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CD36向肌动蛋白细胞骨架发出信号,并通过p130Cas复合物调节小胶质细胞迁移。

CD36 signals to the actin cytoskeleton and regulates microglial migration via a p130Cas complex.

作者信息

Stuart Lynda M, Bell Susan A, Stewart Cameron R, Silver Jessica M, Richard James, Goss Julie L, Tseng Anita A, Zhang Ailiang, Khoury Joseph B El, Moore Kathryn J

机构信息

Developmental Immunology/Department of Pediatrics, the Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114 and; University of Edinburgh Centre for Inflammation Research, Edinburgh EH16 4TJ, United Kingdom.

Lipid Metabolism Unit, and Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114 and.

出版信息

J Biol Chem. 2007 Sep 14;282(37):27392-27401. doi: 10.1074/jbc.M702887200. Epub 2007 Jul 9.

Abstract

The pattern recognition receptor CD36 initiates a signaling cascade that promotes microglial activation and recruitment to beta-amyloid deposits in the brain. In the present study we identify the focal adhesion-associated proteins p130Cas, Pyk2, and paxillin as novel members of the tyrosine kinase signaling pathway downstream of CD36 and show that assembly of this complex is essential for microglial migration. In primary microglia and macrophages exposed to beta-amyloid, the scaffolding protein p130Cas is rapidly tyrosine-phosphorylated and co-localizes with CD36 to membrane ruffles contemporaneous with F-actin polymerization. These beta-amyloid-stimulated events are not detected in CD36 null cells and are dependent on CD36 activation of Src family tyrosine kinases. Fyn, a Src kinase known to interact with CD36, co-precipitates with p130Cas and is an essential upstream intermediate in the signaling pathways leading to phosphorylation of the p130Cas substrate domain. Furthermore, the p130Cas-interacting kinase Pyk2 and the cytoskeletal adapter protein paxillin also demonstrate CD36-dependent phosphorylation, identifying these focal adhesion molecules as additional members of this beta-amyloid signaling cascade. Disruption of this p130Cas complex by small interfering RNA silencing inhibits p44/42 mitogen-activated protein kinase phosphorylation and microglial migration, illustrating the importance of this pathway in microglial activation and recruitment. Together, these data are the first to identify the signaling cascade that directly links CD36 to the actin cytoskeleton and, thus, implicates it in diverse processes such as cellular migration, adhesion, and phagocytosis.

摘要

模式识别受体CD36启动一个信号级联反应,促进小胶质细胞的激活并募集至大脑中的β-淀粉样蛋白沉积物。在本研究中,我们确定粘着斑相关蛋白p130Cas、Pyk2和桩蛋白是CD36下游酪氨酸激酶信号通路的新成员,并表明该复合物的组装对于小胶质细胞迁移至关重要。在暴露于β-淀粉样蛋白的原代小胶质细胞和巨噬细胞中,支架蛋白p130Cas迅速发生酪氨酸磷酸化,并与CD36共定位于膜皱襞,同时伴有F-肌动蛋白聚合。这些β-淀粉样蛋白刺激的事件在CD36基因敲除细胞中未检测到,并且依赖于Src家族酪氨酸激酶的CD36激活。Fyn是一种已知与CD36相互作用的Src激酶,与p130Cas共沉淀,并且是导致p130Cas底物结构域磷酸化的信号通路中必不可少的上游中间体。此外,与p130Cas相互作用的激酶Pyk2和细胞骨架衔接蛋白桩蛋白也表现出CD36依赖性磷酸化,确定这些粘着斑分子是该β-淀粉样蛋白信号级联反应的其他成员。通过小干扰RNA沉默破坏该p130Cas复合物可抑制p44/42丝裂原活化蛋白激酶磷酸化和小胶质细胞迁移,说明了该通路在小胶质细胞激活和募集中的重要性。总之,这些数据首次确定了直接将CD36与肌动蛋白细胞骨架联系起来的信号级联反应,因此,表明其参与细胞迁移、粘附和吞噬等多种过程。

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