The opsonin MFG-E8 is a ligand for the αvβ5 integrin and triggers DOCK180-dependent Rac1 activation for the phagocytosis of apoptotic cells
The opsonin MFG-E8 is a ligand for the αvβ5 integrin and triggers DOCK180-dependent Rac1 activation for the phagocytosis of apoptotic cells
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DOI：
10.1016/j.yexcr.2003.09.011
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发表时间：
2004-01-15
影响因子：
3.7
通讯作者：
Birge, RB
中科院分区：
文献类型：
--
作者：
Akakura, S;Sukhwinder, SA;Birge, RB
凋亡细胞的调理作用促进吞噬细胞的识别，以快速清除潜在的炎性细胞物质。分泌的糖蛋白乳脂肪球因子-E8（MFG-E8）是该桥接分子家族的成员，并且被认为结合垂死细胞上的磷脂酰丝氨酸（PS），将其连接至吞噬细胞上的整联蛋白受体。在这里，我们报告的功能信号模块的表征涉及MFG-E8，α v β 5整合素，和DOCK 180的Rac 1的激活。我们发现，MFG-E8和DOCK 180都表达在吞噬能力的初级未成熟树突状细胞（DC）和DC 2.4细胞，并在DC成熟后被有效下调，这与它们在吞噬和抗原捕获中的作用一致。MFG-E8与α v β 5整联蛋白的共表达增强了整联蛋白介导的Rac 1活化，这通过MFG-E8中RGD基序的诱变而被废除。此外，反义DOCK 180的表达消除了MFG-E8-alphavbeta 5介导的Rac激活，并损害了凋亡细胞的吞噬作用。这些数据证明了凋亡细胞的调理素、α v β 5整联蛋白和Crk-DOCK 180-Rac 1通路之间的生物化学联系，并且重要的是，表明MFG-E8和DOCK 180根据吞噬细胞的功能状态表达。(C)2003年爱思唯尔公司All rights reserved.
Opsonization of apoptotic cells facilitates recognition by phagocytes for the rapid clearance of potentially inflammatory cellular material. The secreted glycoprotein Milk Fat Globule Factor-E8 (MFG-E8) is a member of this family of bridging molecules and is believed to bind phosphatidylserine (PS) on the dying cell, linking it to integrin receptors on the phagocyte. Here we report the characterization of a functional signaling module involving MFG-E8, alphavbeta5 integrin, and DOCK180 for the activation of Rac1. We show that MFG-E8 and DOCK180 are both expressed in phagocytic-competent primary immature dendritic cells (DCs) and DC2.4 cells, and are potently down-regulated upon DC maturation, consistent with their role in phagocytosis and antigen capture. Coexpression of MFG-E8 with alphavbeta5 integrin potentiated integrin-mediated Rac1 activation, which was abrogated by mutagenesis in the RGD motif in MFG-E8. Moreover, expression of antisense DOCK 180 abrogated MFG-E8-alphavbeta5-mediated Rac activation and impaired the phagocytosis of apoptotic cells. These data demonstrate a biochemical link between an opsonin of apoptotic cells, the alphavbeta5 integrin, and the Crk-DOCK180-Rac1 pathway, and importantly, show that MFG-E8 and DOCK180 are expressed according to the functional status of the phagocyte. (C) 2003 Elsevier Inc. All rights reserved.