Affinage

MFGE8

Lactadherin · UniProt Q08431

Length
387 aa
Mass
43.1 kDa
Annotated
2026-06-10
100 papers in source corpus 41 papers cited in narrative 41 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1997 High

    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

    PMID:9260929

    Open questions at the time
    • Did not connect adhesion to a physiological process
    • Downstream signaling not addressed
  2. 2002 High

    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

    PMID:11856354

    Open questions at the time
    • PS specificity not yet demonstrated
    • Functional consequence of vesicle association unresolved
  3. 2003 High

    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

    PMID:12941270

    Open questions at the time
    • Egg-coat receptor for MFGE8 not identified
    • Does not address somatic roles
  4. 2006 Medium

    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

    PMID:16401186

    Open questions at the time
    • In vivo necessity shown elsewhere
    • Phagocyte receptor not defined in this study
  5. 2008 High

    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

    PMID:18490487 PMID:19047058

    Open questions at the time
    • Functional consequence of sulfation not determined
    • Whether sulfation affects integrin or PS binding unknown
  6. 2009 High

    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

    PMID:19884654

    Open questions at the time
    • Phagocyte receptor for collagen-MFGE8 complex not defined
    • Relationship to integrin signaling unclear
  7. 2011 High

    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

    PMID:21737783 PMID:21868707

    Open questions at the time
    • Mechanism by which integrin engagement blocks PDGFRβ ubiquitination not fully defined
    • Identity of the ubiquitin ligase unknown
  8. 2012 High

    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

    PMID:22357850 PMID:22385834 PMID:23269839

    Open questions at the time
    • Context determining proliferative vs. inhibitory outcome not defined
    • Integrin specificity differs across cell types
  9. 2013 High

    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

    PMID:23454767

    Open questions at the time
    • Molecular link between integrin β3 and P2X7 not structurally defined
  10. 2014 High

    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

    PMID:24441829

    Open questions at the time
    • Direct integrin-to-PI3K coupling not biochemically resolved
  11. 2016 High

    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

    PMID:27092791 PMID:27812539

    Open questions at the time
    • How α8β1 engagement modulates PTEN stability unresolved here
  12. 2018 High

    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

    PMID:29763381 PMID:30174295

    Open questions at the time
    • Autocrine receptor on neural stem cells not specified
    • PTEN deubiquitinase counter-enzyme unknown
  13. 2017 High

    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

    PMID:17637751 PMID:28827473

    Open questions at the time
    • Cardiac receptor for MFGE8 not identified
    • Upstream regulators of p63-driven MFGE8 transcription unknown
  14. 2021 Medium

    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

    PMID:33903257 PMID:34041925

    Open questions at the time
    • Single-lab studies
    • Mechanism of dose-dependent switch not biochemically defined
  15. 2023 Medium

    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

    PMID:36596780 PMID:36717543 PMID:37652017

    Open questions at the time
    • USP14 ubiquitination sites on MFGE8 unmapped
    • Single-lab studies for exosomal and synaptic roles
  16. 2024 Medium

    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

    PMID:38378253 PMID:38553831

    Open questions at the time
    • HSPA1L interaction not reciprocally validated beyond Co-IP
    • Single-lab findings

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0060090 molecular adaptor activity 3 GO:0008289 lipid binding 2 GO:0098631 cell adhesion mediator activity 2
Localization
GO:0005576 extracellular region 3 GO:0031012 extracellular matrix 2 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1430728 Metabolism 3 R-HSA-1474244 Extracellular matrix organization 3 R-HSA-168256 Immune System 3 R-HSA-5357801 Programmed Cell Death 3
Partners
HSPA1LITGA8ITGAVITGB3ITGB5P2RX7PDGFRBUSP14

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 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. Gene knockout (SED1-null mice), recombinant protein competition assays, truncated domain proteins, sperm-egg binding assay in vitro Cell High 12941270
2002 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. Domain-deletion mutagenesis in COS-7 cells, immunofluorescence, cell-surface biotinylation, size-exclusion chromatography, ultracentrifugation, scanning electron microscopy European journal of biochemistry High 11856354
1997 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. Cell attachment assay with purified lactadherin, monoclonal antibody inhibition, integrin-blocking antibodies DNA and cell biology High 9260929
2009 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. Mfge8-/- mouse model (bleomycin-induced pulmonary fibrosis), direct binding assay, recombinant domain rescue experiment, macrophage collagen uptake assay The Journal of clinical investigation High 19884654
2008 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. Bone marrow chimeras between WT and Mfge8(-/-) mice, exogenous recombinant Mfge8 rescue, lymphotoxin-deficient mice lacking FDCs The Journal of experimental medicine High 18490487
2012 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. 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 The Journal of neuroscience High 22357850
2013 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. Itgb3-/-, Il1b-/-, P2rx7-/- mouse models, recombinant MFGE8 supplementation, macrophage IL-1β production assays, caspase-1 activation assay, cerebral ischemia mouse model The Journal of clinical investigation High 23454767
2014 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. Mfge8-/- mouse model, integrin-blocking experiments, PI3K/mTORC2 inhibitors, Cd36/Fatp1 subcellular fractionation, fatty acid uptake assays Nature medicine High 24441829
2005 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. Mfge8 mutant (knockout) mice, histological analysis (CD45, CD11b staining), mammary gland involution assay Molecular biology of the cell High 16195353
2007 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. SED1-null mouse model, integrin-binding assays, MAPK activation assays, proliferation assays Proceedings of the National Academy of Sciences of the United States of America High 17299048
2012 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. In vitro VSMC culture, MFG-E8 exogenous addition and siRNA silencing, integrin receptor inhibition, ERK1/2 phosphorylation assay, BrdU incorporation, PCNA/CDK4 western blot Aging cell Medium 22385834
2011 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. 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 Arteriosclerosis, thrombosis, and vascular biology High 21737783
2011 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. Co-immunoprecipitation (MFG-E8 with PDGFRβ), siRNA depletion, anti-MFG-E8 antibodies, ubiquitination assay, confocal microscopy, signaling assays Arteriosclerosis, thrombosis, and vascular biology High 21868707
2012 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). 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 Proceedings of the National Academy of Sciences of the United States of America High 23269839
2016 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. Mfge8-/-, αvβ3/αvβ5 integrin-deficient mice, fat challenge assay, in vitro triglyceride hydrolase activity assay, PI3K/mTORC2 pharmacological inhibition JCI insight High 27812539
2016 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. Smooth muscle-specific α8 deletion, antibody blockade of α8, Mfge8-/- mice, antral smooth muscle contraction assay, RhoA activity assay, PTEN pathway analysis eLife High 27092791
2018 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. Mfge8-null mice, RGL-specific conditional Mfge8 deletion, rapamycin treatment, mTOR1 signaling assays, BrdU label-retaining RGL quantification Cell stem cell High 30174295
2017 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. 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 Hypertension High 28827473
2009 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. SED1-null male mice, in vitro epididymal cell adhesion assay, exogenous SED1 rescue, αV integrin receptor inhibition, immunolocalization Journal of cell science High 19240116
2008 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. Tpst1-/- and Tpst2-/- mice, affinity chromatography with anti-sulfotyrosine antibody, mass spectrometry, metabolic labeling and sulfoamino acid analysis The Journal of biological chemistry High 19047058
2015 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. 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 International journal of molecular medicine Medium 25936372
2018 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. Smooth muscle-specific α8β1 and PTEN conditional KO mice, Mfge8-/- mice, PI3K inhibitor, tracheal ring contraction assay, PTEN ubiquitination assay FASEB journal High 29763381
2021 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. MFGE8 blockade and augmentation experiments, αvβ5 integrin pathway inhibition, co-localization of αvβ5 integrin and insulin receptor, glucose uptake assay, hepatic insulin sensitivity assay Proceedings of the National Academy of Sciences of the United States of America Medium 33903257
2014 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. MFG-E8 KO mice, siRNA knockdown, in vitro capillary-like structure formation assay, immunolocalization, wound healing model The American journal of pathology Medium 24838098
2000 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. Cx43 transfection in C6 glioma cells, conditioned medium analysis, protein identification Cancer research Low 11085522
2007 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. Tetracycline-induced p63 expression, reporter assays, chromatin immunoprecipitation, siRNA silencing, Saos-2 cell adhesion assay Oncogene High 17637751
2014 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. 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 of immunology High 24958900
2015 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. Recombinant MFG-E8 addition and neutralization, MFG-E8 overexpression in ESCs, T cell proliferation and activation assays, PKCθ phosphorylation western blot, integrin receptor blocking Stem cell reports Medium 26455415
2021 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. Receptor inhibition strategies, RGD domain ablation of MFGE8, competitive RGD-peptide inhibition, anti-αV integrin antibody masking, cell culture model, protein redistribution assay Proteomics Medium 33792189
2023 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. Co-immunoprecipitation of USP14 and MFG-E8, USP14 inhibition, proteasome inhibition assays, western blot, in vitro and in vivo cigarette smoke extract models Cell death & disease Medium 36596780
2017 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. 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 BMB reports Medium 28115038
2019 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. Aged mouse carotid artery ligation model, recombinant MFG-E8 administration, NF-κB nuclear translocation assay, immunoblotting, immunofluorescence, Transwell migration assay Journal of biomedical science Medium 31470852
2021 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. 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 of the American Heart Association Medium 34041925
2020 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. siRNA knockdown of MFGE8, recombinant human MFGE8 (rhMFGE8) administration, integrin β3 inhibition, TGF-β1/Smad2/3 pathway western blot, Ang-II rat model Journal of molecular and cellular cardiology Medium 31958465
2023 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. Proteomic sequencing of exosomes, lentiviral MFG-E8 transfection and knockout in SCs, SOCS3/STAT3 signaling assays, BMDM polarization assays, SCI rat model Cell death & disease Medium 36717543
2023 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. 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 Proceedings of the National Academy of Sciences of the United States of America Medium 37816055
2024 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. 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 Gut Medium 38378253
2024 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. 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 of cachexia, sarcopenia and muscle Medium 38553831
2024 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. 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 Cell communication and signaling Medium 38802814
2006 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. Immunoblotting, RNA blotting, immunohistochemistry, in vitro PS-binding assay, apoptotic cell-binding assay, sucrose density-gradient ultracentrifugation The Biochemical journal Medium 16401186
2023 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. Primary mouse and human astrocyte/microglia synapse phagocytosis assay, MFG-E8 interaction inhibition, AD patient-derived synapse preparation Cell reports. Medicine Medium 37652017

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Mfge8 diminishes the severity of tissue fibrosis in mice by binding and targeting collagen for uptake by macrophages. The Journal of clinical investigation 200 19884654
2003 Identification of mouse sperm SED1, a bimotif EGF repeat and discoidin-domain protein involved in sperm-egg binding. Cell 198 12941270
2012 MFG-E8 mediates primary phagocytosis of viable neurons during neuroinflammation. The Journal of neuroscience : the official journal of the Society for Neuroscience 180 22357850
2023 Schwann cell-derived exosomes containing MFG-E8 modify macrophage/microglial polarization for attenuating inflammation via the SOCS3/STAT3 pathway after spinal cord injury. Cell death & disease 146 36717543
2008 Follicular dendritic cells control engulfment of apoptotic bodies by secreting Mfge8. The Journal of experimental medicine 142 18490487
2009 SED1/MFG-E8: a bi-motif protein that orchestrates diverse cellular interactions. Journal of cellular biochemistry 140 19204935
2002 Secretion of a peripheral membrane protein, MFG-E8, as a complex with membrane vesicles. European journal of biochemistry 126 11856354
1997 Lactadherin (formerly BA46), a membrane-associated glycoprotein expressed in human milk and breast carcinomas, promotes Arg-Gly-Asp (RGD)-dependent cell adhesion. DNA and cell biology 118 9260929
2013 MFGE8 inhibits inflammasome-induced IL-1β production and limits postischemic cerebral injury. The Journal of clinical investigation 115 23454767
2008 MFG-E8 regulates microglial phagocytosis of apoptotic neurons. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology 114 18670887
2020 MFG-E8 accelerates wound healing in diabetes by regulating "NLRP3 inflammasome-neutrophil extracellular traps" axis. Cell death discovery 99 32963812
2014 Mfge8 promotes obesity by mediating the uptake of dietary fats and serum fatty acids. Nature medicine 89 24441829
2018 Autocrine Mfge8 Signaling Prevents Developmental Exhaustion of the Adult Neural Stem Cell Pool. Cell stem cell 85 30174295
2012 MFG-E8 activates proliferation of vascular smooth muscle cells via integrin signaling. Aging cell 80 22385834
2005 Mfge8 is critical for mammary gland remodeling during involution. Molecular biology of the cell 79 16195353
2010 Inefficient clearance of dying cells in patients with SLE: anti-dsDNA autoantibodies, MFG-E8, HMGB-1 and other players. Apoptosis : an international journal on programmed cell death 73 20198437
2014 Efficient yeast cell-surface display of exo- and endo-cellulase using the SED1 anchoring region and its original promoter. Biotechnology for biofuels 70 24423072
2020 MFG-E8 attenuates inflammation in subarachnoid hemorrhage by driving microglial M2 polarization. Experimental neurology 67 33245889
2011 Pericyte-derived MFG-E8 regulates pathologic angiogenesis. Arteriosclerosis, thrombosis, and vascular biology 66 21737783
2023 Human astrocytes and microglia show augmented ingestion of synapses in Alzheimer's disease via MFG-E8. Cell reports. Medicine 65 37652017
2000 Connexin43 suppresses MFG-E8 while inducing contact growth inhibition of glioma cells. Cancer research 65 11085522
1996 Cloning and sequence analysis of human breast epithelial antigen BA46 reveals an RGD cell adhesion sequence presented on an epidermal growth factor-like domain. DNA and cell biology 62 8639264
2014 MFG-E8 regulates angiogenesis in cutaneous wound healing. The American journal of pathology 61 24838098
2019 Neurogenesis in Neurodegenerative Diseases: Role of MFG-E8. Frontiers in neuroscience 56 31213977
2007 The EGF repeat and discoidin domain protein, SED1/MFG-E8, is required for mammary gland branching morphogenesis. Proceedings of the National Academy of Sciences of the United States of America 55 17299048
2016 Enhanced cell-surface display and secretory production of cellulolytic enzymes with Saccharomyces cerevisiae Sed1 signal peptide. Biotechnology and bioengineering 49 27183011
2012 Mfge8 suppresses airway hyperresponsiveness in asthma by regulating smooth muscle contraction. Proceedings of the National Academy of Sciences of the United States of America 49 23269839
2014 Protective effect of MFG-E8 after cutaneous ischemia-reperfusion injury. The Journal of investigative dermatology 47 25493650
2015 MFGE8/Integrin β3 pathway alleviates apoptosis and inflammation in early brain injury after subarachnoid hemorrhage in rats. Experimental neurology 46 25936875
2006 Weaning-induced expression of a milk-fat globule protein, MFG-E8, in mouse mammary glands, as demonstrated by the analyses of its mRNA, protein and phosphatidylserine-binding activity. The Biochemical journal 45 16401186
2010 Milk fat globule--epidermal growth factor--factor VIII (MFGE8)/lactadherin promotes bladder tumor development. Oncogene 44 20956946
2023 Targeting MFGE8 secreted by cancer-associated fibroblasts blocks angiogenesis and metastasis in esophageal squamous cell carcinoma. Proceedings of the National Academy of Sciences of the United States of America 42 37816055
2013 New blocking antibodies impede adhesion, migration and survival of ovarian cancer cells, highlighting MFGE8 as a potential therapeutic target of human ovarian carcinoma. PloS one 42 23977342
2023 Human Keratinocyte-Derived Exosomal MALAT1 Promotes Diabetic Wound Healing by Upregulating MFGE8 via microRNA-1914-3p. International journal of nanomedicine 41 36852184
2020 MFGE8 attenuates Ang-II-induced atrial fibrosis and vulnerability to atrial fibrillation through inhibition of TGF-β1/Smad2/3 pathway. Journal of molecular and cellular cardiology 41 31958465
2014 Regulation of osteoclast homeostasis and inflammatory bone loss by MFG-E8. Journal of immunology (Baltimore, Md. : 1950) 41 24958900
2017 Restoration of Circulating MFGE8 (Milk Fat Globule-EGF Factor 8) Attenuates Cardiac Hypertrophy Through Inhibition of Akt Pathway. Hypertension (Dallas, Tex. : 1979) 40 28827473
2020 MFGE8 is down-regulated in cardiac fibrosis and attenuates endothelial-mesenchymal transition through Smad2/3-Snail signalling pathway. Journal of cellular and molecular medicine 39 32945126
2023 MFG-E8 stabilized by deubiquitinase USP14 suppresses cigarette smoke-induced ferroptosis in bronchial epithelial cells. Cell death & disease 36 36596780
2019 MFG-E8 mediates arterial aging by promoting the proinflammatory phenotype of vascular smooth muscle cells. Journal of biomedical science 36 31470852
2016 Mfge8 regulates enterocyte lipid storage by promoting enterocyte triglyceride hydrolase activity. JCI insight 33 27812539
2013 MFG-E8 and HMGB1 are involved in the mechanism underlying alcohol-induced impairment of macrophage efferocytosis. Molecular medicine (Cambridge, Mass.) 33 23552724
2011 Potentiation of platelet-derived growth factor receptor-β signaling mediated by integrin-associated MFG-E8. Arteriosclerosis, thrombosis, and vascular biology 32 21868707
1998 Protective roles of two aluminum (Al)-induced genes, HSP150 and SED1 of Saccharomyces cerevisiae, in Al and oxidative stresses. FEMS microbiology letters 32 9485599
2015 MFG-E8 inhibits neutrophil migration through αvβ₃-integrin-dependent MAP kinase activation. International journal of molecular medicine 31 25936372
2013 Essential role of MFG-E8 for phagocytic properties of microglial cells. PloS one 31 23405209
2022 hMSCs-derived exosome circCDK13 inhibits liver fibrosis by regulating the expression of MFGE8 through miR-17-5p/KAT2B. Cell biology and toxicology 30 35484432
2017 MFG-E8 overexpression promotes colorectal cancer progression via AKT/MMPs signalling. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 30 28653875
2010 Expression of milk fat globule EGF-factor 8 (MFG-E8) mRNA and protein in the human endometrium and its regulation by prolactin. Molecular human reproduction 30 21177637
2005 Production of the long and short forms of MFG-E8 by epidermal keratinocytes. Cell and tissue research 29 15951990
2002 Characterization of novel breast carcinoma-associated BA46-derived peptides in HLA-A2.1/D(b)-beta2m transgenic mice. The Journal of clinical investigation 29 12189239
2023 Extracellular vesicle-derived silk fibroin nanoparticles loaded with MFGE8 accelerate skin ulcer healing by targeting the vascular endothelial cells. Journal of nanobiotechnology 28 38017428
2010 Surface display of active lipase in Pichia pastoris using Sed1 as an anchor protein. Biotechnology letters 28 20383559
2016 α8β1 integrin regulates nutrient absorption through an Mfge8-PTEN dependent mechanism. eLife 27 27092791
2016 MFGE8 regulates TGF-β-induced epithelial mesenchymal transition in endometrial epithelial cells in vitro. Reproduction (Cambridge, England) 27 27340235
2024 Milk fat globule-epidermal growth factor 8 (MFGE8) prevents intestinal fibrosis. Gut 26 38378253
2004 SED1 function during mammalian sperm-egg adhesion. Current opinion in cell biology 26 15363796
2020 MFG-E8 alleviates oxygen-glucose deprivation-induced neuronal cell apoptosis by STAT3 regulating the selective polarization of microglia. The International journal of neuroscience 25 32098538
2019 Regulation of MFGE8 by the intergenic coronary artery disease locus on 15q26.1. Atherosclerosis 25 30861420
2024 Extracellular vesicles containing MFGE8 from colorectal cancer facilitate macrophage efferocytosis. Cell communication and signaling : CCS 24 38802814
2022 Dissecting Heterogeneity Reveals a Unique BAMBIhigh MFGE8high Subpopulation of Human UC-MSCs. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 24 36373720
2019 The glycoproteins EDIL3 and MFGE8 regulate vesicle-mediated eggshell calcification in a new model for avian biomineralization. The Journal of biological chemistry 23 31358619
2014 MFG-E8 expression for progression of oral squamous cell carcinoma and for self-clearance of apoptotic cells. Laboratory investigation; a journal of technical methods and pathology 23 25264705
2021 Identification of MFGE8 and KLK5/7 as mediators of breast tumorigenesis and resistance to COX-2 inhibition. Breast cancer research : BCR 22 33588911
2009 A novel role for SED1 (MFG-E8) in maintaining the integrity of the epididymal epithelium. Journal of cell science 22 19240116
2008 Tyrosylprotein sulfotransferase-2 expression is required for sulfation of RNase 9 and Mfge8 in vivo. The Journal of biological chemistry 22 19047058
2021 MFG-E8 (LACTADHERIN): a novel marker associated with cerebral amyloid angiopathy. Acta neuropathologica communications 21 34530925
2000 Identification of a stromal cell type characterized by the secretion of a soluble integrin-binding protein, MFG-E8, in mouse early gonadogenesis. Mechanisms of development 21 10960788
2019 MFGE8 protects against CCl4 -induced liver injury by reducing apoptosis and promoting proliferation of hepatocytes. Journal of cellular physiology 20 30767216
2017 Identification of MFGE8 in mesenchymal stem cell secretome as an anti-fibrotic factor in liver fibrosis. BMB reports 20 28115038
2005 Use and specificity of breast cancer antigen/milk protein BA46 for generating anti-self-cytotoxic T lymphocytes by recombinant adeno-associated virus-based gene loading of dendritic cells. Cancer gene therapy 20 15565181
2002 SED1 gene length and sequence polymorphisms in feral strains of Saccharomyces cerevisiae. Applied and environmental microbiology 20 12406735
2024 The regulation of MFG-E8 on the mitophagy in diabetic sarcopenia via the HSPA1L-Parkin pathway and the effect of D-pinitol. Journal of cachexia, sarcopenia and muscle 19 38553831
2018 The Mfge8-α8β1-PTEN pathway regulates airway smooth muscle contraction in allergic inflammation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 19 29763381
2015 MFG-E8 Is Critical for Embryonic Stem Cell-Mediated T Cell Immunomodulation. Stem cell reports 19 26455415
2009 Enhancement of beta-glucosidase activity on the cell-surface of sake yeast by disruption of SED1. Journal of bioscience and bioengineering 19 20347765
2018 Immunoregulatory influence of abundant MFG-E8 expression by esophageal cancer treated with chemotherapy. Cancer science 17 30156356
2022 Inframe insertion and splice site variants in MFGE8 associate with protection against coronary atherosclerosis. Communications biology 16 35978133
2021 A novel role for milk fat globule-EGF factor 8 protein (MFGE8) in the mediation of mouse sperm-extracellular vesicle interactions. Proteomics 16 33792189
2017 Enhanced cell-surface display of a heterologous protein using SED1 anchoring system in SED1-disrupted Saccharomyces cerevisiae strain. Journal of bioscience and bioengineering 16 29175124
2010 Loss of SED1/MFG-E8 results in altered luminal physiology in the epididymis. Molecular reproduction and development 16 20422713
2007 p63(TP63) elicits strong trans-activation of the MFG-E8/lactadherin/BA46 gene through interactions between the TA and DeltaN isoforms. Oncogene 16 17637751
1998 Isolation and characterization of full and truncated forms of human breast carcinoma protein BA46 from human milk fat globule membranes. Journal of protein chemistry 16 9535276
2021 CX3CL1(+) Microparticles-Induced MFG-E8 Enhances Apoptotic Cell Clearance by Alveolar Macrophages. Cells 15 34685562
2008 The mouse gamete adhesin, SED1, is expressed on the surface of acrosome-intact human sperm. Fertility and sterility 15 18990388
2021 MFGE8 mitigates brain injury in a rat model of SAH by maintaining vascular endothelial integrity via TIGβ5/PI3K/CXCL12 signaling. Experimental brain research 14 33991211
2021 Increased MFG-E8 at neuromuscular junctions is an exacerbating factor for sarcopenia-associated denervation. Aging cell 14 34953020
2022 Identification of mitochondria-related hub genes in sarcopenia and functional regulation of MFG-E8 on ROS-mediated mitochondrial dysfunction and cell cycle arrest. Food & function 13 34928287
2020 MFGE8, ALB, APOB, APOE, SAA1, A2M, and C3 as Novel Biomarkers for Stress Cardiomyopathy. Cardiovascular therapeutics 13 32695227
2024 MFGE8 in exosomes derived from mesenchymal stem cells prevents esophageal stricture after endoscopic submucosal dissection in pigs. Journal of nanobiotechnology 12 38561800
2024 MFGE8 promotes adult hippocampal neurogenesis in rats following experimental subarachnoid hemorrhage via modifying the integrin β3/Akt signaling pathway. Cell death discovery 12 39128910
2023 Synergistic effects of MFG-E8 and whey protein on mitigating d-galactose-induced sarcopenia through PI3K/AKT/PGC-1α and MAPK/ERK signaling pathways. Journal of dairy science 12 37678791
2024 MFGE8 promotes gastric cancer progression by activating the IL-6/JAK/STAT3 signaling. Cellular signalling 11 39490801
2022 αvβ3-targeted sEVs for efficient intracellular delivery of proteins using MFG-E8. BMC biotechnology 11 35597930
2021 MFG-E8 Regulates Vascular Smooth Muscle Cell Migration Through Dose-Dependent Mediation of Actin Polymerization. Journal of the American Heart Association 11 34041925
2006 Accelerated evolution and loss of a domain of the sperm-egg-binding protein SED1 in ancestral primates. Molecular biology and evolution 11 16864605
2004 SED1 polymorphism within the genus Saccharomyces. FEMS yeast research 11 15381124
2021 Autoregulation of insulin receptor signaling through MFGE8 and the αvβ5 integrin. Proceedings of the National Academy of Sciences of the United States of America 10 33903257
2021 Transcriptome Analysis Reveals MFGE8-HAPLN3 Fusion as a Novel Biomarker in Triple-Negative Breast Cancer. Frontiers in oncology 10 34211850
2020 Absence of the MFG-E8 gene prevents hypoxia-induced pulmonary hypertension in mice. Journal of cellular physiology 10 32592231

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