Affinage

MFGE8

Lactadherin · UniProt Q08431

Length
387 aa
Mass
43.1 kDa
Annotated
2026-04-28
100 papers in source corpus 37 papers cited in narrative 38 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MFGE8 (lactadherin/SED1) is a secreted, PS- and integrin-binding glycoprotein that functions as a versatile bridging molecule linking phosphatidylserine-exposing targets to αv-family and α8β1 integrins on responding cells, thereby orchestrating efferocytosis, tissue remodeling, smooth muscle contractility, and metabolic homeostasis. Its C-terminal discoidin (C1/C2) domains bind phosphatidylserine on apoptotic cells and collagen in the extracellular matrix, while its second EGF-like domain engages αvβ3, αvβ5, and α8β1 integrins through an RGD motif, activating downstream DOCK180–Rac1, PI3K–Akt–mTORC2, PTEN–RhoA, or MAPK cascades depending on cell context (PMID:14697347, PMID:24441829, PMID:27092791, PMID:17299048). Through these integrin-dependent signals, MFGE8 drives macrophage clearance of apoptotic cells and collagen, synchronizes diurnal photoreceptor outer-segment phagocytosis by RPE, maintains neural stem cell quiescence via mTORC1 suppression, modulates inflammasome-derived IL-1β through integrin β3–P2X7 receptor interactions, and stabilizes PDGFRβ at the cell surface to sustain pericyte signaling (PMID:19884654, PMID:22566632, PMID:30174295, PMID:23454767, PMID:21868707). MFGE8 also functions in reproduction, where its discoidin domains mediate sperm–zona pellucida binding and its RGD motif facilitates extracellular vesicle cargo transfer to spermatozoa (PMID:12941270, PMID:33792189).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1997 High

    Establishing the core molecular mechanism: the RGD motif in MFG-E8's EGF-like domain mediates cell adhesion through αvβ3 integrin, defining MFG-E8 as an integrin ligand rather than merely a milk-fat-globule structural protein.

    Evidence Cell attachment assay with purified lactadherin and anti-αvβ3 blocking antibody (LM609) on multiple cell lines

    PMID:9260929

    Open questions at the time
    • αvβ5 engagement not yet tested
    • in vivo relevance of integrin binding unknown
    • no structural detail of RGD–integrin interaction
  2. 1999 Medium

    Alternative splicing produces long (O- and N-glycosylated) and short (N-glycosylated only) MFG-E8 isoforms, with the long form predominating in lactating mammary gland, revealing tissue-specific post-translational diversification.

    Evidence RT-PCR and glycosylation inhibitor analysis in COS7 cells transfected with each splice variant

    PMID:9920772

    Open questions at the time
    • functional distinction between isoforms not established
    • regulation of alternative splicing unknown
  3. 2002 High

    MFG-E8 associates with cell membranes and is secreted on exosome-like vesicles via its two discoidin/C domains, establishing the mode of extracellular delivery.

    Evidence Domain-deletion mutants in COS-7 cells with surface biotinylation, ultracentrifugation, and electron microscopy

    PMID:11856354

    Open questions at the time
    • lipid specificity of membrane binding by C domains not defined
    • whether vesicle-associated form is functionally distinct from soluble form unclear
  4. 2003 High

    The discoidin domains were shown to mediate sperm–zona pellucida binding, and SED1-null males are subfertile, establishing a non-immune reproductive function for MFG-E8.

    Evidence Sed1-null mice, recombinant protein competition, antibody blocking, in vitro fertilization

    PMID:12941270

    Open questions at the time
    • zona pellucida ligand for discoidin domains unidentified
    • whether the RGD-integrin axis also contributes to fertilization not tested
  5. 2004 High

    MFG-E8 was established as the bridging opsonin for efferocytosis: its RGD motif engages αvβ5 integrin on phagocytes while its C domains bind PS on apoptotic cells, activating DOCK180–Rac1 to drive engulfment.

    Evidence RGD mutagenesis, antisense DOCK180, Rac1 activation assay, phagocytosis functional readout

    PMID:14697347

    Open questions at the time
    • relative contribution of αvβ3 vs αvβ5 in different phagocyte types unknown
    • whether additional co-receptors are required not addressed
  6. 2007 High

    Beyond phagocytosis, MFG-E8 was shown to drive mammary gland branching morphogenesis by engaging αv integrins on myoepithelial cells to activate MAPK and proliferation, broadening its role to developmental tissue remodeling.

    Evidence SED1-null mice mammary gland phenotyping, MAPK activation and proliferation assays

    PMID:17299048

    Open questions at the time
    • specific αv heterodimer involved not identified
    • whether MFG-E8 acts on luminal vs myoepithelial cells preferentially not resolved
  7. 2007 Medium

    Transcriptional control of MFGE8 was mapped: p63 activates the MFGE8 promoter via a p53/p63 response element, and separately Sp1 (positively) and c-Jun/AP-1 (negatively) regulate basal and LPS-suppressed expression.

    Evidence ChIP, luciferase reporter mutagenesis, siRNA knockdown of p63

    PMID:17637751 PMID:25711369

    Open questions at the time
    • how p63 and Sp1/AP-1 regulatory circuits integrate in vivo unknown
    • chromatin accessibility at the MFGE8 locus not characterized
  8. 2008 High

    Multiple in vivo roles consolidated: follicular dendritic cells were identified as the primary source of splenic MFG-E8 for germinal center apoptotic B cell clearance, and MFG-E8/αvβ5 was shown to control diurnal RPE phagocytic rhythms and MerTK activation in the retina.

    Evidence Bone marrow chimeras (Mfge8-/-), Mfge8-/- and Itgb5-/- retinal phagocytosis assays, MerTK activation assay

    PMID:18421224 PMID:18490487

    Open questions at the time
    • mechanism linking MFG-E8 to circadian clock machinery unknown
    • how FDC-secreted MFG-E8 reaches tingible-body macrophages not resolved
  9. 2008 High

    TPST-2 was identified as the specific tyrosine sulfotransferase for MFG-E8 in the male reproductive tract, and C/EBPβ was shown to mediate prolactin-induced MFGE8 transcription in macrophages.

    Evidence Tpst1-/- and Tpst2-/- mice with mass spectrometry; promoter-reporter mutagenesis and EMSA for C/EBPβ

    PMID:18392683 PMID:19047058

    Open questions at the time
    • functional consequence of tyrosine sulfation for MFG-E8 activity not tested
    • whether C/EBPβ regulation extends beyond macrophages unknown
  10. 2009 High

    The discoidin domains were shown to bind collagen directly, enabling macrophage-mediated collagen turnover and protection from fibrosis—extending MFG-E8's bridging function beyond PS to extracellular matrix clearance.

    Evidence Mfge8-/- bleomycin-induced pulmonary fibrosis model, direct collagen-binding assay, domain-deletion rescue

    PMID:19884654

    Open questions at the time
    • collagen type specificity of discoidin domain binding not fully mapped
    • whether collagen uptake uses αvβ5 or a distinct integrin receptor unknown
  11. 2012 High

    The NMR structure of the C2 domain revealed that clustered positively charged and aromatic residues in loops 1–3 confer PS-binding specificity, providing the first atomic-level understanding of the opsonin's target-recognition mechanism.

    Evidence NMR solution structure determination and 31P-NMR PS-binding characterization

    PMID:23262193

    Open questions at the time
    • full-length MFG-E8 structure unavailable
    • whether C1 and C2 domains bind PS cooperatively unknown
  12. 2012 High

    MFG-E8 was shown to bridge viable (not just apoptotic) PS-exposing neurons to microglial αvβ5 during neuroinflammation, causing phagoptosis—establishing MFG-E8 as a mediator of pathological neuronal loss.

    Evidence Mfge8-/- cultures, annexin V and VR antagonist blocking, in vivo striatal LPS injection

    PMID:22357850

    Open questions at the time
    • what triggers PS exposure on viable neurons not resolved
    • relative contribution of MFG-E8 vs other PS opsonins in vivo unknown
  13. 2012 High

    A new effector axis was uncovered: MFG-E8 suppresses smooth muscle contraction by inhibiting RhoA activation via its RGD-integrin interaction, protecting against allergic airway hyperresponsiveness.

    Evidence Mfge8-/- asthma model, RGD point mutant, RhoA and NF-κB assays, human airway biopsies

    PMID:23269839

    Open questions at the time
    • specific integrin heterodimer on smooth muscle not identified in this study
    • downstream phosphatase linking integrin to RhoA inhibition not defined
  14. 2013 High

    MFG-E8 was shown to dampen inflammasome-driven IL-1β release through integrin β3-mediated suppression of P2X7 receptor activity, and Mfge8 deficiency worsened cerebral ischemia in an IL-1β-dependent manner.

    Evidence Multiple KO epistasis (Mfge8-/-, Itgb3-/-, Il1b-/-, P2rx7-/-), recombinant MFG-E8 rescue, cerebral ischemia model

    PMID:23454767

    Open questions at the time
    • molecular mechanism by which integrin β3 inhibits P2X7 not defined
    • whether this pathway operates in non-myeloid cells unknown
  15. 2014 High

    MFG-E8 was identified as a metabolic regulator: it drives fatty acid uptake through αvβ3/β5 integrin–PI3K–mTORC2–Akt signaling that translocates CD36 and FATP1 to the cell surface, with Mfge8-/- mice protected from diet-induced obesity.

    Evidence Mfge8-/- high-fat diet model, integrin blocking, PI3K/mTORC2 inhibitors, CD36/FATP1 surface translocation assay

    PMID:24441829

    Open questions at the time
    • tissue-specific source of MFG-E8 in metabolic regulation unclear
    • whether mTORC2 activation is direct or via intermediate kinases not defined
  16. 2016 High

    The integrin receptor for smooth-muscle contractility regulation was resolved: MFG-E8 engages α8β1 integrin, activating PTEN to suppress RhoA, with smooth muscle-specific α8 deletion phenocopying MFG-E8 loss.

    Evidence Smooth muscle-specific α8 conditional KO, PTEN genetic and pharmacologic manipulation, GI transit and contraction assays

    PMID:27092791

    Open questions at the time
    • how α8β1 activates PTEN mechanistically not elucidated
    • whether this pathway operates in vascular smooth muscle not tested
  17. 2018 High

    MFG-E8 was shown to maintain adult neural stem cell quiescence by suppressing mTORC1 signaling; loss of Mfge8 causes stem cell overactivation and depletion, rescuable by rapamycin.

    Evidence RGL-specific conditional Mfge8 deletion, mTORC1 signaling, rapamycin rescue, label-retaining cell analysis

    PMID:30174295

    Open questions at the time
    • integrin receptor mediating mTORC1 suppression in RGLs not identified
    • relationship between mTORC1 and mTORC2 arms in neural stem cells unclear
  18. 2018 High

    The α8β1–PTEN axis was confirmed in airways: IL-13-induced PTEN degradation derepresses RhoA-mediated contraction, and PI3K inhibition blocks enhanced contraction in Mfge8-/- mice, unifying smooth muscle regulation across gastrointestinal and airway tissues.

    Evidence Smooth muscle-specific α8 or PTEN conditional deletion, PI3K inhibitor, PTEN ubiquitination assay, tracheal ring contraction

    PMID:29763381

    Open questions at the time
    • E3 ligase responsible for IL-13-induced PTEN degradation not identified
    • whether MFG-E8 directly prevents PTEN ubiquitination unknown
  19. 2023 Medium

    USP14 was identified as a deubiquitinase that stabilizes MFG-E8 protein by removing ubiquitin, and cigarette smoke reduces USP14, increasing MFG-E8 proteasomal degradation—establishing a post-translational stability mechanism.

    Evidence Co-immunoprecipitation, deubiquitination assay, proteasome inhibitor experiments, USP14 siRNA

    PMID:36596780

    Open questions at the time
    • E3 ubiquitin ligase targeting MFG-E8 not identified
    • whether USP14 regulation of MFG-E8 occurs in non-pulmonary tissues unknown
    • reciprocal co-IP not reported

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the full-length atomic structure of MFG-E8, the identity of the E3 ligase targeting MFG-E8 for degradation, the mechanism by which integrin β3 inhibits P2X7, how MFG-E8 selectively activates mTORC2 vs suppresses mTORC1 in different cellular contexts, and the zona pellucida receptor for the discoidin domains.
  • no full-length structure available
  • E3 ligase unknown
  • mTORC1 vs mTORC2 selectivity unexplained
  • zona pellucida binding partner unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 3 GO:0048018 receptor ligand activity 3 GO:0060090 molecular adaptor activity 3 GO:0098631 cell adhesion mediator activity 2
Localization
GO:0005576 extracellular region 3 GO:0031410 cytoplasmic vesicle 2 GO:0031012 extracellular matrix 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 4 R-HSA-1474165 Reproduction 2 R-HSA-1474244 Extracellular matrix organization 2 R-HSA-1430728 Metabolism 1
Partners
DOCK180FAKITGA8ITGAVITGB3ITGB5PDGFRBUSP14

Evidence

Reading pass · 38 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 binding to the zona pellucida of unfertilized oocytes, and recombinant SED1 or anti-SED1 antibodies competitively inhibit sperm-egg binding. SED1-null males are subfertile with sperm unable to bind the egg coat in vitro. Recombinant protein competition assay, antibody blocking, gene knockout (Sed1-null mice), in vitro sperm-egg binding assay Cell High 12941270
2004 MFG-E8 acts as an opsonin bridging phosphatidylserine (PS)-exposing apoptotic cells to αvβ5 integrin on phagocytes. MFG-E8 and DOCK180 form a functional signaling module: MFG-E8 binding to αvβ5 integrin potentiates Rac1 activation via DOCK180, and this requires the RGD motif in MFG-E8. Antisense DOCK180 abrogates MFG-E8-αvβ5-mediated Rac1 activation and impairs phagocytosis of apoptotic cells. Mutagenesis of RGD motif, co-expression assays, antisense DOCK180, Rac1 activation assay, phagocytosis assay Experimental cell research High 14697347
1997 Human lactadherin (MFG-E8/BA46) promotes RGD-dependent cell adhesion via αvβ3 integrin; anti-αvβ3 mAb (LM609) and denaturation of lactadherin inhibit cell attachment, demonstrating that the RGD motif in the EGF-like domain mediates integrin-dependent adhesion. Cell attachment assay with purified protein, blocking antibody (anti-αvβ3 LM609), protein denaturation controls DNA and cell biology High 9260929
2009 Mfge8 binds collagen via its discoidin domains and targets collagen for uptake by macrophages, thereby reducing tissue fibrosis. Mfge8-/- mice show defective collagen turnover and enhanced pulmonary fibrosis after bleomycin injury. Recombinant Mfge8 containing at least one discoidin domain rescues collagen uptake by Mfge8-/- macrophages. Mfge8-/- mouse model (bleomycin fibrosis), direct collagen-binding assay, domain-deletion rescue experiments, macrophage collagen uptake assay The Journal of clinical investigation High 19884654
2002 MFG-E8 associates with the cell membrane and is secreted as a complex with membrane vesicles (exosomes/microvesicles 100-200 nm). Both C-domains (discoidin-like) are required for membrane association. Expression of MFG-E8 increases the number of secreted membrane vesicles. Domain-deletion mutants in COS-7 cells, surface biotinylation, size-exclusion chromatography, ultracentrifugation, scanning electron microscopy European journal of biochemistry High 11856354
2008 Follicular dendritic cells (FDCs) are the primary source of splenic Mfge8 (identical to FDC marker FDC-M1), which licenses tingible-body macrophages (TBMs) to engulf apoptotic germinal center B cells. In bone marrow chimeras, all splenic Mfge8 derives from FDCs rather than TBMs. Bone marrow chimeras between wild-type and Mfge8-/- mice, immunostaining, in vivo exogenous Mfge8 administration to lymph nodes The Journal of experimental medicine High 18490487
2012 MFG-E8 mediates phagocytosis of viable neurons during LPS-induced neuroinflammation by bridging PS-exposing neurons to the vitronectin receptor (αvβ5) on microglia/macrophages. Blocking PS, MFG-E8, or its receptor (using mutant MFG-E8 unable to bind αvβ5, annexin V, or VR antagonist) inhibits neuronal loss. Mfge8-/- cultures lack inflammatory neuronal loss, which is restored by recombinant MFG-E8. Mfge8 knockout cultures, recombinant MFG-E8 rescue, PS-blocking antibodies, annexin V, receptor antagonist, in vivo striatal injection The Journal of neuroscience High 22357850
2012 MFG-E8/αvβ5 integrin signaling synchronizes diurnal phagocytosis of photoreceptor outer segment (POS) tips by the RPE. PS externalization at POS tips peaks at light onset and promotes shedding and phagocytosis. In Mfge8-/- mice, the diurnal rhythm of PS demarcation of POS tips is lost, demonstrating that RPE-derived MFG-E8 is required for this rhythmic process. Mfge8-/- and Itgb5-/- mouse retina, annexin V and pSIVA biosensor labeling, live photoreceptor imaging, RPE phagocytosis assay in culture Proceedings of the National Academy of Sciences of the United States of America High 22566632
2013 MFGE8 inhibits inflammasome-induced IL-1β production by macrophages through mediation of integrin β3 and P2X7 receptor interactions. Itgb3 deficiency abrogates the inhibitory effect. In vivo, MFGE8 deficiency increases IL-1β and infarct size after cerebral ischemia, effects abolished by IL-1 receptor antagonist or in Il1b-, Itgb3-, or P2rx7-deficient animals. Mfge8-/-, Itgb3-/-, Il1b-/-, P2rx7-/- mice; recombinant MFGE8 supplementation; caspase-1 activation assay; in vivo cerebral ischemia model The Journal of clinical investigation High 23454767
2014 Mfge8 promotes fatty acid and dietary triglyceride uptake 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, steatohepatitis, and insulin resistance. Mfge8-/- mice on high-fat diet, integrin blocking, PI3K/mTORC2 pharmacological inhibition, CD36/FATP1 surface translocation assay, fatty acid uptake assay Nature medicine High 24441829
2012 Mfge8 suppresses airway hyperresponsiveness by inhibiting RhoA activation in airway smooth muscle. Mfge8-/- ASM shows enhanced contraction after cytokine treatment. Recombinant Mfge8 reduces contraction and inhibits IL-13-induced NF-κB activation and RhoA induction. The RGD integrin-binding motif is required for rapid inhibition of RhoA activation. Mfge8-/- mice (allergic asthma model), RGD point mutation of recombinant Mfge8, ASM contraction assay, RhoA activation assay, NF-κB assay, human airway biopsies Proceedings of the National Academy of Sciences of the United States of America High 23269839
2007 SED1/MFG-E8 is required for mammary gland branching morphogenesis. SED1 binds αv integrin receptors on myoepithelial cells, activating MAPK and cell proliferation. Loss of SED1 reduces activated MAPK and cell proliferation throughout the epithelial tree, causing severely reduced ductal branching. SED1-null mice, integrin-binding assay, MAPK activation assay, cell proliferation assay, in vivo mammary gland phenotyping Proceedings of the National Academy of Sciences of the United States of America High 17299048
2012 NMR solution structure of the C2 domain of MFG-E8 was determined. Positively charged and aromatic residues clustered in loops 1-3 of the C2 domain are key for recognizing phosphatidylserine (PS) in apoptotic cells, with the C2 domain showing higher specificity for PS than for phosphatidylcholine. NMR spectroscopy (solution structure determination), 31P-NMR spectroscopy for PS binding characterization Biochimica et biophysica acta High 23262193
2011 Integrin αv-bound MFG-E8 associates with PDGFRβ and focal adhesion kinase (FAK) after PDGF-BB treatment in pericyte precursor cells, retaining PDGFRβ at the cell surface, delaying receptor degradation, potentiating downstream signaling, and enhancing cell migration. MFG-E8 depletion enhances PDGFRβ ubiquitination and degradation. siRNA depletion, co-immunoprecipitation of MFG-E8 with PDGFRβ, confocal microscopy, ubiquitination assay, PDGFRβ signaling assay Arteriosclerosis, thrombosis, and vascular biology High 21868707
2016 Mfge8 ligation of α8β1 integrin reduces antral smooth muscle contractile force by preventing RhoA activation through a PTEN-dependent mechanism. Smooth muscle-specific deletion or antibody blockade of α8 enhances gastric smooth muscle contraction and accelerates gastrointestinal transit, causing malabsorption of dietary fats and carbohydrates. Smooth muscle-specific α8 deletion, antibody blockade, PTEN genetic/pharmacologic manipulation, PI3K inhibition, tracheal ring contraction assay eLife High 27092791
2018 The Mfge8-α8β1 integrin-PTEN pathway regulates airway smooth muscle contraction in allergic inflammation. α8β1 and PTEN mediate Mfge8 effects opposing IL-13-induced increases in airway contractility. IL-13 induces ubiquitination and degradation of PTEN protein, and PI3K inhibition abolishes enhanced contraction in Mfge8-/- mice. Smooth muscle-specific α8 or PTEN deletion, PI3K pharmacological inhibition, tracheal ring contraction assay, PTEN ubiquitination assay FASEB journal High 29763381
2018 Mfge8 is highly enriched in quiescent radial-glia-like neural stem cells (RGLs) in the dentate gyrus and maintains RGL quiescence through autocrine signaling. Loss of Mfge8 elevates mTORC1 signaling in RGLs, causing overactivation and depletion. Rapamycin treatment returns Mfge8-null RGLs to quiescence. Mfge8-null mice, RGL-specific conditional deletion, mTORC1 signaling assay, rapamycin rescue, label-retaining cell analysis Cell stem cell High 30174295
2008 Tyrosylprotein sulfotransferase-2 (TPST-2) is required for tyrosine sulfation of Mfge8 in the male genital tract. Mfge8 is tyrosine-sulfated in wild-type and Tpst1-/- mice but not in Tpst2-/- mice, identifying TPST-2 as the writer of this modification on Mfge8. Tpst1-/- and Tpst2-/- mice, affinity chromatography on anti-sulfotyrosine mAb, mass spectrometry, metabolic labeling with sulfoamino acid analysis The Journal of biological chemistry High 19047058
2009 SED1/MFG-E8 is expressed in the basolateral domain of epididymal epithelial cells and supports epididymal cell adhesion via RGD-mediated binding to αV integrin receptors. SED1-null epididymal cells show reduced adhesion in vitro rescuable by exogenous SED1; loss causes breakdown of the epididymal epithelium and spermatic granulomas. SED1-null mice, improved fixation/immunolocalization, in vitro cell adhesion assay, exogenous SED1 rescue Journal of cell science High 19240116
2012 MFG-E8 released by apoptotic endothelial cells (in a caspase-3-dependent manner) reprograms macrophages to an anti-inflammatory phenotype. Macrophage reprogramming by MFG-E8 occurs through increased phosphorylation of STAT-3. Conditioned media from apoptotic endothelial cells, MFG-E8 neutralization, recombinant MFG-E8 treatment, STAT-3 phosphorylation assay (Western blot), caspase-3 inhibition PloS one Medium 22558449
2015 MFG-E8 inhibits neutrophil migration through αvβ3-integrin-dependent activation of p38 and ERK MAP kinases, which downregulate CXCR2 surface expression and upregulate GRK2. Blocking αv integrin, p38, or ERK reverses MFG-E8-induced inhibition of neutrophil migration. dHL-60 cell migration assay (Boyden chamber), αv integrin neutralizing antibody, p38 and ERK pharmacological inhibitors, flow cytometry for CXCR2 and GRK2 International journal of molecular medicine Medium 25936372
2008 Prolactin induces MFG-E8 expression in macrophages via the transcription factor C/EBPβ; the C/EBPβ binding site in the MFG-E8 promoter is required for prolactin-induced activation, as shown by luciferase reporter assays, mutagenesis, and EMSA demonstrating C/EBPβ binding. Luciferase reporter assay, promoter mutation analysis, EMSA, Western blot, phagocytosis assay Apoptosis Medium 18392683
2007 p63 (TP63) transcriptionally activates MFG-E8 expression through a p53/p63 binding motif at -370 in the MFGE8 promoter. ΔN-p63 isoforms enhance TA-p63-mediated MFGE8 transcription. p63 silencing decreases MFG-E8 production and reduces cell adhesion. Luciferase reporter assay, chromatin immunoprecipitation (ChIP), tetracycline-inducible p63 expression system, siRNA knockdown Oncogene Medium 17637751
2015 MFG-E8 suppresses T cell activation/proliferation and regulates T cell polarization by inhibiting PKCθ phosphorylation through the α3/5βV integrin receptor on T cells. Recombinant MFG-E8 treatment, MFG-E8 neutralization, PKCθ phosphorylation assay, T cell polarization assay, ESC engraftment model Stem cell reports Medium 26455415
2017 MFGE8 deficiency exacerbates cardiac hypertrophy after aortic banding via enhanced Akt/PKB-GSK-3β/mTOR pathway activation. Cardiac-specific MFGE8 overexpression suppresses this pathway and blunts hypertrophy. Akt inhibitor (MK-2206) blocks the prohypertrophic effects of Mfge8 deficiency. Mfge8-/- mice, cardiac-specific transgenic overexpression, aortic banding model, Akt inhibitor MK-2206, Western blot for signaling Hypertension Medium 28827473
2022 MFG-E8 promotes osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs) and vascular calcification by promoting β1 integrin-dependent MMP2 expression, which activates TGF-β1 and subsequent VSMC osteogenic transdifferentiation. MFG-E8-deficient mice are protected from calcium chloride-induced vascular calcification. MFG-E8-/- mice (vascular calcification model), recombinant MFG-E8 application, β1 integrin blocking, MMP2 assay, TGF-β1 signaling analysis Communications biology Medium 35440618
2023 USP14 is a deubiquitinase that interacts with, deubiquitinates, and stabilizes MFG-E8 protein, preventing its proteasomal degradation. Cigarette smoke reduces USP14 expression, leading to increased MFG-E8 ubiquitination and proteasomal degradation. Co-immunoprecipitation, deubiquitination assay, proteasome inhibitor experiments, siRNA knockdown of USP14, Western blot Cell death & disease Medium 36596780
2015 MFGE8 acting via Integrin β3 alleviates apoptosis and neuroinflammation after subarachnoid hemorrhage. The anti-apoptosis and anti-inflammation effects of recombinant human MFGE8 are abolished by Integrin β3 siRNA knockdown. Rat SAH model, recombinant human MFGE8, MFGE8 siRNA, Integrin β3 siRNA, Western blot for caspase-3 and IL-1β Experimental neurology Medium 25936875
2017 MFGE8 from mesenchymal stem cell secretome exerts anti-fibrotic effects in liver fibrosis by binding to αvβ3 integrin on hepatic stellate cells (HSCs), downregulating TGFβ type I receptor expression and inhibiting TGFβ/Smad signaling. Recombinant MFGE8 administration, MFGE8 activity antagonism in vitro and in vivo liver fibrosis models, αvβ3 integrin binding assay, TGFβ receptor expression analysis BMB reports Medium 28115038
2023 MFG-E8 enhances microglial phagocytosis of myelin debris via αVβ3/αVβ5 integrin-Rac1 pathway and promotes IGF-1 production to support oligodendrocyte progenitor differentiation into mature oligodendrocytes. MFG-E8 is primarily derived from astrocytes in this context. MFG-E8 KO mice, AAV overexpression, bilateral carotid artery stenosis model, αVβ3/αVβ5 integrin pathway assay, Rac1 activation, in vitro phagocytosis assay Neuroscience bulletin Medium 37979054
2024 MFGE8 inhibits intestinal fibrosis through integrin αvβ5 and focal adhesion kinase (FAK) signaling in human intestinal myofibroblasts; blockade of integrin αvβ5 or FAK renders myofibroblasts non-responsive to MFGE8's antifibrotic effects. Decellularized intestinal tissue proteomics, recombinant MFGE8 treatment of primary HIMFs, integrin αvβ5 and FAK blockade, next-generation sequencing, in vitro and in vivo fibrosis models Gut Medium 38378253
1999 MFG-E8 is expressed as two splice variants (long and short) from a single pre-mRNA via alternative inclusion of an exon encoding a Pro/Thr-rich domain. The long variant is multiply O-glycosylated (in addition to N-glycosylation), while the short variant has only N-glycan(s). The long variant is expressed predominantly in the mammary gland during lactation. RT-PCR, sequence analysis, glycosylation inhibitor analysis (tunicamycin, α-benzyl-GalNAc) in COS7 cells transfected with each isoform Biochemical and biophysical research communications Medium 9920772
2008 Both αvβ5 integrin receptor and its ligand MFG-E8 are required for the diurnal burst of RPE phagocytic activity and rhythmic Mer tyrosine kinase activation after photoreceptor shedding. MFG-E8-/- and β5-/- RPE cells retain basal phagocytic activity but completely lose the rhythmic phagocytic burst. Mfge8-/- and Itgb5-/- mice, RPE phagocytosis assay, Mer tyrosine kinase activation assay, electroretinogram Ophthalmic research Medium 18421224
2021 MFGE8 mediates efficient exchange of macromolecular cargo from epididymal extracellular vesicles to mouse spermatozoa via its RGD motif binding to αV integrin receptors. RGD domain ablation, competitive RGD-peptide inhibition, and anti-αV integrin antibody all significantly inhibit EV cargo uptake by sperm. RGD domain ablation mutants, competitive RGD peptide inhibition, αV integrin antibody masking, protein uptake and redistribution assay in immature mouse spermatozoa Proteomics Medium 33792189
2015 MFG-E8 suppresses T cell activation by inhibiting PKCθ phosphorylation through αv integrin receptor interactions, and increases regulatory T cell subsets while inhibiting Th1, Th2, and Th17 subpopulations. Recombinant MFG-E8 treatment, MFG-E8 neutralization, PKCθ phosphorylation assay, T cell subset analysis Stem cell reports Medium 26455415
2024 MFG-E8 interacts with HSPA1L (identified by co-immunoprecipitation), and overexpression of MFG-E8 downregulates Parkin via the HSPA1L-Parkin pathway, inhibiting mitophagy. Conversely, MFG-E8 siRNA upregulates PINK1 via SGK1, FOXO1, and STAT3 phosphorylation pathways to stimulate mitophagy. Co-immunoprecipitation, MFG-E8 siRNA and overexpression plasmid in C2C12 cells, Western blot for mitophagy markers (PINK1, Parkin, LC3B-II/I, P62) Journal of cachexia, sarcopenia and muscle Low 38553831
2023 MFGE8 in colorectal cancer-derived extracellular vesicles activates macrophage efferocytosis by increasing αvβ3 integrin surface expression and activating the intracellular Src-FAK-STAT3 signaling pathway. CRISPR-Cas9 MFGE8 knockout in CRC cells, EV isolation, flow cytometry, Western blot for Src-FAK-STAT3 pathway, in vitro and in vivo efferocytosis assays Cell communication and signaling Medium 38802814
2015 The MFG-E8 gene promoter is regulated by Sp1 (positively) and c-Jun/AP-1 (negatively). Sp1 binding motifs in the proximal promoter are required for full MFG-E8 promoter activity. LPS inhibits MFG-E8 promoter activity by targeting these Sp1 and AP-1-like motifs. Both factors physically interact with the MFG-E8 promoter in vivo. Luciferase reporter assay with deletion and mutation constructs, chromatin immunoprecipitation (ChIP) for Sp1 and c-Jun Journal of cellular biochemistry Medium 25711369

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 199 19884654
2003 Identification of mouse sperm SED1, a bimotif EGF repeat and discoidin-domain protein involved in sperm-egg binding. Cell 197 12941270
2004 The opsonin MFG-E8 is a ligand for the alphavbeta5 integrin and triggers DOCK180-dependent Rac1 activation for the phagocytosis of apoptotic cells. Experimental cell research 179 14697347
2012 MFG-E8 mediates primary phagocytosis of viable neurons during neuroinflammation. The Journal of neuroscience : the official journal of the Society for Neuroscience 178 22357850
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
2012 Diurnal, localized exposure of phosphatidylserine by rod outer segment tips in wild-type but not Itgb5-/- or Mfge8-/- mouse retina. Proceedings of the National Academy of Sciences of the United States of America 133 22566632
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 128 36717543
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 113 23454767
2007 Fractalkine-induced MFG-E8 leads to enhanced apoptotic cell clearance by macrophages. Molecular medicine (Cambridge, Mass.) 99 17673941
2016 Correction of MFG-E8 Resolves Inflammation and Promotes Cutaneous Wound Healing in Diabetes. Journal of immunology (Baltimore, Md. : 1950) 90 27194784
2014 Mfge8 promotes obesity by mediating the uptake of dietary fats and serum fatty acids. Nature medicine 87 24441829
2018 Autocrine Mfge8 Signaling Prevents Developmental Exhaustion of the Adult Neural Stem Cell Pool. Cell stem cell 85 30174295
2016 MFG-E8 Drives Melanoma Growth by Stimulating Mesenchymal Stromal Cell-Induced Angiogenesis and M2 Polarization of Tumor-Associated Macrophages. Cancer research 77 27197197
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
2021 MFG-E8 regulated by miR-99b-5p protects against osteoarthritis by targeting chondrocyte senescence and macrophage reprogramming via the NF-κB pathway. Cell death & disease 68 34031369
1999 Lactation-dependent expression of an mRNA splice variant with an exon for a multiply O-glycosylated domain of mouse milk fat globule glycoprotein MFG-E8. Biochemical and biophysical research communications 66 9920772
2023 Human astrocytes and microglia show augmented ingestion of synapses in Alzheimer's disease via MFG-E8. Cell reports. Medicine 62 37652017
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
2022 MFG-E8 alleviates intervertebral disc degeneration by suppressing pyroptosis and extracellular matrix degradation in nucleus pulposus cells via Nrf2/TXNIP/NLRP3 axis. Cell death discovery 60 35440086
2010 The integrin alpha(v)beta(3-5) ligand MFG-E8 is a p63/p73 target gene in triple-negative breast cancers but exhibits suppressive functions in ER(+) and erbB2(+) breast cancers. Cancer research 59 21127199
2012 MFG-E8 released by apoptotic endothelial cells triggers anti-inflammatory macrophage reprogramming. PloS one 58 22558449
2019 Neurogenesis in Neurodegenerative Diseases: Role of MFG-E8. Frontiers in neuroscience 55 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 MFG-E8 Selectively Inhibited Aβ-Induced Microglial M1 Polarization via NF-κB and PI3K-Akt Pathways. Molecular neurobiology 53 27844286
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
2016 Enhanced cell-surface display and secretory production of cellulolytic enzymes with Saccharomyces cerevisiae Sed1 signal peptide. Biotechnology and bioengineering 48 27183011
2015 MFGE8/Integrin β3 pathway alleviates apoptosis and inflammation in early brain injury after subarachnoid hemorrhage in rats. Experimental neurology 46 25936875
2008 Maturation-induced down-regulation of MFG-E8 impairs apoptotic cell clearance and enhances endotoxin response. International journal of molecular medicine 45 19020771
2010 Milk fat globule--epidermal growth factor--factor VIII (MFGE8)/lactadherin promotes bladder tumor development. Oncogene 44 20956946
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
2015 Recombinant human MFG-E8 ameliorates colon damage in DSS- and TNBS-induced colitis in mice. Laboratory investigation; a journal of technical methods and pathology 41 25751740
2014 Regulation of osteoclast homeostasis and inflammatory bone loss by MFG-E8. Journal of immunology (Baltimore, Md. : 1950) 41 24958900
1997 Stage specific expression of milk fat globule membrane glycoproteins in mouse mammary gland: comparison of MFG-E8, butyrophilin, and CD36 with a major milk protein, beta-casein. Biochimica et biophysica acta 41 9101712
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 40 31958465
2013 Proteomic analysis of kidney and protective effects of grape seed procyanidin B2 in db/db mice indicate MFG-E8 as a key molecule in the development of diabetic nephropathy. Biochimica et biophysica acta 40 23474305
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 39 37816055
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
2017 Restoration of Circulating MFGE8 (Milk Fat Globule-EGF Factor 8) Attenuates Cardiac Hypertrophy Through Inhibition of Akt Pathway. Hypertension (Dallas, Tex. : 1979) 39 28827473
2023 Human Keratinocyte-Derived Exosomal MALAT1 Promotes Diabetic Wound Healing by Upregulating MFGE8 via microRNA-1914-3p. International journal of nanomedicine 36 36852184
2023 MFG-E8 stabilized by deubiquitinase USP14 suppresses cigarette smoke-induced ferroptosis in bronchial epithelial cells. Cell death & disease 34 36596780
2013 MFG-E8 and HMGB1 are involved in the mechanism underlying alcohol-induced impairment of macrophage efferocytosis. Molecular medicine (Cambridge, Mass.) 33 23552724
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
2012 NMR solution structure of C2 domain of MFG-E8 and insights into its molecular recognition with phosphatidylserine. Biochimica et biophysica acta 31 23262193
2011 Potentiation of platelet-derived growth factor receptor-β signaling mediated by integrin-associated MFG-E8. Arteriosclerosis, thrombosis, and vascular biology 31 21868707
2015 MFG-E8 inhibits neutrophil migration through αvβ₃-integrin-dependent MAP kinase activation. International journal of molecular medicine 30 25936372
2022 MFG-E8 promotes tendon-bone healing by regualting macrophage efferocytosis and M2 polarization after anterior cruciate ligament reconstruction. Journal of orthopaedic translation 29 35615640
2008 Prolactin induces MFG-E8 production in macrophages via transcription factor C/EBPbeta-dependent pathway. Apoptosis : an international journal on programmed cell death 29 18392683
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
2010 Surface display of active lipase in Pichia pastoris using Sed1 as an anchor protein. Biotechnology letters 28 20383559
2005 Production of the long and short forms of MFG-E8 by epidermal keratinocytes. Cell and tissue research 28 15951990
2022 hMSCs-derived exosome circCDK13 inhibits liver fibrosis by regulating the expression of MFGE8 through miR-17-5p/KAT2B. Cell biology and toxicology 27 35484432
2023 Extracellular vesicle-derived silk fibroin nanoparticles loaded with MFGE8 accelerate skin ulcer healing by targeting the vascular endothelial cells. Journal of nanobiotechnology 26 38017428
2016 α8β1 integrin regulates nutrient absorption through an Mfge8-PTEN dependent mechanism. eLife 26 27092791
2024 Milk fat globule-epidermal growth factor 8 (MFGE8) prevents intestinal fibrosis. Gut 25 38378253
2022 MFG-E8 promotes osteogenic transdifferentiation of smooth muscle cells and vascular calcification by regulating TGF-β1 signaling. Communications biology 25 35440618
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
2004 SED1 function during mammalian sperm-egg adhesion. Current opinion in cell biology 25 15363796
2022 Dissecting Heterogeneity Reveals a Unique BAMBIhigh MFGE8high Subpopulation of Human UC-MSCs. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 24 36373720
2018 Coptisine suppresses tumor growth and progression by down-regulating MFG-E8 in colorectal cancer. RSC advances 24 35548723
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
2006 MFG-E8 in the retina and retinal pigment epithelium of rat and mouse. Molecular vision 23 17167398
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
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
2017 Identification of MFGE8 in mesenchymal stem cell secretome as an anti-fibrotic factor in liver fibrosis. BMB reports 20 28115038
2008 Lack of alphavbeta5 integrin receptor or its ligand MFG-E8: distinct effects on retinal function. Ophthalmic research 20 18421224
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
2023 MFG-E8 Alleviates Cognitive Impairments Induced by Chronic Cerebral Hypoperfusion by Phagocytosing Myelin Debris and Promoting Remyelination. Neuroscience bulletin 19 37979054
2019 MFGE8 protects against CCl4 -induced liver injury by reducing apoptosis and promoting proliferation of hepatocytes. Journal of cellular physiology 19 30767216
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
2012 Recombinant human MFG-E8 attenuates intestinal injury and mortality in severe whole body irradiation in rats. PloS one 18 23056336
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 17 38553831
2018 Immunoregulatory influence of abundant MFG-E8 expression by esophageal cancer treated with chemotherapy. Cancer science 17 30156356
2012 MFG-E8 regulates the immunogenic potential of dendritic cells primed with necrotic cell-mediated inflammatory signals. PloS one 17 22761839
2024 Extracellular vesicles containing MFGE8 from colorectal cancer facilitate macrophage efferocytosis. Cell communication and signaling : CCS 16 38802814
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
2018 Inflammatory bone loss associated with MFG-E8 deficiency is rescued by teriparatide. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 16 29475373
2013 The impact of MFG-E8 in chronic pancreatitis: potential for future immunotherapy? BMC gastroenterology 16 23324439
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
2017 Enhanced cell-surface display of a heterologous protein using SED1 anchoring system in SED1-disrupted Saccharomyces cerevisiae strain. Journal of bioscience and bioengineering 15 29175124
2008 The mouse gamete adhesin, SED1, is expressed on the surface of acrosome-intact human sperm. Fertility and sterility 15 18990388
2021 CX3CL1(+) Microparticles-Induced MFG-E8 Enhances Apoptotic Cell Clearance by Alveolar Macrophages. Cells 14 34685562
2021 Increased MFG-E8 at neuromuscular junctions is an exacerbating factor for sarcopenia-associated denervation. Aging cell 13 34953020
2020 MFGE8, ALB, APOB, APOE, SAA1, A2M, and C3 as Novel Biomarkers for Stress Cardiomyopathy. Cardiovascular therapeutics 13 32695227
2015 Molecular Mechanisms Underlying the Regulation of the MFG-E8 Gene Promoter Activity in Physiological and Inflammatory Conditions. Journal of cellular biochemistry 13 25711369
1999 High fat feeding of lactating mice causing a drastic reduction in fat and energy content in milk without affecting the apparent growth of their pups and the production of major milk fat globule membrane components MFG-E8 and butyrophilin. Bioscience, biotechnology, and biochemistry 13 10586503
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 12 34928287