{"gene":"MYDGF","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2015,"finding":"MYDGF (C19orf10) is a secreted protein produced by bone marrow-derived monocytes and macrophages that promotes cardiac myocyte survival and angiogenesis after myocardial infarction. Mydgf-deficient mice develop larger infarct scars and more severe contractile dysfunction, while recombinant MYDGF treatment reduces scar size and contractile dysfunction after MI, establishing its paracrine role in ischemic tissue repair.","method":"Bioinformatic secretome analysis, functional cell-survival and angiogenesis assays, Mydgf knockout mouse model, recombinant protein treatment","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KO mouse phenotype, recombinant protein rescue, in vitro functional assays) in a single rigorous study; foundational paper assigning first biological function","pmids":["25581518"],"is_preprint":false},{"year":2019,"finding":"The X-ray crystal structure of MYDGF reveals a novel 10-stranded β-sandwich fold with no structural similarity to other known cytokines or growth factors. The receptor-binding epitope was localized to a surface region around two tyrosine residues (Y71 and Y73) and an adjacent loop (residues 97–101), identified by characterizing a neutralizing antibody epitope combined with functional assays of surface patch mutations.","method":"X-ray crystallography, neutralizing antibody epitope mapping, surface patch mutagenesis with functional activity assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with mutagenesis and functional validation in a single rigorous study","pmids":["31772377"],"is_preprint":false},{"year":2001,"finding":"SF20/IL-25 (an alias of MYDGF) is a secreted bone marrow stroma-derived growth factor that signals lymphoid cell proliferation through binding to mouse thymic shared antigen-1 (TSA-1) as its receptor; enforced TSA-1 expression in TSA-1-negative Ba/F3 cells conferred dose-dependent SF20-stimulated proliferation, and anti-TSA-1 antibody blocked both binding and proliferation.","method":"Phenotype-based complementation screening, receptor identification by TSA-1 forced expression in Ba/F3 cells, anti-TSA-1 antibody blocking of binding and proliferation, FDCP2 cell proliferation assay","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor identified by gain-of-function reconstitution and antibody blocking in two cell lines; single lab, no independent replication reported","pmids":["11714798"],"is_preprint":false},{"year":2007,"finding":"C19orf10 (MYDGF) protein localizes intracellularly in a pattern consistent with the endoplasmic reticulum/Golgi in fibroblast-like synoviocytes (FLSs), is produced by FLSs but not by macrophages, B cells, or T cells in synovial tissue, and is secreted into synovial fluid at microgram levels in arthropathy patients.","method":"Monoclonal and polyclonal antibody immunostaining of cultured FLSs and synovial tissue sections, double-staining in situ analysis for cell-type identification, competitive ELISA of synovial fluid","journal":"Arthritis research & therapy","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization by immunostaining with cell-type co-staining and secretion confirmed by ELISA; single lab, no functional consequence linked to localization","pmids":["17362502"],"is_preprint":false},{"year":2020,"finding":"MYDGF promotes cardiomyocyte proliferation and neonatal heart regeneration through activation of the c-Myc/FoxM1 signaling pathway. In neonatal injured hearts, MYDGF is predominantly expressed by endothelial cells rather than macrophages. Mydgf knockout impeded neonatal heart regeneration and injury-induced cardiomyocyte proliferation, while recombinant MYDGF protein promoted primary cardiomyocyte proliferation and improved cardiac function after MI in adults.","method":"Mydgf global knockout mice, Mydgf-EGFP reporter mice, apical resection neonatal and MI adult cardiac injury models, RNA sequencing to identify pathway, immunofluorescence for cardiomyocyte proliferation, recombinant protein injection, echocardiography","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KO phenotype, RNA-seq pathway identification, functional verification, recombinant rescue) in a single study with defined molecular pathway","pmids":["32802181"],"is_preprint":false},{"year":2020,"finding":"MYDGF protects podocytes from injury in diabetic kidney disease by activating the Akt/BAD (Bcl-2-associated death promoter) signaling pathway, preserving nephrin expression and inhibiting podocyte apoptosis. MYDGF deficiency worsened podocyte injury and albuminuria, while AAV-mediated Mydgf gene transfer or recombinant MYDGF treatment attenuated these defects in vivo and in vitro.","method":"Streptozotocin/high-fat diet DKD mouse model, Mydgf knockout mice, AAV-mediated gene transfer, recombinant MYDGF treatment of immortalized podocytes and isolated glomeruli, western blot for Akt/BAD pathway activation, albumin measurement","journal":"Diabetologia","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss- and gain-of-function in vivo plus in vitro mechanistic pathway identification with multiple readouts; single lab but multiple orthogonal methods","pmids":["32588068"],"is_preprint":false},{"year":2023,"finding":"Inflammatory cell-derived MYDGF inhibits LDL transcytosis across endothelial cells to protect against atherosclerosis by suppressing MAP4K4 phosphorylation, enhancing Akt-1 activation, and diminishing FoxO3a signaling. Monocyte/macrophage-targeted MYDGF deletion aggravated LDL transcytosis and atherosclerosis, while restoration by bone marrow transplantation or MYDGF overexpression was protective.","method":"Monocyte/macrophage-targeted Mydgf knockout on Ldlr-/- background, bone marrow transplantation, macrophage-specific MYDGF overexpression, co-culture of primary mouse aortic endothelial cells with macrophages, recombinant MYDGF treatment, western blot for MAP4K4/Akt/FoxO3a pathway","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific KO, multiple gain-of-function strategies, mechanistic pathway identified by multiple orthogonal methods in one study","pmids":["37767706"],"is_preprint":false}],"current_model":"MYDGF is a secreted paracrine protein produced primarily by bone marrow-derived monocytes/macrophages (and by endothelial cells in neonatal injured hearts) that adopts a novel 10-stranded β-sandwich fold and engages a receptor via surface residues Y71/Y73 and an adjacent loop; it promotes cardiac repair after myocardial infarction (via cardiomyocyte survival and c-Myc/FoxM1-driven proliferation), protects podocytes in diabetic kidney disease via Akt/BAD signaling, and attenuates endothelial LDL transcytosis and atherosclerosis by suppressing MAP4K4 and activating Akt/FoxO3a signaling; an earlier alias (SF20/IL-25) identified TSA-1 as a proliferative receptor on lymphoid cells."},"narrative":{"mechanistic_narrative":"MYDGF (originally C19orf10/SF20) is a secreted paracrine factor produced largely by bone marrow-derived monocytes and macrophages that promotes tissue survival, proliferation, and repair across cardiac, renal, and vascular contexts [PMID:25581518]. It adopts a novel 10-stranded β-sandwich fold unlike known cytokines, and engages its receptor through a surface epitope centered on tyrosines Y71/Y73 and an adjacent loop (residues 97–101) [PMID:31772377]. In the heart, MYDGF limits infarct scar and contractile dysfunction by supporting cardiomyocyte survival and angiogenesis after myocardial infarction [PMID:25581518], and drives cardiomyocyte proliferation and neonatal heart regeneration via the c-Myc/FoxM1 pathway [PMID:32802181]. The protein converges on Akt-centered survival signaling in other tissues: it protects podocytes in diabetic kidney disease through Akt/BAD signaling, preserving nephrin and suppressing apoptosis [PMID:32588068], and it attenuates endothelial LDL transcytosis and atherosclerosis by suppressing MAP4K4 phosphorylation, enhancing Akt-1, and diminishing FoxO3a signaling [PMID:37767706]. An earlier study under the SF20/IL-25 alias identified TSA-1 as a receptor mediating MYDGF-driven lymphoid cell proliferation [PMID:11714798]. MYDGF localizes intracellularly in an ER/Golgi-consistent pattern prior to secretion [PMID:17362502].","teleology":[{"year":2001,"claim":"Before any defined receptor was known, this established that the secreted factor signals proliferation through a specific cell-surface receptor, TSA-1, on responsive cells.","evidence":"Receptor identification by forced TSA-1 expression in Ba/F3 cells and anti-TSA-1 antibody blocking of binding and proliferation","pmids":["11714798"],"confidence":"Medium","gaps":["Single lab, no independent replication of the TSA-1 receptor assignment","Whether TSA-1 mediates MYDGF effects in non-lymphoid tissues is untested","No structural mapping of the ligand-receptor interface"]},{"year":2007,"claim":"This clarified where the protein resides before secretion and which cells produce it in an inflamed tissue, framing it as a secreted product processed through the ER/Golgi.","evidence":"Antibody immunostaining of fibroblast-like synoviocytes and synovial tissue with cell-type co-staining, and competitive ELISA of synovial fluid","pmids":["17362502"],"confidence":"Medium","gaps":["No functional consequence linked to the ER/Golgi localization","Cell-source identity differs from later macrophage-centric findings","Single-lab observation"]},{"year":2015,"claim":"This assigned the first definitive in vivo biological function, showing the protein is a monocyte/macrophage-derived paracrine factor required to limit ischemic cardiac damage.","evidence":"Secretome bioinformatics, Mydgf knockout mouse MI model, recombinant protein rescue, and in vitro survival/angiogenesis assays","pmids":["25581518"],"confidence":"High","gaps":["Receptor and downstream signaling in cardiac cells not defined here","Direct cardiomyocyte versus endothelial target not resolved","Molecular mechanism of survival/angiogenesis unspecified"]},{"year":2019,"claim":"This resolved the molecular architecture, revealing a fold unlike known growth factors and pinpointing the surface residues required for receptor engagement.","evidence":"X-ray crystallography with neutralizing antibody epitope mapping and surface-patch mutagenesis coupled to functional activity assays","pmids":["31772377"],"confidence":"High","gaps":["The cognate receptor for the Y71/Y73 epitope is not identified","No co-structure with any receptor","Relationship between this epitope and the earlier TSA-1 receptor is unaddressed"]},{"year":2020,"claim":"These defined tissue-specific downstream pathways, linking MYDGF to c-Myc/FoxM1-driven cardiomyocyte proliferation and to Akt/BAD-mediated podocyte protection.","evidence":"Mydgf knockout and reporter mice, cardiac injury models with RNA-seq, plus DKD models with AAV gene transfer, recombinant protein, and Akt/BAD western blots in podocytes","pmids":["32802181","32588068"],"confidence":"High","gaps":["The receptor coupling MYDGF to c-Myc/FoxM1 and Akt/BAD is not identified","Cell source shifts to endothelial cells in neonatal heart, mechanism of this switch unknown","Direct versus indirect activation of these pathways not dissected"]},{"year":2023,"claim":"This extended MYDGF function to vascular protection, showing it suppresses endothelial LDL transcytosis and atherosclerosis through a MAP4K4/Akt-1/FoxO3a axis.","evidence":"Monocyte/macrophage-targeted Mydgf knockout on Ldlr-/- background, bone marrow transplantation, macrophage overexpression, endothelial-macrophage co-culture, and pathway western blots","pmids":["37767706"],"confidence":"High","gaps":["The receptor linking MYDGF to MAP4K4 suppression is unknown","Whether the Akt convergence across tissues reflects a single receptor is untested","Direct biochemical effect on MAP4K4 not established"]},{"year":null,"claim":"The receptor(s) that transduce MYDGF signaling in cardiac, renal, and vascular cells, and how they relate to the surface epitope and the lymphoid TSA-1 receptor, remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No receptor identified for the Y71/Y73 epitope outside the lymphoid TSA-1 context","No co-structure of MYDGF with any receptor","Mechanism unifying Akt/c-Myc/FoxM1/MAP4K4 outputs is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,2,4,5,6]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,3]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[3]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,5,6]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,4]}],"complexes":[],"partners":["TSA-1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q969H8","full_name":"Myeloid-derived growth 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Stimulates endothelial cell proliferation through a MAPK1/3-, STAT3- and CCND1-mediated signaling pathway. Inhibits cardiac myocyte apoptosis in a PI3K/AKT-dependent signaling pathway (By similarity). Involved in endothelial cell proliferation and angiogenesis (PubMed:25581518)","subcellular_location":"Secreted; Endoplasmic reticulum-Golgi intermediate compartment; Endoplasmic reticulum; Golgi apparatus","url":"https://www.uniprot.org/uniprotkb/Q969H8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MYDGF","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MYDGF","total_profiled":1310},"omim":[{"mim_id":"606746","title":"MYELOID-DERIVED GROWTH FACTOR; MYDGF","url":"https://www.omim.org/entry/606746"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MYDGF"},"hgnc":{"alias_symbol":["R33729_1","IL25","SF20","IL-25","IL-27"],"prev_symbol":["IL27","IL27w","C19orf10"]},"alphafold":{"accession":"Q969H8","domains":[{"cath_id":"-","chopping":"35-167","consensus_level":"high","plddt":96.7777,"start":35,"end":167}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q969H8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q969H8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q969H8-F1-predicted_aligned_error_v6.png","plddt_mean":87.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MYDGF","jax_strain_url":"https://www.jax.org/strain/search?query=MYDGF"},"sequence":{"accession":"Q969H8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q969H8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q969H8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q969H8"}},"corpus_meta":[{"pmid":"24008419","id":"PMC_24008419","title":"Infernal 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Mydgf-deficient mice develop larger infarct scars and more severe contractile dysfunction, while recombinant MYDGF treatment reduces scar size and contractile dysfunction after MI, establishing its paracrine role in ischemic tissue repair.\",\n      \"method\": \"Bioinformatic secretome analysis, functional cell-survival and angiogenesis assays, Mydgf knockout mouse model, recombinant protein treatment\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KO mouse phenotype, recombinant protein rescue, in vitro functional assays) in a single rigorous study; foundational paper assigning first biological function\",\n      \"pmids\": [\"25581518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The X-ray crystal structure of MYDGF reveals a novel 10-stranded β-sandwich fold with no structural similarity to other known cytokines or growth factors. The receptor-binding epitope was localized to a surface region around two tyrosine residues (Y71 and Y73) and an adjacent loop (residues 97–101), identified by characterizing a neutralizing antibody epitope combined with functional assays of surface patch mutations.\",\n      \"method\": \"X-ray crystallography, neutralizing antibody epitope mapping, surface patch mutagenesis with functional activity assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with mutagenesis and functional validation in a single rigorous study\",\n      \"pmids\": [\"31772377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"SF20/IL-25 (an alias of MYDGF) is a secreted bone marrow stroma-derived growth factor that signals lymphoid cell proliferation through binding to mouse thymic shared antigen-1 (TSA-1) as its receptor; enforced TSA-1 expression in TSA-1-negative Ba/F3 cells conferred dose-dependent SF20-stimulated proliferation, and anti-TSA-1 antibody blocked both binding and proliferation.\",\n      \"method\": \"Phenotype-based complementation screening, receptor identification by TSA-1 forced expression in Ba/F3 cells, anti-TSA-1 antibody blocking of binding and proliferation, FDCP2 cell proliferation assay\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor identified by gain-of-function reconstitution and antibody blocking in two cell lines; single lab, no independent replication reported\",\n      \"pmids\": [\"11714798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"C19orf10 (MYDGF) protein localizes intracellularly in a pattern consistent with the endoplasmic reticulum/Golgi in fibroblast-like synoviocytes (FLSs), is produced by FLSs but not by macrophages, B cells, or T cells in synovial tissue, and is secreted into synovial fluid at microgram levels in arthropathy patients.\",\n      \"method\": \"Monoclonal and polyclonal antibody immunostaining of cultured FLSs and synovial tissue sections, double-staining in situ analysis for cell-type identification, competitive ELISA of synovial fluid\",\n      \"journal\": \"Arthritis research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization by immunostaining with cell-type co-staining and secretion confirmed by ELISA; single lab, no functional consequence linked to localization\",\n      \"pmids\": [\"17362502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MYDGF promotes cardiomyocyte proliferation and neonatal heart regeneration through activation of the c-Myc/FoxM1 signaling pathway. In neonatal injured hearts, MYDGF is predominantly expressed by endothelial cells rather than macrophages. Mydgf knockout impeded neonatal heart regeneration and injury-induced cardiomyocyte proliferation, while recombinant MYDGF protein promoted primary cardiomyocyte proliferation and improved cardiac function after MI in adults.\",\n      \"method\": \"Mydgf global knockout mice, Mydgf-EGFP reporter mice, apical resection neonatal and MI adult cardiac injury models, RNA sequencing to identify pathway, immunofluorescence for cardiomyocyte proliferation, recombinant protein injection, echocardiography\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KO phenotype, RNA-seq pathway identification, functional verification, recombinant rescue) in a single study with defined molecular pathway\",\n      \"pmids\": [\"32802181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MYDGF protects podocytes from injury in diabetic kidney disease by activating the Akt/BAD (Bcl-2-associated death promoter) signaling pathway, preserving nephrin expression and inhibiting podocyte apoptosis. MYDGF deficiency worsened podocyte injury and albuminuria, while AAV-mediated Mydgf gene transfer or recombinant MYDGF treatment attenuated these defects in vivo and in vitro.\",\n      \"method\": \"Streptozotocin/high-fat diet DKD mouse model, Mydgf knockout mice, AAV-mediated gene transfer, recombinant MYDGF treatment of immortalized podocytes and isolated glomeruli, western blot for Akt/BAD pathway activation, albumin measurement\",\n      \"journal\": \"Diabetologia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss- and gain-of-function in vivo plus in vitro mechanistic pathway identification with multiple readouts; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"32588068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Inflammatory cell-derived MYDGF inhibits LDL transcytosis across endothelial cells to protect against atherosclerosis by suppressing MAP4K4 phosphorylation, enhancing Akt-1 activation, and diminishing FoxO3a signaling. Monocyte/macrophage-targeted MYDGF deletion aggravated LDL transcytosis and atherosclerosis, while restoration by bone marrow transplantation or MYDGF overexpression was protective.\",\n      \"method\": \"Monocyte/macrophage-targeted Mydgf knockout on Ldlr-/- background, bone marrow transplantation, macrophage-specific MYDGF overexpression, co-culture of primary mouse aortic endothelial cells with macrophages, recombinant MYDGF treatment, western blot for MAP4K4/Akt/FoxO3a pathway\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific KO, multiple gain-of-function strategies, mechanistic pathway identified by multiple orthogonal methods in one study\",\n      \"pmids\": [\"37767706\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MYDGF is a secreted paracrine protein produced primarily by bone marrow-derived monocytes/macrophages (and by endothelial cells in neonatal injured hearts) that adopts a novel 10-stranded β-sandwich fold and engages a receptor via surface residues Y71/Y73 and an adjacent loop; it promotes cardiac repair after myocardial infarction (via cardiomyocyte survival and c-Myc/FoxM1-driven proliferation), protects podocytes in diabetic kidney disease via Akt/BAD signaling, and attenuates endothelial LDL transcytosis and atherosclerosis by suppressing MAP4K4 and activating Akt/FoxO3a signaling; an earlier alias (SF20/IL-25) identified TSA-1 as a proliferative receptor on lymphoid cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MYDGF (originally C19orf10/SF20) is a secreted paracrine factor produced largely by bone marrow-derived monocytes and macrophages that promotes tissue survival, proliferation, and repair across cardiac, renal, and vascular contexts [#0]. It adopts a novel 10-stranded \\u03b2-sandwich fold unlike known cytokines, and engages its receptor through a surface epitope centered on tyrosines Y71/Y73 and an adjacent loop (residues 97\\u2013101) [#1]. In the heart, MYDGF limits infarct scar and contractile dysfunction by supporting cardiomyocyte survival and angiogenesis after myocardial infarction [#0], and drives cardiomyocyte proliferation and neonatal heart regeneration via the c-Myc/FoxM1 pathway [#4]. The protein converges on Akt-centered survival signaling in other tissues: it protects podocytes in diabetic kidney disease through Akt/BAD signaling, preserving nephrin and suppressing apoptosis [#5], and it attenuates endothelial LDL transcytosis and atherosclerosis by suppressing MAP4K4 phosphorylation, enhancing Akt-1, and diminishing FoxO3a signaling [#6]. An earlier study under the SF20/IL-25 alias identified TSA-1 as a receptor mediating MYDGF-driven lymphoid cell proliferation [#2]. MYDGF localizes intracellularly in an ER/Golgi-consistent pattern prior to secretion [#3].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Before any defined receptor was known, this established that the secreted factor signals proliferation through a specific cell-surface receptor, TSA-1, on responsive cells.\",\n      \"evidence\": \"Receptor identification by forced TSA-1 expression in Ba/F3 cells and anti-TSA-1 antibody blocking of binding and proliferation\",\n      \"pmids\": [\"11714798\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, no independent replication of the TSA-1 receptor assignment\", \"Whether TSA-1 mediates MYDGF effects in non-lymphoid tissues is untested\", \"No structural mapping of the ligand-receptor interface\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"This clarified where the protein resides before secretion and which cells produce it in an inflamed tissue, framing it as a secreted product processed through the ER/Golgi.\",\n      \"evidence\": \"Antibody immunostaining of fibroblast-like synoviocytes and synovial tissue with cell-type co-staining, and competitive ELISA of synovial fluid\",\n      \"pmids\": [\"17362502\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional consequence linked to the ER/Golgi localization\", \"Cell-source identity differs from later macrophage-centric findings\", \"Single-lab observation\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"This assigned the first definitive in vivo biological function, showing the protein is a monocyte/macrophage-derived paracrine factor required to limit ischemic cardiac damage.\",\n      \"evidence\": \"Secretome bioinformatics, Mydgf knockout mouse MI model, recombinant protein rescue, and in vitro survival/angiogenesis assays\",\n      \"pmids\": [\"25581518\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor and downstream signaling in cardiac cells not defined here\", \"Direct cardiomyocyte versus endothelial target not resolved\", \"Molecular mechanism of survival/angiogenesis unspecified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"This resolved the molecular architecture, revealing a fold unlike known growth factors and pinpointing the surface residues required for receptor engagement.\",\n      \"evidence\": \"X-ray crystallography with neutralizing antibody epitope mapping and surface-patch mutagenesis coupled to functional activity assays\",\n      \"pmids\": [\"31772377\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The cognate receptor for the Y71/Y73 epitope is not identified\", \"No co-structure with any receptor\", \"Relationship between this epitope and the earlier TSA-1 receptor is unaddressed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"These defined tissue-specific downstream pathways, linking MYDGF to c-Myc/FoxM1-driven cardiomyocyte proliferation and to Akt/BAD-mediated podocyte protection.\",\n      \"evidence\": \"Mydgf knockout and reporter mice, cardiac injury models with RNA-seq, plus DKD models with AAV gene transfer, recombinant protein, and Akt/BAD western blots in podocytes\",\n      \"pmids\": [\"32802181\", \"32588068\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The receptor coupling MYDGF to c-Myc/FoxM1 and Akt/BAD is not identified\", \"Cell source shifts to endothelial cells in neonatal heart, mechanism of this switch unknown\", \"Direct versus indirect activation of these pathways not dissected\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"This extended MYDGF function to vascular protection, showing it suppresses endothelial LDL transcytosis and atherosclerosis through a MAP4K4/Akt-1/FoxO3a axis.\",\n      \"evidence\": \"Monocyte/macrophage-targeted Mydgf knockout on Ldlr-/- background, bone marrow transplantation, macrophage overexpression, endothelial-macrophage co-culture, and pathway western blots\",\n      \"pmids\": [\"37767706\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The receptor linking MYDGF to MAP4K4 suppression is unknown\", \"Whether the Akt convergence across tissues reflects a single receptor is untested\", \"Direct biochemical effect on MAP4K4 not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The receptor(s) that transduce MYDGF signaling in cardiac, renal, and vascular cells, and how they relate to the surface epitope and the lymphoid TSA-1 receptor, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No receptor identified for the Y71/Y73 epitope outside the lymphoid TSA-1 context\", \"No co-structure of MYDGF with any receptor\", \"Mechanism unifying Akt/c-Myc/FoxM1/MAP4K4 outputs is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 2, 4, 5, 6]},\n      {\"term_id\": \"GO:0008083\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 5, 6]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TSA-1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}