Raymond A, Ensslin MA, Shur BD.. SED1/MFG-E8: a bi-motif protein that orchestrates diverse cellular interactions. J Cell Biochem 106: 957-966

Department of Cell Biology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Journal of Cellular Biochemistry (Impact Factor: 3.26). 04/2009; 106(6):957-66. DOI: 10.1002/jcb.22076
Source: PubMed


MFG-E8 was initially identified as a principle component of the Milk Fat Globule, a membrane-encased collection of proteins and triglycerides that bud from the apical surface of mammary epithelia during lactation. It has since been independently identified in many species and by many investigators and given a variety of names, including p47, lactadherin, rAGS, PAS6/7, and BA-46. The acronym SED1 was proposed to bring cohesion to this nomenclature based upon it being a Secreted protein that contains two distinct functional domains: an N-terminal domain with two EGF-repeats, the second of which has an integrin-binding RGD motif, and a C-terminal domain with two Discoidin/F5/8C domains that bind to anionic phospholipids and/or extracellular matrices. SED1/MFG-E8 is now known to participate in a wide variety of cellular interactions, including phagocytosis of apoptotic lymphocytes and other apoptotic cells, adhesion between sperm and the egg coat, repair of intestinal mucosa, mammary gland branching morphogenesis, angiogenesis, among others. This article will explore the various roles proposed for SED1/MFG-E8, as well as its provocative therapeutic potential.

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    • "The recognition of apoptotic cells is mediated by some specific receptors, such as the PS receptor [39] and αvβ3[15]. The soluble PS-binding protein MFG-E8 is required for the recognition and phagocytosis of PS-exposing cells [14,15,40]. MFG-E8 deficiency is accompanied by the induction of pro-inflammatory cytokines and the impaired uptake of apoptotic cells in several inflammatory diseases, including systemic lupus erythematosus [16], sepsis [41] and atherosclerosis [42]. "
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    ABSTRACT: Insufficient clearance by microglial cells, prevalent in several neurological conditions and diseases, is intricately intertwined with MFG-E8 expression and inflammatory responses. Electromagnetic field (EMF) exposure can elicit the pro-inflammatory activation and may also trigger an alteration of the clearance function in microglial cells. Curcumin has important roles in the anti-inflammatory and phagocytic process. Here, we evaluated the ability of curcumin to ameliorate the phagocytic ability of EMF-exposed microglial cells (N9 cells) and documented relative pathways. N9 cells were pretreated with or without recombinant murine MFG-E8 (rmMFG-E8), curcumin and an antibody of toll-like receptor 4 (anti-TLR4), and subsequently treated with EMF or a sham exposure. Their phagocytic ability was evaluated using phosphatidylserine-containing fluorescent bioparticles. The pro-inflammatory activation of microglia was assessed via CD11b immunoreactivity and the production of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), interleukin-1beta (IL-1beta) and nitric oxide (NO) via the enzyme-linked immunosorbent assay or the Griess test. We evaluated the ability of curcumin to ameliorate the phagocytic ability of EMF-exposed N9 cells, including checking the expression of MFG-E8, alphavbeta3 integrin, TLR4, nuclear factor-kappaB (NF-kappaB) and signal transducer and activator of transcription 3 (STAT3) using Western blotting. EMF exposure dramatically enhanced the expression of CD11b and depressed the phagocytic ability of N9 cells. rmMFG-E8 could clearly ameliorate the phagocytic ability of N9 cells after EMF exposure. We also found that EMF exposure significantly increased the secretion of pro-inflammatory cytokines (TNF-alpha, IL-6 and IL-1beta) and the production of NO; however, these increases were efficiently chilled by the addition of curcumin to the culture medium. This reduction led to the amelioration of the phagocytic ability of EMF-exposed N9 cells. Western blot analysis revealed that curcumin and naloxone restored the expression of MFG-E8 but had no effect on TLR4 and cytosolic STAT3. Moreover, curcumin significantly reduced the expression of NF-kappaB p65 in nuclei and phospho-STAT3 (p-STAT3) in cytosols and nuclei. This study indicates that curcumin ameliorates the depressed MFG-E8 expression and the attenuated phagocytic ability of EMF-exposed N9 cells, which is attributable to the inhibition of the pro-inflammatory response through the NF-kappaB and STAT3 pathways.
    Journal of Neuroinflammation 03/2014; 11(1):49. DOI:10.1186/1742-2094-11-49 · 5.41 Impact Factor
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    • "Yet recently, various receptors have been identified that can mediate binding and phagocytosis of apoptotic cells by the recognition of PS on these cells such as Tim1, Tim4 and Stabilin-2 (Kobayashi et al., 2007; Park et al., 2008). In addition, there are several bridging molecules such as the plasma proteins: lactadherin, Gas-6 and protein S, that have been described to bind to PS and direct PS to receptors on phagocytes, α v β 3/5 integrins and receptors of the TAM receptor family and mediate clearance of PS-positive cells (Raymond et al., 2009). Of these receptors, at least Axl, Tim4 and Stabilin-2 are expressed in red pulp macrophages (Burger and van Bruggen, unpublished) (Figure 4). "
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    ABSTRACT: Macrophages tightly control the production and clearance of red blood cells (RBC). During steady state hematopoiesis, approximately 10(10) RBC are produced per hour within erythroblastic islands in humans. In these erythroblastic islands, resident bone marrow macrophages provide erythroblasts with interactions that are essential for erythroid development. New evidence suggests that not only under homeostasis but also under stress conditions, macrophages play an important role in promoting erythropoiesis. Once RBC have matured, these cells remain in circulation for about 120 days. At the end of their life span, RBC are cleared by macrophages residing in the spleen and the liver. Current theories about the removal of senescent RBC and the essential role of macrophages will be discussed as well as the role of macrophages in facilitating the removal of damaged cellular content from the RBC. In this review we will provide an overview on the role of macrophages in the regulation of RBC production, maintenance and clearance. In addition, we will discuss the interactions between these two cell types during transfer of immune complexes and pathogens from RBC to macrophages.
    Frontiers in Physiology 01/2014; 5:9. DOI:10.3389/fphys.2014.00009 · 3.53 Impact Factor
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    • "The present invention relates to TAA peptides derived from a protein selected from the group consisting of uroplakin (UP) [113], PSA, prostate specific membrane antigen (PSMA), prostate acid phosphatase (PAP) (reviewed in [100]), lactadherin (BA-46) [114], mucin (MUCl) [115] and teratocarcinoma-derived growth factor (CRIPTO-l) [116]. More particularly, screening of protein sequences for HLA-A2.1 binders by HLA Peptide Binding Predictions software approachable through a worldwide web interface at BioInformatics and Molecular Analysis Section of NIH (BIMAS, "
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    ABSTRACT: A variety of clinical trials for vaccines against cancer have provided evidence that DNA vaccines are well tolerated and have an excellent safety profile. DNA vaccines require much improvement to make them sufficiently effective against cancer in the clinic. Nowadays, it is clear that an increased antigen expression correlates with improved immunogenicity and it is critical to vaccine performance in large animals and humans. Similarly, additional strategies are required to activate effective immunity against poorly immunogenic tumour antigens. This review discusses very recent scientific references focused on the development of sophisticated DNA vaccines against cancer. We report a selection of novel and relevant patents employed to improve their immunogenicity through several strategies such as the use of tissue-specific transcriptional elements, nuclear localisation signalling, codon-optimisation and by targeting antigenic proteins to secretory pathway. Recent patents validating portions or splice variants of tumour antigens as candidates for cancer DNA vaccines with improved specificity, such as mesothelin and hTERT, are also discussed. astly, we review novel patents on the use of genetic immunomodulators, such as “universal” T helper epitopes derived from tetanus toxin, E. coli heat labile enterotoxin and vegetable proteins, as well as cytokines, chemokines or costimulatory molecules such as IL-6, IL-15, IL-21 to amplify immunity against cancer
    Recent Patents on Anti-Cancer Drug Discovery 01/2014; 9(1):66-82. · 4.30 Impact Factor
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