HDAC2\",\n      \"DMAP1\",\n      \"CTTN\",\n      \"SAX2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}