Integrin α9β1 mediates enhanced cell migration through nitric oxide synthase activity regulated by Src tyrosine kinase
Integrin α9β1 mediates enhanced cell migration through nitric oxide synthase activity regulated by Src tyrosine kinase
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DOI：
10.1242/jcs.041632
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发表时间：
2009-06-15
影响因子：
4
通讯作者：
Vlahakis, Nicholas E.
中科院分区：
文献类型：
--
作者：
Gupta, Shiv K.;Vlahakis, Nicholas E.
整合素是细胞粘附和迁移的重要介质，而细胞粘附和迁移又是多种生物学功能所必需的，包括伤口愈合和癌症转移。整合素α 9 β 1在许多哺乳动物组织上表达，并可介导加速的细胞迁移。由于解释这种效应的分子信号机制定义不清，我们研究了活化的整合素α 9 β 1信号迁移的途径。我们首次发现，整合素α 9 β 1的特异性连接可快速激活Src酪氨酸激酶，伴随着p130 Cas的酪氨酸磷酸化和Rac-1的激活。此外，整合素α 9 β 1的活化也通过诱导型一氧化氮合酶（iNOS）的活化增强NO的产生。Src酪氨酸激酶或NOS的抑制降低了整合素α 9 β 1依赖性细胞迁移。Src似乎在信号级联中起最近端的作用，以不依赖于FAK的方式促进iNOS活化和NO依赖性细胞迁移。整合素α 9的胞质结构域对于整合素α 9 β 1诱导的Src活化、随后的信号传导事件和细胞迁移至关重要。当结合在一起，我们的研究结果描述了一个新的和独特的机制，协调的相互作用的整合素α 9胞质结构域，Src酪氨酸激酶和诱导型一氧化氮合酶抑制剂整合素α 9 β 1介导的细胞迁移。
Integrins are important mediators of cell adhesion and migration, which in turn are essential for diverse biological functions, including wound healing and cancer metastasis. The integrin alpha 9 beta 1 is expressed on numerous mammalian tissues and can mediate accelerated cell migration. As the molecular signaling mechanisms that transduce this effect are poorly defined, we investigated the pathways by which activated integrin alpha 9 beta 1 signals migration. We found for the first time that specific ligation of integrin alpha 9 beta 1 rapidly activates Src tyrosine kinase, with concomitant tyrosine phosphorylation of p130Cas and activation of Rac-1. Furthermore, activation of integrin alpha 9 beta 1 also enhanced NO production through activation of inducible nitric oxide synthase (iNOS). Inhibition of Src tyrosine kinase or NOS decreased integrin-alpha 9 beta 1-dependent cell migration. Src appeared to function most proximal in the signaling cascade, in a FAK-independent manner to facilitate iNOS activation and NO-dependent cell migration. The cytoplasmic domain of integrin alpha 9 was crucial for integrin-alpha 9 beta 1-induced Src activation, subsequent signaling events and cell migration. When taken together, our results describe a novel and unique mechanism of coordinated interactions of the integrin alpha 9 cytoplasmic domain, Src tyrosine kinase and iNOS to transduce integrin-alpha 9 beta 1-mediated cell migration.