Review: milk fat globule-EGF factor 8 expression, function and plausible signal transduction in resolving inflammation

Aziz, Monowar; Jacob, Asha; Matsuda, Akihisa; Wang, Haichao

doi:10.1007/s10495-011-0630-0

Cited by 139 publications

(175 citation statements)

References 56 publications

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“…The reason why D89E, but not ANX V, can efficiently block PtdSer-dependent viral entry is still not clear. Since the ligands of MFG-E8 and TIM receptors are well studied and the common ligand of TIM receptors and MFG-E8 is only PtdSer (54,82,83), it is unlikely that D89E conceals an unidentified molecule(s) that also plays a role in virus binding via MFG-E8 and TIM-1 and -4. One possible explanation is that D89E can completely conceal exposed PtdSer on the viral envelope, while ANX V cannot due to its different access to PtdSer upon binding.…”

Section: Discussionmentioning

confidence: 99%

Role of Phosphatidylserine Receptors in Enveloped Virus Infection

Morizono

Chen

2014

J Virol

154

178

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We recently demonstrated that a soluble protein, Gas6, can facilitate viral entry by bridging viral envelope phosphatidylserine to Axl, a receptor tyrosine kinase expressed on target cells. The interaction between phosphatidylserine, Gas6, and Axl was originally shown to be a molecular mechanism through which phagocytes recognize phosphatidylserine exposed on dead cells. Since our initial report, several groups have confirmed that Axl/Gas6, as well as other phosphatidylserine receptors, facilitate entry of dengue, West Nile, and Ebola viruses. Virus binding by viral envelope phosphatidylserine is now a viral entry mechanism generalized to many families of viruses. In addition to Axl/Gas6, various molecules are known to recognize phosphatidylserine; however, the effects of these molecules on virus binding and entry have not been comprehensively evaluated and compared. In this study, we examined most of the known human phosphatidylserine-recognizing molecules, including MFG-E8, TIM-1, -3, and -4, CD300a, BAI1, and stabilin-1 and -2, for their abilities to facilitate virus binding and infection. Using pseudotyped lentiviral vectors, we found that a soluble phosphatidylserine-binding protein, MFG-E8, enhances transduction. Cell surface receptors TIM-1 and -4 also enhance virus binding/transduction. The extent of enhancement by these molecules varies, depending on the type of pseudotyping envelope proteins. Mutated MFG-E8, which binds viral envelope phosphatidylserine without bridging virus to cells, but, surprisingly, not annexin V, which has been used to block phagocytosis of dead cells by concealing phosphatidylserine, efficiently blocks these phosphatidylserine-dependent viral entry mechanisms. These results provide insight into understanding the role of viral envelope phosphatidylserine in viral infection. IMPORTANCEEnvelope phosphatidylserine has previously been shown to be important for replication of various envelope viruses, but details of this mechanism(s) were unclear. We were the first to report that a bifunctional serum protein, Gas6, bridges envelope phosphatidylserine to a cell surface receptor, Axl. Recent studies demonstrated that many envelope viruses, including vaccinia, dengue, West Nile, and Ebola viruses, utilize Axl/Gas6 to facilitate their entry, suggesting that the phosphatidylserine-mediated viral entry mechanism can be shared by various enveloped viruses. In addition to Axl/Gas6, various molecules are known to recognize phosphatidylserine; however, the effects of these molecules on virus binding and entry have not been comprehensively evaluated and compared. In this study, we examined most human phosphatidylserine-recognizing molecules for their abilities to facilitate viral infection. The results provide insights into the role(s) of envelope phosphatidylserine in viral infection, which can be applicable to the development of novel antiviral reagents that block phosphatidylserine-mediated viral entry.

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Section: Discussionmentioning

confidence: 99%

Role of Phosphatidylserine Receptors in Enveloped Virus Infection

Morizono

Chen

2014

J Virol

154

178

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“…Tumor-derived MFG-E8 -Although MFG-E8 is expressed in many tissues and cells, its expression in prostate cancer cell lines has remained unknown (31). To determine whether MFG-E8 is expressed in prostate cancer cells, protein was collected and analyzed from RAW 264.7 macrophages and three different prostate cancer cell lines: a prostate cancer murine-derived cell line, RM-1, and two bone metastatic human-derived cell lines, PC-3 and C42B (Fig.…”

Section: Mfg-e8 Expression In Macrophages Andmentioning

confidence: 99%

Polarization of Prostate Cancer-associated Macrophages Is Induced by Milk Fat Globule-EGF Factor 8 (MFG-E8)-mediated Efferocytosis

Soki

Koh

Jones

et al. 2014

Journal of Biological Chemistry

151

160

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Background:The growing body of data on tumor-associated macrophages largely neglects phagocytosis of apoptotic cells. Results: MFG-E8, induced during efferocytosis, contributes to macrophage polarization with STAT3/SOCS3 pathway involvement. Conclusion: Efferocytosis induces macrophage polarization into tumor-associated macrophages mediated by MFG-E8. Significance: A novel tumor-promoting mechanism for macrophage polarization through efferocytosis and MFG-E8 and its corresponding signaling pathway were identified.

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“…One explanation for this observation is that post-lactational efferocytosis promotes breast tumor malignancy through production of wound healing cytokines, which are known to drive breast cancer growth and invasion. In support of this idea, MFG-E8 [203] and its receptor v 3/5, as well as Gas6 and its ligand MerTK [116,204] are frequently overexpressed in breast cancers. One recent study demonstrated that the protumorigenic cytokine IL-6 induces expression of MerTK, enhancing the ability of macrophages to engulf apoptotic cells and increasing production of wound healing cytokines such as IL-4 and IL-10 [205].…”

Section: Physiological and Pathological Consequences Of Efferocytosismentioning

confidence: 84%