Ack1 mediates Cdc42-dependent cell migration and signaling to p130Cas
Ack1 mediates Cdc42-dependent cell migration and signaling to p130Cas
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DOI：
10.1074/jbc.m604342200
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发表时间：
2006-12-08
影响因子：
4.8
通讯作者：
Keely, Patricia J.
中科院分区：
文献类型：
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作者：
Modzelewska, Katarzyna;Newman, Laura P.;Keely, Patricia J.
我们之前的研究表明，小GTP酶CDC42的激活促进了乳腺细胞在胶原基质上的迁移。在这里，我们进一步定义了驱动这一反应的信号通路，并表明Cdc42介导的迁移依赖于适配器分子p130(Cas)。活化的Cdc42增强p130(CaS)的磷酸化及其与Crk的结合。CDC42诱导的迁移和p130(Cas)的磷酸化依赖于CDC42效应蛋白AcK1(激活的CDC42相关激酶)。AcK1形成一个信号复合体，该复合体还包括CDC42、p130(Cas)和Crk，其形成受胶原刺激的调节。AcK1和p130(Cas)之间的相互作用通过各自的SH3结构域进行，而p130(Cas)的底物结构域是AcK1依赖的磷酸化的主要部位。通过这个复合体的信号传递在功能上是相关的，因为用p130(Cas)或AcK1 siRNA处理可以阻断Cdc42诱导的迁移。这些结果表明，CDC42对细胞迁移的影响部分是通过其调控p130(Cas)信号的效应元件AcK1来实现的。
We previously showed that activation of the small GTPase Cdc42 promotes breast cell migration on a collagen matrix. Here we further define the signaling pathways that drive this response and show that Cdc42-mediated migration relies on the adaptor molecule p130(Cas). Activated Cdc42 enhanced p130(Cas) phosphorylation and its binding to Crk. Cdc42-driven migration and p130(Cas) phosphorylation were dependent on the Cdc42 effector Ack1(activated Cdc42-associated kinase). Ack1 formed a signaling complex that also included Cdc42, p130(Cas), and Crk, formation of which was regulated by collagen stimulation. The interaction between Ack1 and p130(Cas) occurred through their respective SH3 domains, while the substrate domain of p130(Cas) was the major site of Ack1-dependent phosphorylation. Signaling through this complex is functionally relevant, because treatment with either p130(Cas) or Ack1 siRNA blocked Cdc42-induced migration. These results suggest that Cdc42 exerts its effects on cell migration in part through its effector Ack1, which regulates p130(Cas) signaling.