A NPxY-independent β5 integrin activation signal regulates phagocytosis of apoptotic cells
A NPxY-independent β5 integrin activation signal regulates phagocytosis of apoptotic cells
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DOI：
10.1016/j.bbrc.2007.10.049
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发表时间：
2007-12-21
影响因子：
3.1
通讯作者：
Birge, Raymond B.
中科院分区：
文献类型：
--
作者：
Singh, Sukhwinder;D'mello, Veera;Birge, Raymond B.
整合素受体是异二聚体跨膜受体，在细胞粘附和迁移、细胞周期进展、分化、凋亡和凋亡细胞的吞噬中具有关键功能。整合素通过细胞内信号传导激活，细胞内信号传导改变细胞外配体的结合亲和力，所谓的从内到外信号传导。整合素活化的一个共同要素涉及细胞骨架蛋白talin通过其FERM结构域与P链胞质尾中高度保守的NPxY基序结合，该基序参与影响配体亲和力的胞外结构域的长程构象变化。当人β-5（β 5）整联蛋白cDNA在α v阳性、β 5和β 3阴性仓鼠CS-1细胞中表达时，其促进NPxY依赖性粘附于VN包被的表面、FAK的磷酸化，并且伴随地，β 5整联蛋白-EGFP蛋白被募集到含有talin和paxillin的粘着斑中。NPxY去稳定化β 5突变体（Y 750 A）的表达消除了粘附，并且β 5-Y 750 A-EGFP被排除在应力纤维尖端的粘着斑之外。令人惊讶的是，β 5 Y 750 A整联蛋白的表达对凋亡细胞吞噬作用具有有效的功能获得效应，而且，β 5-Y 750 A-EGFP融合整联蛋白容易结合MFG-E8包被的10 μ m直径微球，该微球被开发为凋亡细胞模拟物。将β 5整联蛋白中的关键序列定位到紧邻NPxY基序的YEMAS基序。我们的研究表明，β 5整合素的吞噬功能是由一个非常规的NPxY-塔林非依赖性激活信号调节，并认为在β 5细胞质尾部的粘附和吞噬作用的分子开关的存在。(C)2007年爱思唯尔公司All rights reserved.
Integrin receptors are heterodimeric transmembrane receptors with critical functions in cell adhesion and migration, cell cycle progression, differentiation, apoptosis, and phagocytosis of apoptotic cells. Integrins are activated by intracellular signaling that alter the binding affinity for extracellular ligands, so-called inside to outside signaling. A common element for integrin activation involves binding of the cytoskeletal protein talin, via its FERM domain, to a highly conserved NPxY motif in the P chain cytoplasmic tails, which is involved in long-range conformation changes to the extracellular domain that impinges on ligand affinity. When the human beta-5 (beta 5) integrin cDNA was expressed in alpha v positive, beta 5 and beta 3 negative hamster CS-1 cells, it promoted NPxY-dependent adhesion to VTN-coated surfaces, phosphorylation of FAK, and concomitantly, beta 5 integrin-EGFP protein was recruited into talin and paxillin-containing focal adhesions. Expression of a NPxY destabilizing beta 5 mutant (Y750A) abrogated adhesion and beta 5-Y750A-EGFP was excluded from focal adhesions at the tips of stress fibers. Surprisingly, expression of beta 5 Y750A integrin had a potent gain-of-function effect on apoptotic cell phagocytosis, and further, a beta 5-Y750A-EGFP fusion integrin readily bound MFG-E8-coated 10 mu m diameter microspheres developed as apoptotic cell mimetics. The critical sequences in beta 5 integrin were mapped to a YEMAS motif just proximal to the NPxY motif. Our studies suggest that the phagocytic function of beta 5 integrin is regulated by an unconventional NPxY-talin-independent activation signal and argue for the existence of molecular switches in the beta 5 cytoplasmic tail for adhesion and phagocytosis. (C) 2007 Elsevier Inc. All rights reserved.