Lactadherin binds selectively to membranes containing phosphatidyl-l-serine and increased curvature

Shi, Jialan; Heegaard, Christian W.; Rasmussen, Jan T.; Gilbert, Gary E.

doi:10.1016/j.bbamem.2004.09.006

Cited by 184 publications

(183 citation statements)

References 45 publications

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“…MFGE8/lactadherin binds to phosphatidylserine at the surface of membrane vesicles (Oshima et al, 2002;Veron et al, 2005) and apoptotic cells (Hanayama et al, 2002) through its FactorVIII-like domain (Shi et al, 2004), and exposes its EGF-like domain for recognition by avb3/b5 integrins (Andersen et al, 2000). MFGE8 displays three types of functions.…”

Section: Introductionmentioning

confidence: 99%

Milk fat globule—epidermal growth factor—factor VIII (MFGE8)/lactadherin promotes bladder tumor development

Sugano

Bernard‐Pierrot

et al. 2010

Oncogene

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Milk fat globule-epidermal growth factor-factor VIII (MFGE8), also called lactadherin or SED1, is a secreted integrin-binding protein that promotes elimination of apoptotic cells by phagocytes leading to tolerogenic immune responses, and vascular endothelial growth factor (VEGF)-induced angiogenesis: two important processes for cancer development. Here, by transcriptomic analysis of 228 biopsies of bladder carcinomas, we observed overexpression of MFGE8 during tumor development, correlated with expression of genes involved in cell adhesion or migration and in immune responses, but not in VEGF-mediated angiogenesis. To test whether MFGE8 expression was instrumental in bladder tumor development, or a simple consequence of this development, we used genetic ablation in a mouse model of carcinogen-induced bladder carcinoma. We showed that Mfge8 was also upregulated in mouse carcinoma, and that in its absence, Mfge8-deficient animals developed less advanced tumors. Angiogenesis was similar in carcinogen-treated Mfge8-expressing or -deficient bladders, thus ruling out a major role of the proangiogenic function of Mfge8 for its protumoral role. By contrast, the tumorpromoting role of Mfge8 was not observed anymore in mice devoid of adaptive immune system, and human tumors overexpressing MFGE8 where invaded with macrophages and regulatory T cells, thus suggesting that MFGE8/ lactadherin favors development of bladder tumors at least partly by an immune system-dependent mechanism. Our observations suggest future use of MFGE8-inhibiting molecules as therapies of bladder carcinomas, and of a limited number of other human cancers, in which our analysis of public databases also revealed overexpression of MFGE8.

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Section: Introductionmentioning

confidence: 99%

Milk fat globule—epidermal growth factor—factor VIII (MFGE8)/lactadherin promotes bladder tumor development

Sugano

Bernard‐Pierrot

et al. 2010

Oncogene

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“…7e11 The C-terminal domains of MFG-E8 can bind to negatively charged and oxidized phospholipids, 12,13 facilitating opsonization of apoptotic cells for uptake by phagocytes. 10,14 This process has been reported to contribute to autoimmunity, mastitis, sepsis, atherosclerosis, and Alzheimer disease.…”

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confidence: 99%

MFG-E8 Regulates Angiogenesis in Cutaneous Wound Healing

Uchiyama¹

2015

kmj

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Our research group recently demonstrated that pericytes are major sources of the secreted glycoprotein and integrin ligand lactadherin (MFG-E8) in B16 melanoma tumors, and that MFG-E8 promotes angiogenesis via enhanced PDGFePDGFRb signaling mediated by integrinegrowth factor receptor crosstalk. However, sources of MFG-E8 and its possible roles in skin physiology are not well characterized. The objective of this study was to characterize the involvement of MFG-E8 in skin wound healing. In the dermis of normal murine and human skin, accumulations of MFG-E8 were found around CD31 þ blood vessels, and MFG-E8 colocalized with PDGFRb þ , aSMA þ , and NG2 þ pericytes. MFG-E8 protein and mRNA levels were elevated in the dermis during full-thickness wound healing in mice. MFG-E8 was diffusely present in granulation tissue and was localized around blood vessels. Wound healing was delayed in MFG-E8 knockout mice, compared with the wild type, and myofibroblast and vessel numbers in wound areas were significantly reduced in knockout mice. Inhibition of MFG-E8 production with siRNA attenuated the formation of capillary-like structures in vitro. Expression of MFG-E8 in fibrous human granulation tissue with scant blood vessels was less than that in granulation tissue with many blood vessels. These findings suggest that MFG-E8 promotes cutaneous wound healing by enhancing angiogenesis. (Am J Pathol 2014 http://dx

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“…At this moment, there is no direct evidence indicating that MFG-E8 binds to Ptd-Ser exposed on the MFG surface. However, MFG-E8 binding through Ptd-Ser is most likely, because MFGs in L10 milk-stained positive for annexin V, which binds to Ptd-Ser by competing for MFG-E8, and the number of MFG-E8 binding sites on Ptd-Sercontaining membranes was reported to depend on Ptd-Ser content of each target membrane (29). Furthermore, it seems reasonable for the long form of MFG-E8 to become dominant after weaning ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Post-weaning increases in the milk-fat globule EGF-factor VIII on fat globules in mouse milk and in the uptake of the fat globules by HC11 mammary epithelial cells

Nakatani

Yasueda

Oshima

et al. 2012

Journal of Biochemistry

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Milk fat globules (MFGs) secreted by lactating mammary gland are unique lipid surrounded by a phospholipid bi-layer. We report here post-weaning changes in MFG EGF factor VIII (MFG-E8) and annexin V-accessible phosphatidyl-L-serine on the surface of MFGs. The MFG content in milk markedly decreased to about one-half within 2 days after forced weaning, despite a slight increase in milk protein content. Immunofluorescence-staining of MFGs using anti-MFG-E8 and annexin V indicated that MFG-E8 was present on some, but not all, MFGs before weaning, whereas most of MFGs were MFG-E8-positive and annexin V-negative after weaning. Free MFG-E8 with binding activity to phosphatidyl-L-serine was present abundantly in the post-weaning milk, and indeed exhibited binding to MFGs in pre-weaning milk. MFGs were taken up by HC11 mouse mammary epithelial cells in vitro, and those from post-weaning milk were remarkable for such cellular uptake. Moreover, the uptake of MFGs by the cells was inhibited by an anti-MFG-E8 antibody. Taken together, these findings suggest that MFG-E8 plays a critical role in regulation of MFG dynamics after weaning or during the suckling interval through the control of MFG-epithelial cell interaction in lactating mammary glands.Keywords: fat metabolism/involution/lactation/mammary gland/milk fat globule membrane.

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Lactadherin binds selectively to membranes containing phosphatidyl-l-serine and increased curvature

Cited by 184 publications

References 45 publications

Milk fat globule—epidermal growth factor—factor VIII (MFGE8)/lactadherin promotes bladder tumor development

Milk fat globule—epidermal growth factor—factor VIII (MFGE8)/lactadherin promotes bladder tumor development

MFG-E8 Regulates Angiogenesis in Cutaneous Wound Healing

Post-weaning increases in the milk-fat globule EGF-factor VIII on fat globules in mouse milk and in the uptake of the fat globules by HC11 mammary epithelial cells

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