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MFG-E8: Origin, Structure, Expression, Functions and Regulation

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MFG-E8 and Inflammation

Abstract

Milk Fat Globule-Epidermal Growth Factor-Factor 8 (MFG-E8) with bivalent binding activity to integrin receptors and acidic phospholipids is a secretary glycoprotein exhibiting versatile functions in cell physiology affecting health and diseases. Recent progress in genomics and structural biology studies, in addition to long time accumulation of classical biochemical studies, has been showing its unique molecular structure advantageous to the link between cells and their target cells as well as molecular complexes and its critical roles in regulating inflammation and immunity. MFG-E8 is expressed and secreted by a variety of cells and tissues, especially professional and non-professional phagocytes such as macrophages, immature dendritic cells and the epithelial cells of mammary glands and epididymis. Although MFG-E8 expression has been shown to be up-regulated by a lactogenic hormone, prolactin (PRL), and neuronal chemokine, fractalkine, molecular mechanisms involved in MFG-E8 expression in health and disease states remain largely unknown. The secreted MFG-E8 specifically recognizes the acidic phospholipids and opsonized the targets to be cleared by phagocytosis mainly in paracrine and occasionally in endocrine manners. In addition to the enhancing role in phagocytosis, MFG-E8 binds to its target cells expressing MFG-E8 receptors and acts as a ligand, which modulates inflammatory responses. Moreover, MFG-E8 alone shows ligand activity to intestinal epithelial cells locally exposing the acidic phospholipids and vascular endothelial cells expressing the integrins.

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References

  1. Hanayama R, Tanaka M, Miwa K, Shinohara A, Iwamatsu A, Nagata S (2002) Identification of a factor that links apoptotic cells to phagocytes. Nature 417(6885):182–187

    Article  PubMed  CAS  Google Scholar 

  2. Hanayama R, Tanaka M, Miyasaka K et al (2004) Autoimmune disease and impaired uptake of apoptotic cells in MFG-E8-deficient mice. Science 304(5674):1147–1150

    Article  PubMed  CAS  Google Scholar 

  3. Kanai Y, Kanai-Azuma M, Tajima Y, Birk OS, Hayashi Y, Sanai Y (2000) Identification of a stromal cell type characterized by the secretion of a soluble integrin-binding protein, MFG-E8, in mouse early gonadogenesis. Mech Dev 96(2):223–227

    Article  PubMed  CAS  Google Scholar 

  4. Ensslin MA, Shur BD (2003) Identification of mouse sperm SED1, a bimotif EGF repeat and discoidin-domain protein involved in sperm-egg binding. Cell 114(4):405–417

    Article  PubMed  CAS  Google Scholar 

  5. Hanayama R, Nagata S (2005) Impaired involution of mammary glands in the absence of milk fat globule EGF factor 8. Proc Natl Acad Sci U S A 102(46):16886–16891

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  6. Ensslin MA, Shur BD (2007) The EGF repeat and discoidin domain protein, SED1/MFG-E8, is required for mammary gland branching morphogenesis. Proc Natl Acad Sci U S A 104(8):2715–2720

    Article  PubMed Central  PubMed  Google Scholar 

  7. Aziz M, Jacob A, Matsuda A et al (2011) Pre-treatment of recombinant mouse MFG-E8 downregulates LPS-induced TNF-α production in macrophages via STAT3-mediated SOCS3 activation. PLoS One 6(11):e27685

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  8. Brissette MJ, Lepage S, Lamonde AS et al (2012) MFG-E8 released by apoptotic endothelial cells triggers anti-inflammatory macrophage reprogramming. PLoS One 7(4):e36368

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  9. Aziz M, Matsuda A, Yang WL, Jacob A, Wang P (2012) Milk fat globule-epidermal growth factor-factor 8 attenuates neutrophil infiltration in acute lung injury via modulation of CXCR2. J Immunol 189(1):393–402

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  10. Stubbs JD, Lekutis C, Singer KL et al (1990) CDNA cloning of a mouse mammary epithelial cell surface protein reveals the existence of epidermal growth factor-like domains linked to factor VIII-like sequences. Proc Natl Acad Sci U S A 87(21):8417–8421

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  11. Larocca D, Peterson JA, Urrea R, Kuniyoshi J, Bistrain AM, Ceriani RL (1991) A Mr 46,000 human milk fat globule protein that is highly expressed in human breast tumors contains factor VIII-like domains. Cancer Res 51(18):4994–4998

    PubMed  CAS  Google Scholar 

  12. Couto JR, Taylor MR, Godwin SG, Ceriani RL, Peterson JA (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 Cell Biol 15(4):281–286

    Article  PubMed  CAS  Google Scholar 

  13. Mather IH (2000) A review and proposed nomenclature for major proteins of the milk-fat globule membrane. J Dairy Sci 83(2):203–247

    Article  PubMed  CAS  Google Scholar 

  14. Nakatani H, Aoki N, Nakagawa Y et al (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. Biochem J 395(1):21–30

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  15. Nakatani H, Yasueda T, Oshima K et al (2013) Post-weaning increases in the milk-fat globule EGF-factor VIII (MFG-E8) on fat globules in mouse milk and in the uptake of the fat globules by HC11 mammary epithelial cells. J Biochem 153(1):31–41

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  16. Nakatani H, Yasueda T, Oshima K, Nadano D, Matsuda T (2012) Re-evaluation of milk-fat globule EGF-factor VIII (MFG-E8) as an intrinsic component of the mouse milk-fat globule membrane. Biosci Biotechnol Biochem 76(11):2055–2060

    Article  PubMed  CAS  Google Scholar 

  17. Aoki N, Kishi M, Taniguchi Y, Adachi T, Nakamura R, Matsuda T (1995) Molecular cloning of glycoprotein antigens MGP57/53 recognized by monoclonal antibodies raised against bovine milk fat globule membrane. Biochim Biophys Acta 1245(3):385–391

    Article  PubMed  Google Scholar 

  18. Hvarregaard J, Andersen MH, Berglund L, Rasmussen JT, Petersen TE (1996) Characterization of glycoprotein PAS-6/7 from membranes of bovine milk fat globules. Eur J Biochem 240(3):628–636

    Article  PubMed  CAS  Google Scholar 

  19. Ensslin M, Vogel T, Calvete JJ et al (1998) Molecular cloning and characterization of P47, a novel boar sperm-associated zona pellucida-binding protein homologous to a family of mammalian secretory proteins. Biol Reprod 58(4):1057–1064

    Article  PubMed  CAS  Google Scholar 

  20. Ogura K, Nara K, Watanabe Y, Kohno K, Tai T, Sanai Y (1996) Cloning and expression of cDNA for O-acetylation of GD3 ganglioside. Biochem Biophys Res Commun 225(3):932–938

    Article  PubMed  CAS  Google Scholar 

  21. Hidai C, Zupancic T, Penta K et al (1998) Cloning and characterization of developmental endothelial locus-1: an embryonic endothelial cell protein that binds the alphavbeta3 integrin receptor. Genes Dev 12(1):21–33

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  22. Hanayama R, Tanaka M, Miwa K, Nagata S (2004) Expression of developmental endothelial locus-1 in a subset of macrophages for engulfment of apoptotic cells. J Immunol 172(6):3876–3882

    Article  PubMed  CAS  Google Scholar 

  23. Ruan J, Li H, Chen Z et al (2008) TreeFam: 2008 update. Nucleic Acids Res 36(Database issue):D735–D740

    PubMed Central  PubMed  CAS  Google Scholar 

  24. Oshima K, Aoki N, Negi M, Kishi M, Kitajima K, Matsuda T (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. Biochem Biophys Res Commun 254(3):522–528

    Article  PubMed  CAS  Google Scholar 

  25. Podlaha O, Webb DM, Zhang J (2006) Accelerated evolution and loss of a domain of the sperm-egg-binding protein SED1 in ancestral primates. Mol Biol Evol 23(10):1828–1831

    Article  PubMed  CAS  Google Scholar 

  26. Kim DH, Kanno C, Mizokami Y (1992) Purification and characterization of major glycoproteins, PAS-6 and PAS-7, from bovine milk fat globule membrane. Biochim Biophys Acta 1122(2):203–211

    Article  PubMed  CAS  Google Scholar 

  27. Picariello G, Ferranti P, Mamone G, Roepstorff P, Addeo F (2008) Identification of N-linked glycoproteins in human milk by hydrophilic interaction liquid chromatography and mass spectrometry. Proteomics 8(18):3833–3847

    Article  PubMed  CAS  Google Scholar 

  28. Yamaguchi H, Fujimoto T, Nakamura S et al (2010) Aberrant splicing of the milk fat globule-EGF factor 8 (MFG-E8) gene in human systemic lupus erythematosus. Eur J Immunol 40(6):1778–1785

    Article  PubMed  CAS  Google Scholar 

  29. Andersen MH, Berglund L, Rasmussen JT, Petersen TE (1997) Bovine PAS-6/7 binds alpha v beta 5 integrins and anionic phospholipids through two domains. Biochemistry 36(18):5441–5446

    Article  PubMed  CAS  Google Scholar 

  30. Taylor MR, Couto JR, Scallan CD, Ceriani RL, Peterson JA (1997) Lactadherin (formerly BA46), a membrane-associated glycoprotein expressed in human milk and breast carcinomas, promotes Arg-Gly-Asp (RGD)-dependent cell adhesion. DNA Cell Biol 16(7):861–869

    Article  PubMed  CAS  Google Scholar 

  31. Andersen MH, Graversen H, Fedosov SN, Petersen TE, Rasmussen JT (2000) Functional analyses of two cellular binding domains of bovine lactadherin. Biochemistry 39(20):6200–6206

    Article  PubMed  CAS  Google Scholar 

  32. Schürpf T, Chen Q, Liu JH, Wang R, Springer TA, Wang JH (2012) The RGD finger of Del-1 is a unique structural feature critical for integrin binding. FASEB J 26(8):3412–3420

    Article  PubMed Central  PubMed  Google Scholar 

  33. Oshima K, Aoki N, Kato T, Kitajima K, Matsuda T (2002) Secretion of a peripheral membrane protein, MFG-E8, as a complex with membrane vesicles. Eur J Biochem 269(4):1209–1218

    Article  PubMed  CAS  Google Scholar 

  34. Shi J, Heegaard CW, Rasmussen JT, Gilbert GE (2004) Lactadherin binds selectively to membranes containing phosphatidyl-L-serine and increased curvature. Biochim Biophys Acta 1667(1):82–90

    Article  PubMed  CAS  Google Scholar 

  35. Dasgupta SK, Abdel-Monem H, Niravath P et al (2009) Lactadherin and clearance of platelet-derived microvesicles. Blood 113(6):1332–1339

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  36. Otzen DE, Blans K, Wang H, Gilbert GE, Rasmussen JT (2012) Lactadherin binds to phosphatidylserine-containing vesicles in a two-step mechanism sensitive to vesicle size and composition. Biochim Biophys Acta 1818(4):1019–1027

    Article  PubMed  CAS  Google Scholar 

  37. Yeung T, Heit B, Dubuisson JF et al (2009) Contribution of phosphatidylserine to membrane surface charge and protein targeting during phagosome maturation. J Cell Biol 185(5):917–928

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  38. Fairn GD, Schieber NL, Ariotti N et al (2011) High-resolution mapping reveals topologically distinct cellular pools of phosphatidylserine. J Cell Biol 194(2):257–275

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  39. Shao C, Novakovic VA, Head JF, Seaton BA, Gilbert GE (2008) Crystal structure of lactadherin C2 domain at 1.7A resolution with mutational and computational analyses of its membrane-binding motif. J Biol Chem 283(11):7230–7241

    Article  PubMed  CAS  Google Scholar 

  40. Ye H, Li B, Subramanian V et al (2013) NMR solution structure of C2 domain of MFG-E8 and insights into its molecular recognition with phosphatidylserine. Biochim Biophys Acta 1828(3):1083–1093

    Article  PubMed  CAS  Google Scholar 

  41. Häggqvist B, Näslund J, Sletten K et al (1999) Medin: an integral fragment of aortic smooth muscle cell-produced lactadherin forms the most common human amyloid. Proc Natl Acad Sci U S A 96(15):8669–8674

    Article  PubMed Central  PubMed  Google Scholar 

  42. Peng S, Glennert J, Westermark P (2005) Medin-amyloid: a recently characterized age-associated arterial amyloid form affects mainly arteries in the upper part of the body. Amyloid 12(2):96–102

    Article  PubMed  CAS  Google Scholar 

  43. Larsson A, Peng S, Persson H et al (2006) Lactadherin binds to elastin–a starting point for medin amyloid formation? Amyloid 13(2):78–85

    Article  PubMed  CAS  Google Scholar 

  44. Boddaert J, Kinugawa K, Lambert JC et al (2007) Evidence of a role for lactadherin in Alzheimer's disease. Am J Pathol 170(3):921–929

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  45. Atabai K, Jame S, Azhar N et al (2009) Mfge8 diminishes the severity of tissue fibrosis in mice by binding and targeting collagen for uptake by macrophages. J Clin Invest 119(12):3713–3722

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  46. Watanabe T, Totsuka R, Miyatani S et al (2005) Production of the long and short forms of MFG-E8 by epidermal keratinocytes. Cell Tissue Res 321(2):185–193

    Article  PubMed  CAS  Google Scholar 

  47. Burgess BL, Abrams TA, Nagata S, Hall MO (2006) MFG-E8 in the retina and retinal pigment epithelium of rat and mouse. Mol Vis 12:1437–1447

    PubMed  CAS  Google Scholar 

  48. Aziz M, Jacob A, Matsuda A, Wang P (2011) Review: milk fat globule-EGF factor 8 expression, function and plausible signal transduction in resolving inflammation. Apoptosis 16(11):1077–1086

    Article  PubMed  CAS  Google Scholar 

  49. Krupp M, Itzel T, Maass T, Hildebrandt A, Galle PR, Teufel A (2013) Cell LineNavigator: a workbench for cancer cell line analysis. Nucleic Acids Res 41(Database issue):D942–D948

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  50. Mercier JC, Vilotte JL (1993) Structure and function of milk protein genes. J Dairy Sci 76(10):3079–3098

    Article  PubMed  CAS  Google Scholar 

  51. Leonardi-Essmann F, Emig M, Kitamura Y, Spanagel R, Gebicke-Haerter PJ (2005) Fractalkine-upregulated milk-fat globule EGF factor-8 protein in cultured rat microglia. J Neuroimmunol 160(1–2):92–101

    Article  PubMed  CAS  Google Scholar 

  52. Miksa M, Amin D, Wu R, Ravikumar TS, Wang P (2007) Fractalkine-induced MFG-E8 leads to enhanced apoptotic cell clearance by macrophages. Mol Med 13(11–12):553–560

    PubMed Central  PubMed  CAS  Google Scholar 

  53. Komura H, Miksa M, Wu R, Goyert SM, Wang P (2009) Milk fat globule epidermal growth factor-factor VIII is down-regulated in sepsis via the lipopolysaccharide-CD14 pathway. J Immunol 182(1):581–587

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  54. Aziz MM, Ishihara S, Rumi MA et al (2008) Prolactin induces MFG-E8 production in macrophages via transcription factor C/EBPbeta-dependent pathway. Apoptosis 13(5):609–620

    Article  PubMed  CAS  Google Scholar 

  55. Franchi A, Bocca S, Anderson S, Riggs R, Oehninger S (2011) Expression of milk fat globule EGF-factor 8 (MFG-E8) mRNA and protein in the human endometrium and its regulation by prolactin. Mol Hum Reprod 17(6):360–371

    Article  PubMed  CAS  Google Scholar 

  56. Okuyama T, Kurata S, Tomimori Y et al (2008) p63(TP63) elicits strong trans-activation of the MFG-E8/lactadherin/BA46 gene through interactions between the TA and DeltaN isoforms. Oncogene 27(3):308–317

    Article  PubMed  CAS  Google Scholar 

  57. Mukundan L, Odegaard JI, Morel CR et al (2009) PPAR-delta senses and orchestrates clearance of apoptotic cells to promote tolerance. Nat Med 15(11):1266–1272

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  58. Nagata S, Hanayama R, Kawane K (2010) Autoimmunity and the clearance of dead cells. Cell 140(5):619–630

    Article  PubMed  CAS  Google Scholar 

  59. Suzuki J, Denning DP, Imanishi E, Horvitz HR, Nagata S (2013) Xk-related protein 8 and CED-8 promote phosphatidylserine exposure in apoptotic cells. Science 341(6144):403–406

    Article  PubMed  CAS  Google Scholar 

  60. Borisenko GG, Iverson SL, Ahlberg S, Kagan VE, Fadeel B (2004) Milk fat globule epidermal growth factor 8 (MFG-E8) binds to oxidized phosphatidylserine: implications for macrophage clearance of apoptotic cells. Cell Death Differ 11(8):943–945

    Article  PubMed  CAS  Google Scholar 

  61. Albert ML, Kim JI, Birge RB (2000) alphavbeta5 integrin recruits the CrkII-Dock180-rac1 complex for phagocytosis of apoptotic cells. Nat Cell Biol 2(12):899–905

    Article  PubMed  CAS  Google Scholar 

  62. Akakura S, Singh S, Spataro M et al (2004) The opsonin MFG-E8 is a ligand for the alphavbeta5 integrin and triggers DOCK180-dependent Rac1 activation for the phagocytosis of apoptotic cells. Exp Cell Res 292(2):403–416

    Article  PubMed  CAS  Google Scholar 

  63. Tóth B, Garabuczi E, Sarang Z et al (2009) Transglutaminase 2 is needed for the formation of an efficient phagocyte portal in macrophages engulfing apoptotic cells. J Immunol 182(4):2084–2092

    Article  PubMed  Google Scholar 

  64. Nandrot EF, Anand M, Almeida D, Atabai K, Sheppard D, Finnemann SC (2007) Essential role for MFG-E8 as ligand for alphavbeta5 integrin in diurnal retinal phagocytosis. Proc Natl Acad Sci U S A 104(29):12005–12010

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  65. Théry C, Ostrowski M, Segura E (2009) Membrane vesicles as conveyors of immune responses. Nat Rev Immunol 9(8):581–593

    Article  PubMed  Google Scholar 

  66. Hartman ZC, Wei J, Glass OK et al (2011) Increasing vaccine potency through exosome antigen targeting. Vaccine 29(50):9361–9367

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  67. Morelli AE, Larregina AT, Shufesky WJ et al (2004) Endocytosis, intracellular sorting, and processing of exosomes by dendritic cells. Blood 104(10):3257–3266

    Article  PubMed  CAS  Google Scholar 

  68. Asano K, Miwa M, Miwa K et al (2004) Masking of phosphatidylserine inhibits apoptotic cell engulfment and induces autoantibody production in mice. J Exp Med 200(4):459–467

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  69. Miyanishi M, Segawa K, Nagata S (2012) Synergistic effect of Tim4 and MFG-E8 null mutations on the development of autoimmunity. Int Immunol 24(9):551–559

    Article  PubMed  CAS  Google Scholar 

  70. Chikazawa M, Otaki N, Shibata T, Yasueda T, Matsuda T, Uchida K (2013) An apoptosis-associated mammary protein deficiency leads to enhanced production of IgM antibodies against multiple damage-associated molecules. PLoS One 8(7):e68468

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  71. Peng Y, Elkon KB (2011) Autoimmunity in MFG-E8-deficient mice is associated with altered trafficking and enhanced cross-presentation of apoptotic cell antigens. J Clin Invest 121(6):2221–2241

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  72. Voll RE, Herrmann M, Roth EA, Stach C, Kalden JR, Girkontaite I (1997) Immunosuppressive effects of apoptotic cells. Nature 390(6658):350–351

    Article  PubMed  CAS  Google Scholar 

  73. Miksa M, Amin D, Wu R et al (2008) Maturation-induced down-regulation of MFG-E8 impairs apoptotic cell clearance and enhances endotoxin response. Int J Mol Med 22(6):743–748

    PubMed Central  PubMed  CAS  Google Scholar 

  74. Cui T, Miksa M, Wu R et al (2010) Milk fat globule epidermal growth factor 8 attenuates acute lung injury in mice after intestinal ischemia and reperfusion. Am J Respir Crit Care Med 181(3):238–246

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  75. Choi EY, Chavakis E, Czabanka MA et al (2008) Del-1, an endogenous leukocyte-endothelial adhesion inhibitor, limits inflammatory cell recruitment. Science 322(5904):1101–1104

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  76. Eskan MA, Jotwani R, Abe T et al (2012) The leukocyte integrin antagonist Del-1 inhibits IL-17-mediated inflammatory bone loss. Nat Immunol 13(5):465–473

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  77. Kanczkowski W, Chatzigeorgiou A, Grossklaus S, Sprott D, Bornstein SR, Chavakis T (2013) Role of the endothelial-derived endogenous anti-inflammatory factor Del-1 in inflammation-mediated adrenal gland dysfunction. Endocrinology 154(3):1181–1189

    Article  PubMed  CAS  Google Scholar 

  78. Aziz MM, Ishihara S, Mishima Y et al (2009) MFG-E8 attenuates intestinal inflammation in murine experimental colitis by modulating osteopontin-dependent alphavbeta3 integrin signaling. J Immunol 182(11):7222–7232

    Article  PubMed  CAS  Google Scholar 

  79. Jinushi M, Nakazaki Y, Dougan M, Carrasco DR, Mihm M, Dranoff G (2007) MFG-E8-mediated uptake of apoptotic cells by APCs links the pro- and antiinflammatory activities of GM-CSF. J Clin Invest 117(7):1902–1913

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  80. Kleinclauss F, Perruche S, Masson E et al (2006) Intravenous apoptotic spleen cell infusion induces a TGF-beta-dependent regulatory T-cell expansion. Cell Death Differ 13(1):41–52

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  81. Matsuda A, Jacob A, Wu R et al (2011) Milk fat globule-EGF factor VIII in sepsis and ischemia-reperfusion injury. Mol Med 17(1–2):126–133

    PubMed Central  PubMed  CAS  Google Scholar 

  82. Silvestre JS, Théry C, Hamard G et al (2005) Lactadherin promotes VEGF-dependent neovascularization. Nat Med 11(5):499–506

    Article  PubMed  CAS  Google Scholar 

  83. Motegi S, Leitner WW, Lu M et al (2011) Pericyte-derived MFG-E8 regulates pathologic angiogenesis. Arterioscler Thromb Vasc Biol 31(9):2024–2034

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  84. Motegi S, Garfield S, Feng X, Sárdy M, Udey MC (2011) Potentiation of platelet-derived growth factor receptor-β signaling mediated by integrin-associated MFG-E8. Arterioscler Thromb Vasc Biol 31(11):2653–2664

    Article  PubMed  CAS  Google Scholar 

  85. Oba J, Moroi Y, Nakahara T, Abe T, Hagihara A, Furue M (2011) Expression of milk fat globule epidermal growth factor-VIII may be an indicator of poor prognosis in malignant melanoma. Br J Dermatol 165(3):506–512

    Article  PubMed  CAS  Google Scholar 

  86. Sugano G, Bernard-Pierrot I, Laé M et al (2011) Milk fat globule–epidermal growth factor–factor VIII (MFGE8)/lactadherin promotes bladder tumor development. Oncogene 30(6):642–653

    Article  PubMed  CAS  Google Scholar 

  87. Neutzner M, Lopez T, Feng X, Bergmann-Leitner ES, Leitner WW, Udey MC (2007) MFG-E8/lactadherin promotes tumor growth in an angiogenesis-dependent transgenic mouse model of multistage carcinogenesis. Cancer Res 67(14):6777–6785

    Article  PubMed  CAS  Google Scholar 

  88. Jinushi M, Nakazaki Y, Carrasco DR et al (2008) Milk fat globule EGF-8 promotes melanoma progression through coordinated Akt and twist signaling in the tumor microenvironment. Cancer Res 68(21):8889–8898

    Article  PubMed  CAS  Google Scholar 

  89. Jinushi M, Chiba S, Yoshiyama H et al (2011) Tumor-associated macrophages regulate tumorigenicity and anticancer drug responses of cancer stem/initiating cells. Proc Natl Acad Sci U S A 108(30):12425–12430

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  90. Bu HF, Zuo XL, Wang X et al (2007) Milk fat globule-EGF factor 8/lactadherin plays a crucial role in maintenance and repair of murine intestinal epithelium. J Clin Invest 117(12):3673–3683

    PubMed Central  PubMed  CAS  Google Scholar 

  91. Ajakaiye MA, Jacob A, Wu R et al (2012) Recombinant human MFG-E8 attenuates intestinal injury and mortality in severe whole body irradiation in rats. PLoS One 7(10):e46540

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  92. Chogle A, Bu HF, Wang X, Brown JB, Chou PM, Tan XD (2011) Milk fat globule-EGF factor 8 is a critical protein for healing of dextran sodium sulfate-induced acute colitis in mice. Mol Med 17(5–6):502–507

    PubMed Central  PubMed  CAS  Google Scholar 

  93. Kusunoki R, Ishihara S, Aziz M, Oka A, Tada Y, Kinoshita Y (2012) Roles of milk fat globule-epidermal growth factor 8 in intestinal inflammation. Digestion 85(2):103–107

    Article  PubMed  CAS  Google Scholar 

  94. Raymond AS, Shur BD (2009) A novel role for SED1 (MFG-E8) in maintaining the integrity of the epididymal epithelium. J Cell Sci 122(Pt 6):849–858

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  95. Raymond AS, Elder B, Ensslin M, Shur BD (2010) Loss of SED1/MFG-E8 results in altered luminal physiology in the epididymis. Mol Reprod Dev 77(6):550–563

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  96. Park YS, Suzuki K, Taniguchi N, Gutteridge JM (1999) Glutathione peroxidase-like activity of caeruloplasmin as an important lung antioxidant. FEBS Lett 458(2):133–136

    Article  PubMed  CAS  Google Scholar 

  97. Nakamura M, Tomita A, Nakatani H, Matsuda T, Nadano D (2006) Antioxidant and antibacterial genes are upregulated in early involution of the mouse mammary gland: sharp increase of ceruloplasmin and lactoferrin in accumulating breast milk. DNA Cell Biol 25(9):491–500

    Article  PubMed  CAS  Google Scholar 

  98. Roth RB, Hevezi P, Lee J, Willhite D, Lechner SM, Foster AC, Zlotnik A (2006) Gene expression analyses reveal molecular relationships among 20 regions of the human CNS. Neurogenetics 7(2):67–80

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Tsukasa Matsuda PhD .

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Oshima, K., Yasueda, T., Nishio, S., Matsuda, T. (2014). MFG-E8: Origin, Structure, Expression, Functions and Regulation. In: Wang, P. (eds) MFG-E8 and Inflammation. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-8765-9_1

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