{"gene":"MFGE8","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2003,"finding":"SED1/MFG-E8 is required for mouse sperm binding to the egg zona pellucida; its discoidin/F5/8C domains mediate this binding, as truncated proteins containing only the discoidin domain competitively inhibit sperm-egg binding. SED1-null males are subfertile with sperm unable to bind the egg coat in vitro.","method":"Gene knockout (SED1-null mice), recombinant protein competition assays, truncated domain proteins, sperm-egg binding assay in vitro","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted domain function with truncated proteins, knockout phenotype, multiple orthogonal methods in a single rigorous study","pmids":["12941270"],"is_preprint":false},{"year":2002,"finding":"Both C-domains (discoidin-like domains) of MFG-E8 are required for membrane association; MFG-E8 is secreted as a complex with membrane vesicles (100–200 nm diameter), and its expression increases the number of membrane vesicles secreted.","method":"Domain-deletion mutagenesis in COS-7 cells, immunofluorescence, cell-surface biotinylation, size-exclusion chromatography, ultracentrifugation, scanning electron microscopy","journal":"European journal of biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis combined with multiple biochemical methods in a single study","pmids":["11856354"],"is_preprint":false},{"year":1997,"finding":"Lactadherin (BA46/MFGE8) promotes RGD-dependent cell adhesion via integrin αvβ3; cell attachment is inhibited by the anti-integrin αvβ3 antibody LM609, and denaturation of lactadherin diminishes attachment, indicating structural dependence.","method":"Cell attachment assay with purified lactadherin, monoclonal antibody inhibition, integrin-blocking antibodies","journal":"DNA and cell biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of adhesion with purified protein, multiple cell lines, antibody blocking, and structural validation","pmids":["9260929"],"is_preprint":false},{"year":2009,"finding":"Mfge8 directly binds collagen through its discoidin domains and facilitates macrophage uptake of collagen; Mfge8-/- macrophages have defective collagen uptake rescued by recombinant Mfge8 containing at least one discoidin domain. This identifies a role for Mfge8 in collagen turnover and limiting tissue fibrosis independent of apoptotic cell clearance.","method":"Mfge8-/- mouse model (bleomycin-induced pulmonary fibrosis), direct binding assay, recombinant domain rescue experiment, macrophage collagen uptake assay","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct binding demonstrated, domain rescue experiment, KO mouse with defined cellular phenotype","pmids":["19884654"],"is_preprint":false},{"year":2008,"finding":"Follicular dendritic cells (FDCs) are the source of splenic Mfge8, not tingible-body macrophages (TBMphis); FDC-derived Mfge8 licenses TBMphis to engulf apoptotic germinal center B cells. Mfge8 is identical to the FDC marker FDC-M1.","method":"Bone marrow chimeras between WT and Mfge8(-/-) mice, exogenous recombinant Mfge8 rescue, lymphotoxin-deficient mice lacking FDCs","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal chimera experiments with genetic controls, multiple mouse models, replicated cellular source identification","pmids":["18490487"],"is_preprint":false},{"year":2012,"finding":"MFG-E8 mediates phagocytosis of viable neurons during neuroinflammation by bridging phosphatidylserine (PS)-exposing neurons to the vitronectin receptor (VR) on microglia/macrophages. This pathway is required for LPS-induced neuronal loss; blocking PS, MFG-E8, or VR prevents neuronal death. Mfge8 KO cultures lack this neuronal loss, restored by recombinant MFG-E8.","method":"Mfge8 knockout cultures, recombinant MFG-E8 rescue, PS-blocking antibodies, annexin V, dominant-negative MFG-E8 (unable to bind VR), VR antagonist, in vivo LPS injection in Mfge8 KO mice","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal blocking strategies, KO with rescue, in vitro and in vivo validation","pmids":["22357850"],"is_preprint":false},{"year":2013,"finding":"MFGE8 inhibits inflammasome-induced IL-1β production by macrophages through mediation of integrin β3 and P2X7 receptor interactions. Itgb3-deficient macrophages lose the inhibitory effect of MFGE8 on ATP-induced IL-1β production. In cerebral ischemia, MFGE8 reduces infarct size in a manner dependent on IL-1β, integrin β3, and P2X7 receptor.","method":"Itgb3-/-, Il1b-/-, P2rx7-/- mouse models, recombinant MFGE8 supplementation, macrophage IL-1β production assays, caspase-1 activation assay, cerebral ischemia mouse model","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic KO models, defined receptor requirement, in vitro and in vivo confirmation","pmids":["23454767"],"is_preprint":false},{"year":2014,"finding":"Mfge8 promotes fatty acid uptake and dietary triglyceride absorption through αvβ3 and αvβ5 integrin-dependent phosphorylation of Akt via PI3K and mTORC2, leading to translocation of Cd36 and Fatp1 from cytoplasmic vesicles to the cell surface. Mfge8-/- mice are protected from diet-induced obesity and steatohepatitis.","method":"Mfge8-/- mouse model, integrin-blocking experiments, PI3K/mTORC2 inhibitors, Cd36/Fatp1 subcellular fractionation, fatty acid uptake assays","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse with defined pathway, multiple orthogonal pharmacological/genetic approaches, subcellular fractionation","pmids":["24441829"],"is_preprint":false},{"year":2005,"finding":"Mfge8 regulates clearance of apoptotic epithelial cells during mammary gland involution; absence of Mfge8 leads to increased apoptotic cell accumulation, delayed alveolar collapse, inflammation, and abnormal gland remodeling across pregnancies.","method":"Mfge8 mutant (knockout) mice, histological analysis (CD45, CD11b staining), mammary gland involution assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — KO mice with defined cellular phenotype and tissue-level readout, multiple involution time points","pmids":["16195353"],"is_preprint":false},{"year":2007,"finding":"SED1/MFG-E8 is required for mammary gland branching morphogenesis; it is expressed by luminal and myoepithelial cells, binds αv integrin receptors on myoepithelial cells, activates MAPK, and promotes cell proliferation. SED1-null glands have severely reduced branching and reduced activated MAPK.","method":"SED1-null mouse model, integrin-binding assays, MAPK activation assays, proliferation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — KO mouse with defined signaling pathway, integrin binding, MAPK assay","pmids":["17299048"],"is_preprint":false},{"year":2012,"finding":"MFG-E8 activates vascular smooth muscle cell (VSMC) proliferation via αvβ5 integrin/ERK1/2 signaling, increasing CDK4 and PCNA levels and accelerating cell cycle S and G2 phases. MFG-E8 silencing or receptor/ERK1/2 blockade reduces proliferative capacity.","method":"In vitro VSMC culture, MFG-E8 exogenous addition and siRNA silencing, integrin receptor inhibition, ERK1/2 phosphorylation assay, BrdU incorporation, PCNA/CDK4 western blot","journal":"Aging cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined integrin/ERK signaling pathway, multiple methods, single lab","pmids":["22385834"],"is_preprint":false},{"year":2011,"finding":"Pericytes are a major source of MFG-E8 in vivo; MFG-E8 promotes pathological angiogenesis (tumor and retinopathy models) by enhancing pericyte/pericyte precursor migration via αv integrin signaling. MFG-E8 knockout reduces angiogenesis and pericyte coverage of neovessels.","method":"MFG-E8 knockout mice, anti-MFG-E8 antibodies, siRNA/shRNA knockdown in 10T1/2 cells, in vitro migration assay, in vivo tumor and oxygen-induced retinopathy models","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mice, siRNA/shRNA, antibody inhibition, in vitro and in vivo correlation, multiple orthogonal approaches","pmids":["21737783"],"is_preprint":false},{"year":2011,"finding":"Integrin αv-bound MFG-E8 associates transiently with PDGFRβ and focal adhesion kinase (FAK) after PDGF-BB treatment, preventing PDGFRβ ubiquitination and degradation, thereby retaining PDGFRβ at the cell surface and potentiating downstream PDGF-BB signaling and cell migration in pericyte/pericyte precursor-like cells.","method":"Co-immunoprecipitation (MFG-E8 with PDGFRβ), siRNA depletion, anti-MFG-E8 antibodies, ubiquitination assay, confocal microscopy, signaling assays","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — Co-IP showing physical interaction, siRNA and antibody inhibition, receptor degradation/ubiquitination assay, multiple orthogonal methods","pmids":["21868707"],"is_preprint":false},{"year":2012,"finding":"Mfge8 suppresses airway smooth muscle (ASM) hypercontractility in asthma by inhibiting IL-13-induced NF-κB activation and RhoA induction; this effect requires the RGD integrin-binding motif in Mfge8 (inactivating point mutation abolishes rapid RhoA inhibition).","method":"Mfge8-/- mice (asthma models), recombinant Mfge8 with RGD point mutant, IL-13/IL-17A/TNF-α treatment of murine and human ASM, NF-κB and RhoA activity assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — KO mice, RGD point mutant mechanistic dissection, human and mouse ASM, multiple cytokine conditions","pmids":["23269839"],"is_preprint":false},{"year":2016,"finding":"Mfge8 regulates hydrolysis of cytoplasmic lipid droplets in enterocytes after interacting with αvβ3 and αvβ5 integrins, increasing intracellular triglyceride hydrolase activity through a PI3K/mTORC2-dependent signaling pathway.","method":"Mfge8-/-, αvβ3/αvβ5 integrin-deficient mice, fat challenge assay, in vitro triglyceride hydrolase activity assay, PI3K/mTORC2 pharmacological inhibition","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple genetic KO models, defined signaling pathway, in vitro and in vivo validation","pmids":["27812539"],"is_preprint":false},{"year":2016,"finding":"The α8β1 integrin mediates Mfge8-dependent inhibition of gastrointestinal smooth muscle contraction; Mfge8 ligates α8β1 to reduce contractile force by preventing RhoA activation through a PTEN-dependent mechanism.","method":"Smooth muscle-specific α8 deletion, antibody blockade of α8, Mfge8-/- mice, antral smooth muscle contraction assay, RhoA activity assay, PTEN pathway analysis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO, antibody blockade, defined PTEN-RhoA signaling pathway, in vivo and in vitro","pmids":["27092791"],"is_preprint":false},{"year":2018,"finding":"Mfge8 maintains neural stem cell (RGL) quiescence in the dentate gyrus via an autocrine mechanism; loss of Mfge8 elevates mTOR1 signaling in RGLs, causing RGL overactivation and depletion. Rapamycin inhibition of mTOR1 returns RGLs to quiescence in Mfge8-null mice.","method":"Mfge8-null mice, RGL-specific conditional Mfge8 deletion, rapamycin treatment, mTOR1 signaling assays, BrdU label-retaining RGL quantification","journal":"Cell stem cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — global KO and cell-type-specific conditional KO, defined mTOR1 pathway with pharmacological rescue, multiple timepoints","pmids":["30174295"],"is_preprint":false},{"year":2017,"finding":"Mfge8 is an endogenous negative regulator of cardiac hypertrophy; Mfge8 deficiency potentiates the Akt/PKB-Gsk-3β/mTOR pathway after aortic banding, promoting hypertrophy. Mfge8 overexpression blunts this pathway. Akt inhibitor MK-2206 blocks the pro-hypertrophic effects of Mfge8 deficiency.","method":"Mfge8-/- mice, cardiac-specific Mfge8 transgenic mice, aortic banding, Akt inhibitor (MK-2206), neonatal rat cardiomyocytes with angiotensin II, MAPK and Akt pathway assays, recombinant MFGE8 administration in vivo","journal":"Hypertension","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO and transgenic overexpression, pharmacological pathway rescue, in vitro confirmation, multiple genetic and pharmacological tools","pmids":["28827473"],"is_preprint":false},{"year":2009,"finding":"SED1/MFG-E8 supports epididymal epithelial cell adhesion via RGD binding to αV integrin receptors on epididymal cells; SED1 is secreted basally as well as apically and is found at basolateral domains of epididymal epithelial cells. Loss of SED1 reduces epithelial cell adhesion in vitro, rescued by exogenous SED1.","method":"SED1-null male mice, in vitro epididymal cell adhesion assay, exogenous SED1 rescue, αV integrin receptor inhibition, immunolocalization","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — KO mice, in vitro adhesion rescue, integrin blocking, localization with functional consequence","pmids":["19240116"],"is_preprint":false},{"year":2008,"finding":"TPST-2 (tyrosylprotein sulfotransferase-2) is the writer responsible for tyrosine sulfation of Mfge8 in the male genital tract; Mfge8 is tyrosine-sulfated in wild-type and Tpst1-/- but not in Tpst2-/- mice.","method":"Tpst1-/- and Tpst2-/- mice, affinity chromatography with anti-sulfotyrosine antibody, mass spectrometry, metabolic labeling and sulfoamino acid analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — metabolic labeling with sulfoamino acid analysis, mass spectrometry, two KO models confirming enzyme specificity","pmids":["19047058"],"is_preprint":false},{"year":2015,"finding":"MFG-E8 inhibits neutrophil migration through αvβ3-integrin-dependent activation of p38 and ERK MAP kinases, which downregulates CXCR2 and upregulates GRK2 expression on neutrophils. Blocking αv integrin or p38/ERK activity reverses MFG-E8-induced inhibition of migration.","method":"dHL-60 cell migration assay (Boyden chamber), recombinant MFG-E8, p38 inhibitor (SB203580), ERK inhibitor (PD98059), anti-αv integrin neutralizing antibody, flow cytometry, western blot","journal":"International journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined receptor/kinase pathway, multiple pharmacological inhibitors, single lab","pmids":["25936372"],"is_preprint":false},{"year":2018,"finding":"The Mfge8-α8β1 integrin-PTEN pathway regulates airway smooth muscle contraction in allergic inflammation; smooth muscle-specific deletion of α8β1 or PTEN enhances IL-13-induced tracheal ring contraction. IL-13 induces ubiquitination and degradation of PTEN protein, and this is antagonized by Mfge8/α8β1 signaling.","method":"Smooth muscle-specific α8β1 and PTEN conditional KO mice, Mfge8-/- mice, PI3K inhibitor, tracheal ring contraction assay, PTEN ubiquitination assay","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple conditional KO models, defined PTEN ubiquitination mechanism, pharmacological rescue, in vitro and in vivo","pmids":["29763381"],"is_preprint":false},{"year":2021,"finding":"Insulin-stimulated signaling induces cell-surface enrichment of MFGE8 in skeletal muscle; MFGE8 then promotes interaction between αvβ5 integrin and the insulin receptor, dampening insulin receptor signaling and creating an autoregulatory negative feedback loop on glucose uptake.","method":"MFGE8 blockade and augmentation experiments, αvβ5 integrin pathway inhibition, co-localization of αvβ5 integrin and insulin receptor, glucose uptake assay, hepatic insulin sensitivity assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined receptor interaction with functional consequence, acute pharmacological blockade and augmentation, single lab","pmids":["33903257"],"is_preprint":false},{"year":2014,"finding":"MFG-E8 promotes angiogenesis in cutaneous wound healing by enhancing PDGF-PDGFRβ signaling mediated by integrin-growth factor receptor crosstalk; MFG-E8 colocalizes with PDGFRβ+ pericytes. MFG-E8 KO mice show delayed wound healing with reduced myofibroblast and vessel numbers.","method":"MFG-E8 KO mice, siRNA knockdown, in vitro capillary-like structure formation assay, immunolocalization, wound healing model","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mice with defined cellular phenotype, siRNA, in vitro assay; single lab","pmids":["24838098"],"is_preprint":false},{"year":2000,"finding":"Connexin43 (Cx43) suppresses MFG-E8 secretion in C6 glioma cells as part of its growth-regulatory mechanism; a major component of conditioned medium affected by Cx43 expression was identified as MFG-E8.","method":"Cx43 transfection in C6 glioma cells, conditioned medium analysis, protein identification","journal":"Cancer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, protein identification from conditioned medium without mechanistic follow-up on MFG-E8 itself","pmids":["11085522"],"is_preprint":false},{"year":2007,"finding":"p63 (TP63) transcriptionally activates MFGE8 through a p53/p63-binding motif at -370 upstream of MFGE8. TA-p63 isoforms activate MFGE8 transcription, and ΔN-p63 (when dominant) enhances this activation. siRNA-mediated p63 silencing in squamous carcinoma cells decreases MFG-E8 and reduces cell adhesion.","method":"Tetracycline-induced p63 expression, reporter assays, chromatin immunoprecipitation, siRNA silencing, Saos-2 cell adhesion assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — ChIP confirming binding, reporter assay with defined motif, siRNA with functional readout, multiple isoform analysis","pmids":["17637751"],"is_preprint":false},{"year":2014,"finding":"MFG-E8 regulates osteoclastogenesis; MFG-E8-deficient osteoclast precursors undergo increased RANKL-induced osteoclastogenesis with enhanced resorption pit formation. Exogenous MFG-E8 inhibits RANKL-induced osteoclastogenesis from mouse and human precursors. In vivo, Mfge8-/- mice show more osteoclasts and greater inflammatory bone loss.","method":"Mfge8-/- mouse bone marrow-derived osteoclast precursors, exogenous MFG-E8 addition, RANKL-induced osteoclastogenesis assay, resorption pit formation, experimental periodontitis model, local anti-MFG-E8 mAb microinjection","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse, human and mouse precursors, exogenous protein addition, antibody inhibition and supplementation in vivo","pmids":["24958900"],"is_preprint":false},{"year":2015,"finding":"MFG-E8 suppresses T cell activation and proliferation and regulates T cell polarization (inhibiting Th1/Th2/Th17, increasing Treg) by inhibiting PKCθ phosphorylation through the α3/5βV integrin receptor on T cells.","method":"Recombinant MFG-E8 addition and neutralization, MFG-E8 overexpression in ESCs, T cell proliferation and activation assays, PKCθ phosphorylation western blot, integrin receptor blocking","journal":"Stem cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined receptor and signaling step, multiple T cell readouts, single lab","pmids":["26455415"],"is_preprint":false},{"year":2021,"finding":"MFGE8 RGD tripeptide motif mediates sperm-extracellular vesicle interactions in the epididymis; ablation of the RGD domain, competitive RGD-peptide inhibition, or antibody masking of alpha V integrin receptors all significantly inhibit uptake and redistribution of EV-delivered proteins into mouse spermatozoa.","method":"Receptor inhibition strategies, RGD domain ablation of MFGE8, competitive RGD-peptide inhibition, anti-αV integrin antibody masking, cell culture model, protein redistribution assay","journal":"Proteomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple complementary inhibition strategies, defined RGD motif requirement, single lab","pmids":["33792189"],"is_preprint":false},{"year":2023,"finding":"USP14 is a deubiquitinase that interacts with, deubiquitinates, and stabilizes MFG-E8 protein in bronchial epithelial cells, preventing proteasomal degradation. Cigarette smoke reduces USP14 expression, leading to MFG-E8 proteasomal degradation and increased ferroptosis.","method":"Co-immunoprecipitation of USP14 and MFG-E8, USP14 inhibition, proteasome inhibition assays, western blot, in vitro and in vivo cigarette smoke extract models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating interaction, proteasomal pathway confirmed by inhibitor, single lab","pmids":["36596780"],"is_preprint":false},{"year":2017,"finding":"MFGE8 in MSC secretome exerts anti-fibrotic effects in hepatic stellate cells by binding αvβ3 integrin and downregulating TGFβ type I receptor expression, thereby inhibiting TGFβ/Smad signaling.","method":"Antagonizing MFGE8 activity (blocking antibody/knockdown), recombinant MFGE8 protein, αvβ3 integrin binding assay, TGFβ receptor expression assay, in vitro HSC activation, in vivo liver fibrosis models","journal":"BMB reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined receptor/TGFβ receptor mechanism, in vitro and in vivo validation, single lab","pmids":["28115038"],"is_preprint":false},{"year":2019,"finding":"MFG-E8 promotes the proinflammatory phenotypic shift of aged VSMCs by activating NF-κB, increasing proinflammatory gene expression and cell proliferation via integrin-mediated signaling. At the same time, high-dose rMFG-E8 attenuates VSMC migration.","method":"Aged mouse carotid artery ligation model, recombinant MFG-E8 administration, NF-κB nuclear translocation assay, immunoblotting, immunofluorescence, Transwell migration assay","journal":"Journal of biomedical science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro, NF-κB pathway defined, multiple readouts, single lab","pmids":["31470852"],"is_preprint":false},{"year":2021,"finding":"MFG-E8 regulates VSMC migration through dose-dependent regulation of Arp2-mediated actin polymerization; low-dose MFG-E8 upregulates Arp2 via β1 integrin and Rac1, while high-dose MFG-E8 reduces Arp2 and attenuates actin assembly and migration. Genetic deletion of MFG-E8 decreases Arp2 and attenuates injury-induced neointimal hyperplasia.","method":"MFG-E8 KO mice (carotid artery ligation), recombinant MFG-E8 dose-response, β1 integrin function-blocking antibody, Rac1 inhibitor, actin assembly assay, immunofluorescence and immunoblotting","journal":"Journal of the American Heart Association","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse, defined integrin-Rac1-Arp2 pathway, dose-response in vitro and in vivo, single lab","pmids":["34041925"],"is_preprint":false},{"year":2020,"finding":"MFGE8 attenuates atrial fibrosis by inhibiting TGF-β1/Smad2/3 signaling through integrin β3; knockdown of integrin β3 suppresses the TGF-β1/Smad2/3-activating effects of MFGE8 knockdown in Ang-II-treated rat atrial fibroblasts.","method":"siRNA knockdown of MFGE8, recombinant human MFGE8 (rhMFGE8) administration, integrin β3 inhibition, TGF-β1/Smad2/3 pathway western blot, Ang-II rat model","journal":"Journal of molecular and cellular cardiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA and recombinant protein approaches, integrin β3 receptor blocking, defined signaling pathway, single lab","pmids":["31958465"],"is_preprint":false},{"year":2023,"finding":"Schwann cell-derived exosomal MFG-E8 modifies macrophage/microglial polarization toward M2 by activating the SOCS3/STAT3 pathway. Knockout of MFG-E8 in Schwann cells reverses the anti-inflammatory effects of SCDEs.","method":"Proteomic sequencing of exosomes, lentiviral MFG-E8 transfection and knockout in SCs, SOCS3/STAT3 signaling assays, BMDM polarization assays, SCI rat model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomic identification, lentiviral KO, defined signaling pathway, in vitro and in vivo, single lab","pmids":["36717543"],"is_preprint":false},{"year":2023,"finding":"MFGE8 secreted by cancer-associated fibroblasts (CAFs) promotes esophageal squamous cell carcinoma tumor progression by binding Integrin αVβ3/αVβ5 receptors and activating both PI3K/AKT and ERK/AKT pathways.","method":"RNA sequencing of CAFs and tumor cells, MFGE8 knockdown in CAFs, integrin αVβ3/αVβ5 receptor blocking, PI3K/AKT and ERK pathway analysis, in vivo tumor models","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined receptor/pathway, KD and receptor blocking, in vivo validation, single lab","pmids":["37816055"],"is_preprint":false},{"year":2024,"finding":"MFGE8 inhibits intestinal fibrosis through integrin αvβ5-mediated and FAK-dependent signaling in intestinal myofibroblasts; blockade of integrin αvβ5 or FAK renders myofibroblasts non-responsive to MFGE8. MFGE8 prevents and reverses experimental intestinal fibrosis in vitro and in vivo.","method":"Decellularized tissue proteomics, primary human intestinal myofibroblast treatment, integrin αvβ5 and FAK blockade, next-generation sequencing of signaling pathways, experimental fibrosis models in vitro and in vivo","journal":"Gut","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined integrin/FAK pathway, proteomics validation, multiple experimental fibrosis models, single lab","pmids":["38378253"],"is_preprint":false},{"year":2024,"finding":"MFG-E8 interacts with HSPA1L and suppresses Parkin expression via the HSPA1L-Parkin pathway, leading to mitophagy inhibition; conversely, MFG-E8 knockdown upregulates PINK1 via SGK1/FOXO1/STAT3 phosphorylation pathways to stimulate mitophagy.","method":"Co-immunoprecipitation and immunoprecipitation identifying HSPA1L as MFG-E8 binding partner, MFG-E8 overexpression and siRNA in C2C12 cells, Parkin/PINK1 western blot, mitophagy assays","journal":"Journal of cachexia, sarcopenia and muscle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying direct binding partner, defined pathway mechanism, in vitro and in vivo, single lab","pmids":["38553831"],"is_preprint":false},{"year":2024,"finding":"CRC-derived extracellular vesicles carrying MFGE8 stimulate macrophage efferocytosis by increasing αvβ3 integrin expression on the macrophage cell surface, thereby activating the intracellular Src-FAK-STAT3 signaling pathway. MFGE8-knockout CRC cells generate EVs that fail to upregulate macrophage efferocytosis.","method":"CRISPR-Cas9 MFGE8 knockout in CRC cells, EV isolation and proteomic analysis, flow cytometry for αvβ3 expression, Src-FAK-STAT3 signaling western blot, in vitro and in vivo efferocytosis assays","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO, defined receptor and signaling pathway, in vitro and in vivo, single lab","pmids":["38802814"],"is_preprint":false},{"year":2006,"finding":"MFG-E8 protein is upregulated in involuting mammary glands and exhibits phosphatidylserine (PS)-binding activity that facilitates recognition and engulfment of apoptotic cells; post-weaning milk MFG-E8 enhanced the binding of apoptotic cells to macrophages, with PS-binding activity enriched in membrane vesicle fractions rather than milk fat globule fractions.","method":"Immunoblotting, RNA blotting, immunohistochemistry, in vitro PS-binding assay, apoptotic cell-binding assay, sucrose density-gradient ultracentrifugation","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct PS-binding assay, fractionation, multiple biochemical methods, single lab","pmids":["16401186"],"is_preprint":false},{"year":2023,"finding":"Human astrocytes and microglia phagocytose AD patient-derived synapses more than control synapses via an MFG-E8 opsonophagocytic mechanism; inhibiting MFG-E8 interactions rescues the elevated engulfment of AD synapses without affecting control synapse uptake.","method":"Primary mouse and human astrocyte/microglia synapse phagocytosis assay, MFG-E8 interaction inhibition, AD patient-derived synapse preparation","journal":"Cell reports. Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human and mouse primary cell assays, defined MFG-E8 bridging mechanism, pharmacological inhibition, single lab","pmids":["37652017"],"is_preprint":false}],"current_model":"MFGE8/MFG-E8/SED1 is a secreted glycoprotein containing N-terminal EGF-like domains (with an RGD integrin-binding motif) and C-terminal discoidin/F5/8C domains (which bind phosphatidylserine and extracellular matrix including collagen); it functions as a versatile extracellular bridge and integrin ligand that mediates apoptotic/viable cell phagocytosis (by linking PS-exposing cells to vitronectin receptor/αvβ3/5 on phagocytes), sperm-egg adhesion, collagen turnover, fatty acid uptake (via αvβ3/5–PI3K/mTORC2–Akt–Cd36/Fatp1 axis), gastrointestinal and airway smooth muscle contractility (via α8β1/αvβ3–PTEN–RhoA), angiogenesis (via integrin–PDGFRβ crosstalk on pericytes), neural stem cell quiescence (via suppression of mTOR1), cardiac hypertrophy (via Akt/GSK-3β/mTOR suppression), inflammasome-induced IL-1β production (via integrin β3–P2X7), and tissue fibrosis (via integrin–TGFβ/Smad pathway modulation), with its own protein stability regulated post-translationally by the deubiquitinase USP14 and by TPST-2-mediated tyrosine sulfation."},"narrative":{"mechanistic_narrative":"MFGE8 (MFG-E8/SED1/lactadherin) is a secreted glycoprotein that functions as a bifunctional extracellular bridge, using its C-terminal discoidin/F5/8C domains to bind phosphatidylserine (PS), collagen, and membrane vesicles while engaging integrins through an N-terminal RGD motif to transduce signals into target cells [PMID:11856354, PMID:9260929, PMID:19884654, PMID:16401186]. Its best-defined role is opsonization: by tethering PS-exposing surfaces to the αvβ3/αvβ5 vitronectin receptor on phagocytes, it licenses macrophages, microglia, and astrocytes to engulf apoptotic cells, viable PS-exposing neurons, and synapses [PMID:22357850, PMID:16195353, PMID:37652017], with follicular dendritic cells supplying the MFG-E8 that enables tingible-body macrophages to clear germinal-center B cells [PMID:18490487]. The discoidin domains independently mediate collagen binding and macrophage collagen uptake, linking MFGE8 to extracellular-matrix turnover [PMID:19884654]. Beyond bridging, integrin-bound MFGE8 acts as a signaling ligand: through αvβ3/αvβ5 it drives PI3K/mTORC2–Akt signaling to translocate CD36/FATP1 and promote enterocyte fatty-acid uptake and lipid-droplet hydrolysis [PMID:24441829, PMID:27812539], stabilizes PDGFRβ to potentiate pericyte migration and angiogenesis [PMID:21737783, PMID:21868707, PMID:24838098], and activates MAPK/ERK to drive epithelial and smooth-muscle proliferation [PMID:17299048, PMID:22385834]. Acting through α8β1 and αvβ3 integrins it restrains contractility and fibrosis by preventing RhoA activation via PTEN and by suppressing TGFβ/Smad and NF-κB signaling [PMID:23269839, PMID:27092791, PMID:29763381, PMID:28115038, PMID:31958465, PMID:38378253], and it enforces neural stem-cell quiescence and limits cardiac hypertrophy by suppressing mTOR/Akt signaling [PMID:30174295, PMID:28827473]. MFGE8 also dampens inflammasome IL-1β output via integrin β3–P2X7 coupling [PMID:23454767]. The original genetic phenotype is reproductive: SED1-null males are subfertile because the discoidin domains are required for sperm binding to the egg zona pellucida [PMID:12941270]. MFGE8 protein abundance is controlled post-translationally by USP14-mediated deubiquitination and by TPST-2-mediated tyrosine sulfation [PMID:19047058, PMID:36596780], and its transcription is activated by p63 [PMID:17637751].","teleology":[{"year":1997,"claim":"Established that lactadherin/MFGE8 is an integrin ligand, defining the receptor arm of its later-recognized bridging function.","evidence":"Cell attachment assays with purified protein and αvβ3-blocking antibody LM609","pmids":["9260929"],"confidence":"High","gaps":["Did not connect adhesion to a physiological process","Downstream signaling not addressed"]},{"year":2002,"claim":"Showed that the two C-terminal discoidin domains drive membrane-vesicle association and secretion, defining the lipid/membrane-binding arm of the molecule.","evidence":"Domain-deletion mutagenesis in COS-7 cells with biochemical and electron-microscopy analysis","pmids":["11856354"],"confidence":"High","gaps":["PS specificity not yet demonstrated","Functional consequence of vesicle association unresolved"]},{"year":2003,"claim":"Identified the first genetic loss-of-function phenotype—SED1-null male subfertility—and mapped sperm-egg binding to the discoidin domains.","evidence":"SED1-null mice, truncated-domain competition, in vitro sperm-egg binding","pmids":["12941270"],"confidence":"High","gaps":["Egg-coat receptor for MFGE8 not identified","Does not address somatic roles"]},{"year":2006,"claim":"Linked MFGE8 PS-binding to apoptotic-cell engulfment, establishing the opsonization model.","evidence":"PS-binding and apoptotic-cell-binding assays with density-gradient fractionation of involuting mammary gland","pmids":["16401186"],"confidence":"Medium","gaps":["In vivo necessity shown elsewhere","Phagocyte receptor not defined in this study"]},{"year":2008,"claim":"Resolved the cellular source problem in the spleen, showing FDC-derived MFGE8 licenses macrophage clearance of apoptotic B cells, and tied protein modification to enzymatic regulation by identifying TPST-2 as its tyrosine-sulfation writer.","evidence":"Bone-marrow chimeras and rescue; Tpst1/Tpst2 KO mice with mass spectrometry","pmids":["18490487","19047058"],"confidence":"High","gaps":["Functional consequence of sulfation not determined","Whether sulfation affects integrin or PS binding unknown"]},{"year":2009,"claim":"Extended discoidin-domain function to collagen binding and macrophage collagen uptake, defining a clearance role independent of apoptotic cells.","evidence":"Mfge8-/- mice (bleomycin fibrosis), direct binding and domain-rescue, collagen-uptake assays","pmids":["19884654"],"confidence":"High","gaps":["Phagocyte receptor for collagen-MFGE8 complex not defined","Relationship to integrin signaling unclear"]},{"year":2011,"claim":"Defined a signaling (non-bridging) mechanism in pericytes: integrin-bound MFGE8 stabilizes PDGFRβ to potentiate angiogenesis.","evidence":"KO mice, siRNA, Co-IP with PDGFRβ/FAK, ubiquitination assays, tumor and retinopathy models","pmids":["21737783","21868707"],"confidence":"High","gaps":["Mechanism by which integrin engagement blocks PDGFRβ ubiquitination not fully defined","Identity of the ubiquitin ligase unknown"]},{"year":2012,"claim":"Showed MFGE8 transduces both proliferative (ERK in vascular smooth muscle) and contractility-suppressing (RhoA via RGD in airway smooth muscle) signals, and bridges PS-exposing viable neurons for microglial phagocytosis.","evidence":"VSMC culture with ERK readouts; Mfge8-/- asthma models with RGD point mutant; KO neuronal cultures with PS/VR blockade in vivo","pmids":["22385834","23269839","22357850"],"confidence":"High","gaps":["Context determining proliferative vs. inhibitory outcome not defined","Integrin specificity differs across cell types"]},{"year":2013,"claim":"Connected MFGE8 to innate immune regulation by showing it dampens inflammasome IL-1β output through integrin β3–P2X7 coupling.","evidence":"Itgb3/Il1b/P2rx7 KO macrophages, recombinant MFGE8, caspase-1 assays, cerebral ischemia model","pmids":["23454767"],"confidence":"High","gaps":["Molecular link between integrin β3 and P2X7 not structurally defined"]},{"year":2014,"claim":"Established the integrin–PI3K/mTORC2–Akt axis driving CD36/FATP1 surface translocation, defining MFGE8's role in lipid uptake and metabolic disease.","evidence":"Mfge8-/- mice, integrin blockade, mTORC2 inhibitors, subcellular fractionation","pmids":["24441829"],"confidence":"High","gaps":["Direct integrin-to-PI3K coupling not biochemically resolved"]},{"year":2016,"claim":"Defined the α8β1–PTEN–RhoA pathway for smooth-muscle relaxation and extended lipid metabolism to enterocyte lipid-droplet hydrolysis.","evidence":"Smooth-muscle-specific α8 deletion and Mfge8-/- mice with RhoA/PTEN assays; integrin-deficient mice with triglyceride hydrolase assays","pmids":["27092791","27812539"],"confidence":"High","gaps":["How α8β1 engagement modulates PTEN stability unresolved here"]},{"year":2018,"claim":"Showed MFGE8 enforces tissue homeostasis through mTOR suppression (neural stem-cell quiescence) and defined IL-13-driven PTEN ubiquitination as the target of the α8β1 pathway in airway smooth muscle.","evidence":"Conditional Mfge8 KO with rapamycin rescue; smooth-muscle-specific α8β1/PTEN KO with PTEN ubiquitination assays","pmids":["30174295","29763381"],"confidence":"High","gaps":["Autocrine receptor on neural stem cells not specified","PTEN deubiquitinase counter-enzyme unknown"]},{"year":2017,"claim":"Defined MFGE8 as an endogenous negative regulator of cardiac hypertrophy via Akt/GSK-3β/mTOR suppression, and demonstrated p63 as a transcriptional activator of MFGE8.","evidence":"Mfge8-/- and transgenic mice with Akt inhibitor rescue; ChIP/reporter assays with p63 isoforms","pmids":["28827473","17637751"],"confidence":"High","gaps":["Cardiac receptor for MFGE8 not identified","Upstream regulators of p63-driven MFGE8 transcription unknown"]},{"year":2021,"claim":"Identified MFGE8 as a negative-feedback regulator of insulin signaling and a dose-dependent modulator of actin-based VSMC migration, expanding its metabolic and vascular roles.","evidence":"MFGE8 blockade/augmentation with αvβ5–insulin receptor colocalization; KO mice and dose-response with β1-integrin/Rac1/Arp2 readouts","pmids":["33903257","34041925"],"confidence":"Medium","gaps":["Single-lab studies","Mechanism of dose-dependent switch not biochemically defined"]},{"year":2023,"claim":"Established post-translational control of MFGE8 abundance by the deubiquitinase USP14 and broadened its roles to exosome-delivered macrophage polarization and synaptic phagocytosis in disease.","evidence":"Co-IP and proteasome inhibition for USP14; Schwann-cell exosomal KO with SOCS3/STAT3 assays; human AD synapse phagocytosis with MFG-E8 inhibition","pmids":["36596780","36717543","37652017"],"confidence":"Medium","gaps":["USP14 ubiquitination sites on MFGE8 unmapped","Single-lab studies for exosomal and synaptic roles"]},{"year":2024,"claim":"Extended MFGE8 to mitophagy regulation via a novel HSPA1L–Parkin partnership and reinforced its anti-fibrotic αvβ5/FAK signaling in the intestine.","evidence":"Co-IP identifying HSPA1L; siRNA/overexpression with Parkin/PINK1 readouts; integrin αvβ5/FAK blockade in human myofibroblasts","pmids":["38553831","38378253"],"confidence":"Medium","gaps":["HSPA1L interaction not reciprocally validated beyond Co-IP","Single-lab findings"]},{"year":null,"claim":"How a single secreted bridge protein integrates opposing outputs—proliferative vs. quiescent, profibrotic vs. antifibrotic, dose-dependent migration—across diverse integrins and cell types remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying structural model linking integrin choice to downstream pathway selection","Egg-coat and neural stem-cell receptors unidentified","Functional consequences of tyrosine sulfation undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[2,39]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[2,7,9]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,5,39]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[2,18]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,4,39]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[1,39]},{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[3,36]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[5,8,40]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,6,27]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,9,12,17]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[3,30,36]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[7,14,22]}],"complexes":[],"partners":["ITGAV","ITGB3","ITGB5","ITGA8","PDGFRB","P2RX7","HSPA1L","USP14"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q08431","full_name":"Lactadherin","aliases":["Breast epithelial antigen BA46","HMFG","MFGM","Milk fat globule-EGF factor 8","MFG-E8","SED1"],"length_aa":387,"mass_kda":43.1,"function":"Plays an important role in the maintenance of intestinal epithelial homeostasis and the promotion of mucosal healing. Promotes VEGF-dependent neovascularization (By similarity). Contributes to phagocytic removal of apoptotic cells in many tissues. Specific ligand for the alpha-v/beta-3 and alpha-v/beta-5 receptors. Also binds to phosphatidylserine-enriched cell surfaces in a receptor-independent manner. Zona pellucida-binding protein which may play a role in gamete interaction Main constituent of aortic medial amyloid","subcellular_location":"Membrane; Secreted; Cytoplasmic vesicle, secretory vesicle, acrosome membrane","url":"https://www.uniprot.org/uniprotkb/Q08431/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MFGE8","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":[{"gene":"CANX","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/MFGE8","total_profiled":1310},"omim":[{"mim_id":"602281","title":"MILK FAT GLOBULE-EGF FACTOR 8; MFGE8","url":"https://www.omim.org/entry/602281"},{"mim_id":"600979","title":"LYMPHOTOXIN B RECEPTOR; LTBR","url":"https://www.omim.org/entry/600979"},{"mim_id":"176640","title":"PRION PROTEIN; PRNP","url":"https://www.omim.org/entry/176640"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"blood vessel","ntpm":2177.9}],"url":"https://www.proteinatlas.org/search/MFGE8"},"hgnc":{"alias_symbol":["SED1","EDIL1","BA46","OAcGD3S","HsT19888","MFG-E8","hP47"],"prev_symbol":["SPAG10"]},"alphafold":{"accession":"Q08431","domains":[{"cath_id":"2.10.25.10","chopping":"31-45_52-69","consensus_level":"medium","plddt":77.3327,"start":31,"end":69},{"cath_id":"2.60.120.260","chopping":"73-227","consensus_level":"high","plddt":92.5686,"start":73,"end":227},{"cath_id":"2.60.120.260","chopping":"233-387","consensus_level":"high","plddt":94.5308,"start":233,"end":387}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q08431","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q08431-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q08431-F1-predicted_aligned_error_v6.png","plddt_mean":87.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MFGE8","jax_strain_url":"https://www.jax.org/strain/search?query=MFGE8"},"sequence":{"accession":"Q08431","fasta_url":"https://rest.uniprot.org/uniprotkb/Q08431.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q08431/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q08431"}},"corpus_meta":[{"pmid":"19884654","id":"PMC_19884654","title":"Mfge8 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SED1-null males are subfertile with sperm unable to bind the egg coat in vitro.\",\n      \"method\": \"Gene knockout (SED1-null mice), recombinant protein competition assays, truncated domain proteins, sperm-egg binding assay in vitro\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted domain function with truncated proteins, knockout phenotype, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"12941270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Both C-domains (discoidin-like domains) of MFG-E8 are required for membrane association; MFG-E8 is secreted as a complex with membrane vesicles (100–200 nm diameter), and its expression increases the number of membrane vesicles secreted.\",\n      \"method\": \"Domain-deletion mutagenesis in COS-7 cells, immunofluorescence, cell-surface biotinylation, size-exclusion chromatography, ultracentrifugation, scanning electron microscopy\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis combined with multiple biochemical methods in a single study\",\n      \"pmids\": [\"11856354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Lactadherin (BA46/MFGE8) promotes RGD-dependent cell adhesion via integrin αvβ3; cell attachment is inhibited by the anti-integrin αvβ3 antibody LM609, and denaturation of lactadherin diminishes attachment, indicating structural dependence.\",\n      \"method\": \"Cell attachment assay with purified lactadherin, monoclonal antibody inhibition, integrin-blocking antibodies\",\n      \"journal\": \"DNA and cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of adhesion with purified protein, multiple cell lines, antibody blocking, and structural validation\",\n      \"pmids\": [\"9260929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Mfge8 directly binds collagen through its discoidin domains and facilitates macrophage uptake of collagen; Mfge8-/- macrophages have defective collagen uptake rescued by recombinant Mfge8 containing at least one discoidin domain. This identifies a role for Mfge8 in collagen turnover and limiting tissue fibrosis independent of apoptotic cell clearance.\",\n      \"method\": \"Mfge8-/- mouse model (bleomycin-induced pulmonary fibrosis), direct binding assay, recombinant domain rescue experiment, macrophage collagen uptake assay\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct binding demonstrated, domain rescue experiment, KO mouse with defined cellular phenotype\",\n      \"pmids\": [\"19884654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Follicular dendritic cells (FDCs) are the source of splenic Mfge8, not tingible-body macrophages (TBMphis); FDC-derived Mfge8 licenses TBMphis to engulf apoptotic germinal center B cells. Mfge8 is identical to the FDC marker FDC-M1.\",\n      \"method\": \"Bone marrow chimeras between WT and Mfge8(-/-) mice, exogenous recombinant Mfge8 rescue, lymphotoxin-deficient mice lacking FDCs\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal chimera experiments with genetic controls, multiple mouse models, replicated cellular source identification\",\n      \"pmids\": [\"18490487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MFG-E8 mediates phagocytosis of viable neurons during neuroinflammation by bridging phosphatidylserine (PS)-exposing neurons to the vitronectin receptor (VR) on microglia/macrophages. This pathway is required for LPS-induced neuronal loss; blocking PS, MFG-E8, or VR prevents neuronal death. Mfge8 KO cultures lack this neuronal loss, restored by recombinant MFG-E8.\",\n      \"method\": \"Mfge8 knockout cultures, recombinant MFG-E8 rescue, PS-blocking antibodies, annexin V, dominant-negative MFG-E8 (unable to bind VR), VR antagonist, in vivo LPS injection in Mfge8 KO mice\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal blocking strategies, KO with rescue, in vitro and in vivo validation\",\n      \"pmids\": [\"22357850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MFGE8 inhibits inflammasome-induced IL-1β production by macrophages through mediation of integrin β3 and P2X7 receptor interactions. Itgb3-deficient macrophages lose the inhibitory effect of MFGE8 on ATP-induced IL-1β production. In cerebral ischemia, MFGE8 reduces infarct size in a manner dependent on IL-1β, integrin β3, and P2X7 receptor.\",\n      \"method\": \"Itgb3-/-, Il1b-/-, P2rx7-/- mouse models, recombinant MFGE8 supplementation, macrophage IL-1β production assays, caspase-1 activation assay, cerebral ischemia mouse model\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic KO models, defined receptor requirement, in vitro and in vivo confirmation\",\n      \"pmids\": [\"23454767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Mfge8 promotes fatty acid uptake and dietary triglyceride absorption through αvβ3 and αvβ5 integrin-dependent phosphorylation of Akt via PI3K and mTORC2, leading to translocation of Cd36 and Fatp1 from cytoplasmic vesicles to the cell surface. Mfge8-/- mice are protected from diet-induced obesity and steatohepatitis.\",\n      \"method\": \"Mfge8-/- mouse model, integrin-blocking experiments, PI3K/mTORC2 inhibitors, Cd36/Fatp1 subcellular fractionation, fatty acid uptake assays\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse with defined pathway, multiple orthogonal pharmacological/genetic approaches, subcellular fractionation\",\n      \"pmids\": [\"24441829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Mfge8 regulates clearance of apoptotic epithelial cells during mammary gland involution; absence of Mfge8 leads to increased apoptotic cell accumulation, delayed alveolar collapse, inflammation, and abnormal gland remodeling across pregnancies.\",\n      \"method\": \"Mfge8 mutant (knockout) mice, histological analysis (CD45, CD11b staining), mammary gland involution assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mice with defined cellular phenotype and tissue-level readout, multiple involution time points\",\n      \"pmids\": [\"16195353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SED1/MFG-E8 is required for mammary gland branching morphogenesis; it is expressed by luminal and myoepithelial cells, binds αv integrin receptors on myoepithelial cells, activates MAPK, and promotes cell proliferation. SED1-null glands have severely reduced branching and reduced activated MAPK.\",\n      \"method\": \"SED1-null mouse model, integrin-binding assays, MAPK activation assays, proliferation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with defined signaling pathway, integrin binding, MAPK assay\",\n      \"pmids\": [\"17299048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MFG-E8 activates vascular smooth muscle cell (VSMC) proliferation via αvβ5 integrin/ERK1/2 signaling, increasing CDK4 and PCNA levels and accelerating cell cycle S and G2 phases. MFG-E8 silencing or receptor/ERK1/2 blockade reduces proliferative capacity.\",\n      \"method\": \"In vitro VSMC culture, MFG-E8 exogenous addition and siRNA silencing, integrin receptor inhibition, ERK1/2 phosphorylation assay, BrdU incorporation, PCNA/CDK4 western blot\",\n      \"journal\": \"Aging cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined integrin/ERK signaling pathway, multiple methods, single lab\",\n      \"pmids\": [\"22385834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Pericytes are a major source of MFG-E8 in vivo; MFG-E8 promotes pathological angiogenesis (tumor and retinopathy models) by enhancing pericyte/pericyte precursor migration via αv integrin signaling. MFG-E8 knockout reduces angiogenesis and pericyte coverage of neovessels.\",\n      \"method\": \"MFG-E8 knockout mice, anti-MFG-E8 antibodies, siRNA/shRNA knockdown in 10T1/2 cells, in vitro migration assay, in vivo tumor and oxygen-induced retinopathy models\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mice, siRNA/shRNA, antibody inhibition, in vitro and in vivo correlation, multiple orthogonal approaches\",\n      \"pmids\": [\"21737783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Integrin αv-bound MFG-E8 associates transiently with PDGFRβ and focal adhesion kinase (FAK) after PDGF-BB treatment, preventing PDGFRβ ubiquitination and degradation, thereby retaining PDGFRβ at the cell surface and potentiating downstream PDGF-BB signaling and cell migration in pericyte/pericyte precursor-like cells.\",\n      \"method\": \"Co-immunoprecipitation (MFG-E8 with PDGFRβ), siRNA depletion, anti-MFG-E8 antibodies, ubiquitination assay, confocal microscopy, signaling assays\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — Co-IP showing physical interaction, siRNA and antibody inhibition, receptor degradation/ubiquitination assay, multiple orthogonal methods\",\n      \"pmids\": [\"21868707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Mfge8 suppresses airway smooth muscle (ASM) hypercontractility in asthma by inhibiting IL-13-induced NF-κB activation and RhoA induction; this effect requires the RGD integrin-binding motif in Mfge8 (inactivating point mutation abolishes rapid RhoA inhibition).\",\n      \"method\": \"Mfge8-/- mice (asthma models), recombinant Mfge8 with RGD point mutant, IL-13/IL-17A/TNF-α treatment of murine and human ASM, NF-κB and RhoA activity assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — KO mice, RGD point mutant mechanistic dissection, human and mouse ASM, multiple cytokine conditions\",\n      \"pmids\": [\"23269839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Mfge8 regulates hydrolysis of cytoplasmic lipid droplets in enterocytes after interacting with αvβ3 and αvβ5 integrins, increasing intracellular triglyceride hydrolase activity through a PI3K/mTORC2-dependent signaling pathway.\",\n      \"method\": \"Mfge8-/-, αvβ3/αvβ5 integrin-deficient mice, fat challenge assay, in vitro triglyceride hydrolase activity assay, PI3K/mTORC2 pharmacological inhibition\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic KO models, defined signaling pathway, in vitro and in vivo validation\",\n      \"pmids\": [\"27812539\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The α8β1 integrin mediates Mfge8-dependent inhibition of gastrointestinal smooth muscle contraction; Mfge8 ligates α8β1 to reduce contractile force by preventing RhoA activation through a PTEN-dependent mechanism.\",\n      \"method\": \"Smooth muscle-specific α8 deletion, antibody blockade of α8, Mfge8-/- mice, antral smooth muscle contraction assay, RhoA activity assay, PTEN pathway analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO, antibody blockade, defined PTEN-RhoA signaling pathway, in vivo and in vitro\",\n      \"pmids\": [\"27092791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Mfge8 maintains neural stem cell (RGL) quiescence in the dentate gyrus via an autocrine mechanism; loss of Mfge8 elevates mTOR1 signaling in RGLs, causing RGL overactivation and depletion. Rapamycin inhibition of mTOR1 returns RGLs to quiescence in Mfge8-null mice.\",\n      \"method\": \"Mfge8-null mice, RGL-specific conditional Mfge8 deletion, rapamycin treatment, mTOR1 signaling assays, BrdU label-retaining RGL quantification\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — global KO and cell-type-specific conditional KO, defined mTOR1 pathway with pharmacological rescue, multiple timepoints\",\n      \"pmids\": [\"30174295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Mfge8 is an endogenous negative regulator of cardiac hypertrophy; Mfge8 deficiency potentiates the Akt/PKB-Gsk-3β/mTOR pathway after aortic banding, promoting hypertrophy. Mfge8 overexpression blunts this pathway. Akt inhibitor MK-2206 blocks the pro-hypertrophic effects of Mfge8 deficiency.\",\n      \"method\": \"Mfge8-/- mice, cardiac-specific Mfge8 transgenic mice, aortic banding, Akt inhibitor (MK-2206), neonatal rat cardiomyocytes with angiotensin II, MAPK and Akt pathway assays, recombinant MFGE8 administration in vivo\",\n      \"journal\": \"Hypertension\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO and transgenic overexpression, pharmacological pathway rescue, in vitro confirmation, multiple genetic and pharmacological tools\",\n      \"pmids\": [\"28827473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SED1/MFG-E8 supports epididymal epithelial cell adhesion via RGD binding to αV integrin receptors on epididymal cells; SED1 is secreted basally as well as apically and is found at basolateral domains of epididymal epithelial cells. Loss of SED1 reduces epithelial cell adhesion in vitro, rescued by exogenous SED1.\",\n      \"method\": \"SED1-null male mice, in vitro epididymal cell adhesion assay, exogenous SED1 rescue, αV integrin receptor inhibition, immunolocalization\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mice, in vitro adhesion rescue, integrin blocking, localization with functional consequence\",\n      \"pmids\": [\"19240116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TPST-2 (tyrosylprotein sulfotransferase-2) is the writer responsible for tyrosine sulfation of Mfge8 in the male genital tract; Mfge8 is tyrosine-sulfated in wild-type and Tpst1-/- but not in Tpst2-/- mice.\",\n      \"method\": \"Tpst1-/- and Tpst2-/- mice, affinity chromatography with anti-sulfotyrosine antibody, mass spectrometry, metabolic labeling and sulfoamino acid analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — metabolic labeling with sulfoamino acid analysis, mass spectrometry, two KO models confirming enzyme specificity\",\n      \"pmids\": [\"19047058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MFG-E8 inhibits neutrophil migration through αvβ3-integrin-dependent activation of p38 and ERK MAP kinases, which downregulates CXCR2 and upregulates GRK2 expression on neutrophils. Blocking αv integrin or p38/ERK activity reverses MFG-E8-induced inhibition of migration.\",\n      \"method\": \"dHL-60 cell migration assay (Boyden chamber), recombinant MFG-E8, p38 inhibitor (SB203580), ERK inhibitor (PD98059), anti-αv integrin neutralizing antibody, flow cytometry, western blot\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined receptor/kinase pathway, multiple pharmacological inhibitors, single lab\",\n      \"pmids\": [\"25936372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The Mfge8-α8β1 integrin-PTEN pathway regulates airway smooth muscle contraction in allergic inflammation; smooth muscle-specific deletion of α8β1 or PTEN enhances IL-13-induced tracheal ring contraction. IL-13 induces ubiquitination and degradation of PTEN protein, and this is antagonized by Mfge8/α8β1 signaling.\",\n      \"method\": \"Smooth muscle-specific α8β1 and PTEN conditional KO mice, Mfge8-/- mice, PI3K inhibitor, tracheal ring contraction assay, PTEN ubiquitination assay\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple conditional KO models, defined PTEN ubiquitination mechanism, pharmacological rescue, in vitro and in vivo\",\n      \"pmids\": [\"29763381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Insulin-stimulated signaling induces cell-surface enrichment of MFGE8 in skeletal muscle; MFGE8 then promotes interaction between αvβ5 integrin and the insulin receptor, dampening insulin receptor signaling and creating an autoregulatory negative feedback loop on glucose uptake.\",\n      \"method\": \"MFGE8 blockade and augmentation experiments, αvβ5 integrin pathway inhibition, co-localization of αvβ5 integrin and insulin receptor, glucose uptake assay, hepatic insulin sensitivity assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined receptor interaction with functional consequence, acute pharmacological blockade and augmentation, single lab\",\n      \"pmids\": [\"33903257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MFG-E8 promotes angiogenesis in cutaneous wound healing by enhancing PDGF-PDGFRβ signaling mediated by integrin-growth factor receptor crosstalk; MFG-E8 colocalizes with PDGFRβ+ pericytes. MFG-E8 KO mice show delayed wound healing with reduced myofibroblast and vessel numbers.\",\n      \"method\": \"MFG-E8 KO mice, siRNA knockdown, in vitro capillary-like structure formation assay, immunolocalization, wound healing model\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mice with defined cellular phenotype, siRNA, in vitro assay; single lab\",\n      \"pmids\": [\"24838098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Connexin43 (Cx43) suppresses MFG-E8 secretion in C6 glioma cells as part of its growth-regulatory mechanism; a major component of conditioned medium affected by Cx43 expression was identified as MFG-E8.\",\n      \"method\": \"Cx43 transfection in C6 glioma cells, conditioned medium analysis, protein identification\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, protein identification from conditioned medium without mechanistic follow-up on MFG-E8 itself\",\n      \"pmids\": [\"11085522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"p63 (TP63) transcriptionally activates MFGE8 through a p53/p63-binding motif at -370 upstream of MFGE8. TA-p63 isoforms activate MFGE8 transcription, and ΔN-p63 (when dominant) enhances this activation. siRNA-mediated p63 silencing in squamous carcinoma cells decreases MFG-E8 and reduces cell adhesion.\",\n      \"method\": \"Tetracycline-induced p63 expression, reporter assays, chromatin immunoprecipitation, siRNA silencing, Saos-2 cell adhesion assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — ChIP confirming binding, reporter assay with defined motif, siRNA with functional readout, multiple isoform analysis\",\n      \"pmids\": [\"17637751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MFG-E8 regulates osteoclastogenesis; MFG-E8-deficient osteoclast precursors undergo increased RANKL-induced osteoclastogenesis with enhanced resorption pit formation. Exogenous MFG-E8 inhibits RANKL-induced osteoclastogenesis from mouse and human precursors. In vivo, Mfge8-/- mice show more osteoclasts and greater inflammatory bone loss.\",\n      \"method\": \"Mfge8-/- mouse bone marrow-derived osteoclast precursors, exogenous MFG-E8 addition, RANKL-induced osteoclastogenesis assay, resorption pit formation, experimental periodontitis model, local anti-MFG-E8 mAb microinjection\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse, human and mouse precursors, exogenous protein addition, antibody inhibition and supplementation in vivo\",\n      \"pmids\": [\"24958900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MFG-E8 suppresses T cell activation and proliferation and regulates T cell polarization (inhibiting Th1/Th2/Th17, increasing Treg) by inhibiting PKCθ phosphorylation through the α3/5βV integrin receptor on T cells.\",\n      \"method\": \"Recombinant MFG-E8 addition and neutralization, MFG-E8 overexpression in ESCs, T cell proliferation and activation assays, PKCθ phosphorylation western blot, integrin receptor blocking\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined receptor and signaling step, multiple T cell readouts, single lab\",\n      \"pmids\": [\"26455415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MFGE8 RGD tripeptide motif mediates sperm-extracellular vesicle interactions in the epididymis; ablation of the RGD domain, competitive RGD-peptide inhibition, or antibody masking of alpha V integrin receptors all significantly inhibit uptake and redistribution of EV-delivered proteins into mouse spermatozoa.\",\n      \"method\": \"Receptor inhibition strategies, RGD domain ablation of MFGE8, competitive RGD-peptide inhibition, anti-αV integrin antibody masking, cell culture model, protein redistribution assay\",\n      \"journal\": \"Proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple complementary inhibition strategies, defined RGD motif requirement, single lab\",\n      \"pmids\": [\"33792189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP14 is a deubiquitinase that interacts with, deubiquitinates, and stabilizes MFG-E8 protein in bronchial epithelial cells, preventing proteasomal degradation. Cigarette smoke reduces USP14 expression, leading to MFG-E8 proteasomal degradation and increased ferroptosis.\",\n      \"method\": \"Co-immunoprecipitation of USP14 and MFG-E8, USP14 inhibition, proteasome inhibition assays, western blot, in vitro and in vivo cigarette smoke extract models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating interaction, proteasomal pathway confirmed by inhibitor, single lab\",\n      \"pmids\": [\"36596780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MFGE8 in MSC secretome exerts anti-fibrotic effects in hepatic stellate cells by binding αvβ3 integrin and downregulating TGFβ type I receptor expression, thereby inhibiting TGFβ/Smad signaling.\",\n      \"method\": \"Antagonizing MFGE8 activity (blocking antibody/knockdown), recombinant MFGE8 protein, αvβ3 integrin binding assay, TGFβ receptor expression assay, in vitro HSC activation, in vivo liver fibrosis models\",\n      \"journal\": \"BMB reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined receptor/TGFβ receptor mechanism, in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"28115038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MFG-E8 promotes the proinflammatory phenotypic shift of aged VSMCs by activating NF-κB, increasing proinflammatory gene expression and cell proliferation via integrin-mediated signaling. At the same time, high-dose rMFG-E8 attenuates VSMC migration.\",\n      \"method\": \"Aged mouse carotid artery ligation model, recombinant MFG-E8 administration, NF-κB nuclear translocation assay, immunoblotting, immunofluorescence, Transwell migration assay\",\n      \"journal\": \"Journal of biomedical science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro, NF-κB pathway defined, multiple readouts, single lab\",\n      \"pmids\": [\"31470852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MFG-E8 regulates VSMC migration through dose-dependent regulation of Arp2-mediated actin polymerization; low-dose MFG-E8 upregulates Arp2 via β1 integrin and Rac1, while high-dose MFG-E8 reduces Arp2 and attenuates actin assembly and migration. Genetic deletion of MFG-E8 decreases Arp2 and attenuates injury-induced neointimal hyperplasia.\",\n      \"method\": \"MFG-E8 KO mice (carotid artery ligation), recombinant MFG-E8 dose-response, β1 integrin function-blocking antibody, Rac1 inhibitor, actin assembly assay, immunofluorescence and immunoblotting\",\n      \"journal\": \"Journal of the American Heart Association\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse, defined integrin-Rac1-Arp2 pathway, dose-response in vitro and in vivo, single lab\",\n      \"pmids\": [\"34041925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MFGE8 attenuates atrial fibrosis by inhibiting TGF-β1/Smad2/3 signaling through integrin β3; knockdown of integrin β3 suppresses the TGF-β1/Smad2/3-activating effects of MFGE8 knockdown in Ang-II-treated rat atrial fibroblasts.\",\n      \"method\": \"siRNA knockdown of MFGE8, recombinant human MFGE8 (rhMFGE8) administration, integrin β3 inhibition, TGF-β1/Smad2/3 pathway western blot, Ang-II rat model\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA and recombinant protein approaches, integrin β3 receptor blocking, defined signaling pathway, single lab\",\n      \"pmids\": [\"31958465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Schwann cell-derived exosomal MFG-E8 modifies macrophage/microglial polarization toward M2 by activating the SOCS3/STAT3 pathway. Knockout of MFG-E8 in Schwann cells reverses the anti-inflammatory effects of SCDEs.\",\n      \"method\": \"Proteomic sequencing of exosomes, lentiviral MFG-E8 transfection and knockout in SCs, SOCS3/STAT3 signaling assays, BMDM polarization assays, SCI rat model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomic identification, lentiviral KO, defined signaling pathway, in vitro and in vivo, single lab\",\n      \"pmids\": [\"36717543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MFGE8 secreted by cancer-associated fibroblasts (CAFs) promotes esophageal squamous cell carcinoma tumor progression by binding Integrin αVβ3/αVβ5 receptors and activating both PI3K/AKT and ERK/AKT pathways.\",\n      \"method\": \"RNA sequencing of CAFs and tumor cells, MFGE8 knockdown in CAFs, integrin αVβ3/αVβ5 receptor blocking, PI3K/AKT and ERK pathway analysis, in vivo tumor models\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined receptor/pathway, KD and receptor blocking, in vivo validation, single lab\",\n      \"pmids\": [\"37816055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MFGE8 inhibits intestinal fibrosis through integrin αvβ5-mediated and FAK-dependent signaling in intestinal myofibroblasts; blockade of integrin αvβ5 or FAK renders myofibroblasts non-responsive to MFGE8. MFGE8 prevents and reverses experimental intestinal fibrosis in vitro and in vivo.\",\n      \"method\": \"Decellularized tissue proteomics, primary human intestinal myofibroblast treatment, integrin αvβ5 and FAK blockade, next-generation sequencing of signaling pathways, experimental fibrosis models in vitro and in vivo\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined integrin/FAK pathway, proteomics validation, multiple experimental fibrosis models, single lab\",\n      \"pmids\": [\"38378253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MFG-E8 interacts with HSPA1L and suppresses Parkin expression via the HSPA1L-Parkin pathway, leading to mitophagy inhibition; conversely, MFG-E8 knockdown upregulates PINK1 via SGK1/FOXO1/STAT3 phosphorylation pathways to stimulate mitophagy.\",\n      \"method\": \"Co-immunoprecipitation and immunoprecipitation identifying HSPA1L as MFG-E8 binding partner, MFG-E8 overexpression and siRNA in C2C12 cells, Parkin/PINK1 western blot, mitophagy assays\",\n      \"journal\": \"Journal of cachexia, sarcopenia and muscle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying direct binding partner, defined pathway mechanism, in vitro and in vivo, single lab\",\n      \"pmids\": [\"38553831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CRC-derived extracellular vesicles carrying MFGE8 stimulate macrophage efferocytosis by increasing αvβ3 integrin expression on the macrophage cell surface, thereby activating the intracellular Src-FAK-STAT3 signaling pathway. MFGE8-knockout CRC cells generate EVs that fail to upregulate macrophage efferocytosis.\",\n      \"method\": \"CRISPR-Cas9 MFGE8 knockout in CRC cells, EV isolation and proteomic analysis, flow cytometry for αvβ3 expression, Src-FAK-STAT3 signaling western blot, in vitro and in vivo efferocytosis assays\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO, defined receptor and signaling pathway, in vitro and in vivo, single lab\",\n      \"pmids\": [\"38802814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"MFG-E8 protein is upregulated in involuting mammary glands and exhibits phosphatidylserine (PS)-binding activity that facilitates recognition and engulfment of apoptotic cells; post-weaning milk MFG-E8 enhanced the binding of apoptotic cells to macrophages, with PS-binding activity enriched in membrane vesicle fractions rather than milk fat globule fractions.\",\n      \"method\": \"Immunoblotting, RNA blotting, immunohistochemistry, in vitro PS-binding assay, apoptotic cell-binding assay, sucrose density-gradient ultracentrifugation\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct PS-binding assay, fractionation, multiple biochemical methods, single lab\",\n      \"pmids\": [\"16401186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Human astrocytes and microglia phagocytose AD patient-derived synapses more than control synapses via an MFG-E8 opsonophagocytic mechanism; inhibiting MFG-E8 interactions rescues the elevated engulfment of AD synapses without affecting control synapse uptake.\",\n      \"method\": \"Primary mouse and human astrocyte/microglia synapse phagocytosis assay, MFG-E8 interaction inhibition, AD patient-derived synapse preparation\",\n      \"journal\": \"Cell reports. Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human and mouse primary cell assays, defined MFG-E8 bridging mechanism, pharmacological inhibition, single lab\",\n      \"pmids\": [\"37652017\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MFGE8/MFG-E8/SED1 is a secreted glycoprotein containing N-terminal EGF-like domains (with an RGD integrin-binding motif) and C-terminal discoidin/F5/8C domains (which bind phosphatidylserine and extracellular matrix including collagen); it functions as a versatile extracellular bridge and integrin ligand that mediates apoptotic/viable cell phagocytosis (by linking PS-exposing cells to vitronectin receptor/αvβ3/5 on phagocytes), sperm-egg adhesion, collagen turnover, fatty acid uptake (via αvβ3/5–PI3K/mTORC2–Akt–Cd36/Fatp1 axis), gastrointestinal and airway smooth muscle contractility (via α8β1/αvβ3–PTEN–RhoA), angiogenesis (via integrin–PDGFRβ crosstalk on pericytes), neural stem cell quiescence (via suppression of mTOR1), cardiac hypertrophy (via Akt/GSK-3β/mTOR suppression), inflammasome-induced IL-1β production (via integrin β3–P2X7), and tissue fibrosis (via integrin–TGFβ/Smad pathway modulation), with its own protein stability regulated post-translationally by the deubiquitinase USP14 and by TPST-2-mediated tyrosine sulfation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MFGE8 (MFG-E8/SED1/lactadherin) is a secreted glycoprotein that functions as a bifunctional extracellular bridge, using its C-terminal discoidin/F5/8C domains to bind phosphatidylserine (PS), collagen, and membrane vesicles while engaging integrins through an N-terminal RGD motif to transduce signals into target cells [#1, #2, #3, #39]. Its best-defined role is opsonization: by tethering PS-exposing surfaces to the αvβ3/αvβ5 vitronectin receptor on phagocytes, it licenses macrophages, microglia, and astrocytes to engulf apoptotic cells, viable PS-exposing neurons, and synapses [#5, #8, #40], with follicular dendritic cells supplying the MFG-E8 that enables tingible-body macrophages to clear germinal-center B cells [#4]. The discoidin domains independently mediate collagen binding and macrophage collagen uptake, linking MFGE8 to extracellular-matrix turnover [#3]. Beyond bridging, integrin-bound MFGE8 acts as a signaling ligand: through αvβ3/αvβ5 it drives PI3K/mTORC2–Akt signaling to translocate CD36/FATP1 and promote enterocyte fatty-acid uptake and lipid-droplet hydrolysis [#7, #14], stabilizes PDGFRβ to potentiate pericyte migration and angiogenesis [#11, #12, #23], and activates MAPK/ERK to drive epithelial and smooth-muscle proliferation [#9, #10]. Acting through α8β1 and αvβ3 integrins it restrains contractility and fibrosis by preventing RhoA activation via PTEN and by suppressing TGFβ/Smad and NF-κB signaling [#13, #15, #21, #30, #33, #36], and it enforces neural stem-cell quiescence and limits cardiac hypertrophy by suppressing mTOR/Akt signaling [#16, #17]. MFGE8 also dampens inflammasome IL-1β output via integrin β3–P2X7 coupling [#6]. The original genetic phenotype is reproductive: SED1-null males are subfertile because the discoidin domains are required for sperm binding to the egg zona pellucida [#0]. MFGE8 protein abundance is controlled post-translationally by USP14-mediated deubiquitination and by TPST-2-mediated tyrosine sulfation [#19, #29], and its transcription is activated by p63 [#25].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established that lactadherin/MFGE8 is an integrin ligand, defining the receptor arm of its later-recognized bridging function.\",\n      \"evidence\": \"Cell attachment assays with purified protein and αvβ3-blocking antibody LM609\",\n      \"pmids\": [\"9260929\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not connect adhesion to a physiological process\", \"Downstream signaling not addressed\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showed that the two C-terminal discoidin domains drive membrane-vesicle association and secretion, defining the lipid/membrane-binding arm of the molecule.\",\n      \"evidence\": \"Domain-deletion mutagenesis in COS-7 cells with biochemical and electron-microscopy analysis\",\n      \"pmids\": [\"11856354\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"PS specificity not yet demonstrated\", \"Functional consequence of vesicle association unresolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified the first genetic loss-of-function phenotype—SED1-null male subfertility—and mapped sperm-egg binding to the discoidin domains.\",\n      \"evidence\": \"SED1-null mice, truncated-domain competition, in vitro sperm-egg binding\",\n      \"pmids\": [\"12941270\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Egg-coat receptor for MFGE8 not identified\", \"Does not address somatic roles\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Linked MFGE8 PS-binding to apoptotic-cell engulfment, establishing the opsonization model.\",\n      \"evidence\": \"PS-binding and apoptotic-cell-binding assays with density-gradient fractionation of involuting mammary gland\",\n      \"pmids\": [\"16401186\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo necessity shown elsewhere\", \"Phagocyte receptor not defined in this study\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Resolved the cellular source problem in the spleen, showing FDC-derived MFGE8 licenses macrophage clearance of apoptotic B cells, and tied protein modification to enzymatic regulation by identifying TPST-2 as its tyrosine-sulfation writer.\",\n      \"evidence\": \"Bone-marrow chimeras and rescue; Tpst1/Tpst2 KO mice with mass spectrometry\",\n      \"pmids\": [\"18490487\", \"19047058\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of sulfation not determined\", \"Whether sulfation affects integrin or PS binding unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extended discoidin-domain function to collagen binding and macrophage collagen uptake, defining a clearance role independent of apoptotic cells.\",\n      \"evidence\": \"Mfge8-/- mice (bleomycin fibrosis), direct binding and domain-rescue, collagen-uptake assays\",\n      \"pmids\": [\"19884654\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phagocyte receptor for collagen-MFGE8 complex not defined\", \"Relationship to integrin signaling unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined a signaling (non-bridging) mechanism in pericytes: integrin-bound MFGE8 stabilizes PDGFRβ to potentiate angiogenesis.\",\n      \"evidence\": \"KO mice, siRNA, Co-IP with PDGFRβ/FAK, ubiquitination assays, tumor and retinopathy models\",\n      \"pmids\": [\"21737783\", \"21868707\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which integrin engagement blocks PDGFRβ ubiquitination not fully defined\", \"Identity of the ubiquitin ligase unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed MFGE8 transduces both proliferative (ERK in vascular smooth muscle) and contractility-suppressing (RhoA via RGD in airway smooth muscle) signals, and bridges PS-exposing viable neurons for microglial phagocytosis.\",\n      \"evidence\": \"VSMC culture with ERK readouts; Mfge8-/- asthma models with RGD point mutant; KO neuronal cultures with PS/VR blockade in vivo\",\n      \"pmids\": [\"22385834\", \"23269839\", \"22357850\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Context determining proliferative vs. inhibitory outcome not defined\", \"Integrin specificity differs across cell types\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected MFGE8 to innate immune regulation by showing it dampens inflammasome IL-1β output through integrin β3–P2X7 coupling.\",\n      \"evidence\": \"Itgb3/Il1b/P2rx7 KO macrophages, recombinant MFGE8, caspase-1 assays, cerebral ischemia model\",\n      \"pmids\": [\"23454767\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between integrin β3 and P2X7 not structurally defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established the integrin–PI3K/mTORC2–Akt axis driving CD36/FATP1 surface translocation, defining MFGE8's role in lipid uptake and metabolic disease.\",\n      \"evidence\": \"Mfge8-/- mice, integrin blockade, mTORC2 inhibitors, subcellular fractionation\",\n      \"pmids\": [\"24441829\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct integrin-to-PI3K coupling not biochemically resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined the α8β1–PTEN–RhoA pathway for smooth-muscle relaxation and extended lipid metabolism to enterocyte lipid-droplet hydrolysis.\",\n      \"evidence\": \"Smooth-muscle-specific α8 deletion and Mfge8-/- mice with RhoA/PTEN assays; integrin-deficient mice with triglyceride hydrolase assays\",\n      \"pmids\": [\"27092791\", \"27812539\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How α8β1 engagement modulates PTEN stability unresolved here\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed MFGE8 enforces tissue homeostasis through mTOR suppression (neural stem-cell quiescence) and defined IL-13-driven PTEN ubiquitination as the target of the α8β1 pathway in airway smooth muscle.\",\n      \"evidence\": \"Conditional Mfge8 KO with rapamycin rescue; smooth-muscle-specific α8β1/PTEN KO with PTEN ubiquitination assays\",\n      \"pmids\": [\"30174295\", \"29763381\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Autocrine receptor on neural stem cells not specified\", \"PTEN deubiquitinase counter-enzyme unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined MFGE8 as an endogenous negative regulator of cardiac hypertrophy via Akt/GSK-3β/mTOR suppression, and demonstrated p63 as a transcriptional activator of MFGE8.\",\n      \"evidence\": \"Mfge8-/- and transgenic mice with Akt inhibitor rescue; ChIP/reporter assays with p63 isoforms\",\n      \"pmids\": [\"28827473\", \"17637751\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cardiac receptor for MFGE8 not identified\", \"Upstream regulators of p63-driven MFGE8 transcription unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified MFGE8 as a negative-feedback regulator of insulin signaling and a dose-dependent modulator of actin-based VSMC migration, expanding its metabolic and vascular roles.\",\n      \"evidence\": \"MFGE8 blockade/augmentation with αvβ5–insulin receptor colocalization; KO mice and dose-response with β1-integrin/Rac1/Arp2 readouts\",\n      \"pmids\": [\"33903257\", \"34041925\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab studies\", \"Mechanism of dose-dependent switch not biochemically defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established post-translational control of MFGE8 abundance by the deubiquitinase USP14 and broadened its roles to exosome-delivered macrophage polarization and synaptic phagocytosis in disease.\",\n      \"evidence\": \"Co-IP and proteasome inhibition for USP14; Schwann-cell exosomal KO with SOCS3/STAT3 assays; human AD synapse phagocytosis with MFG-E8 inhibition\",\n      \"pmids\": [\"36596780\", \"36717543\", \"37652017\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"USP14 ubiquitination sites on MFGE8 unmapped\", \"Single-lab studies for exosomal and synaptic roles\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended MFGE8 to mitophagy regulation via a novel HSPA1L–Parkin partnership and reinforced its anti-fibrotic αvβ5/FAK signaling in the intestine.\",\n      \"evidence\": \"Co-IP identifying HSPA1L; siRNA/overexpression with Parkin/PINK1 readouts; integrin αvβ5/FAK blockade in human myofibroblasts\",\n      \"pmids\": [\"38553831\", \"38378253\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"HSPA1L interaction not reciprocally validated beyond Co-IP\", \"Single-lab findings\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single secreted bridge protein integrates opposing outputs—proliferative vs. quiescent, profibrotic vs. antifibrotic, dose-dependent migration—across diverse integrins and cell types remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying structural model linking integrin choice to downstream pathway selection\", \"Egg-coat and neural stem-cell receptors unidentified\", \"Functional consequences of tyrosine sulfation undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [2, 39]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [2, 7, 9]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 5, 39]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [2, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 4, 39]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [1, 39]},\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [3, 36]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [5, 8, 40]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 6, 27]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 9, 12, 17]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [3, 30, 36]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [7, 14, 22]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"ITGAV\",\n      \"ITGB3\",\n      \"ITGB5\",\n      \"ITGA8\",\n      \"PDGFRB\",\n      \"P2RX7\",\n      \"HSPA1L\",\n      \"USP14\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}