GIT2 represses Crk- and Rac1-regulated cell spreading and Cdc42-mediated focal adhesion turnover
GIT2 represses Crk- and Rac1-regulated cell spreading and Cdc42-mediated focal adhesion turnover
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DOI：
10.1038/sj.emboj.7601092
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发表时间：
2006-05-03
期刊：
影响因子：
11.4
通讯作者：
Hansen, Steen H.
中科院分区：
文献类型：
--
作者：
Frank, Scott R.;Adelstein, Molly R.;Hansen, Steen H.
G蛋白偶联受体激酶相互作用物（GIT）通过与桩蛋白和Rac交换因子Pak相互作用交换因子β（β PIX）直接相互作用，调节粘着斑（FA）周转、细胞铺展和运动性。然而，目前尚不清楚GIT是否具有激活或抑制运动的功能，或者主要的GIT形式GIT 1和GIT 2是否具有不同或冗余的作用。在这里，我们证明了一个强制性的作用，内源性GIT 2在抑制lamellipodial延伸和FA营业额的Rac 1和Cdc 42依赖的信号通路，分别。此外，我们表明SH 2-SH 3衔接蛋白Crk是GIT 2抑制的重要靶点。出乎意料的是，我们发现bPIX对于GIT 2敲低引起的效应是无效的。最后，我们发现GIT 2的丢失足以诱导非转化上皮细胞系MCF 10A的迁移。这些结果表明，GIT 2功能的失活是诱导细胞运动的必要步骤，并且GIT 2可能是调节细胞迁移的致癌信号通路的靶点。
G protein-coupled receptor kinase interactors (GITs) regulate focal adhesion (FA) turnover, cell spreading, and motility through direct interaction with paxillin and the Rac-exchange factor Pak-interacting exchange factor beta (beta PIX). However, it is not clear whether GITs function to activate or repress motility or if the predominant GIT forms, GIT1 and GIT2, serve distinct or redundant roles. Here we demonstrate an obligatory role for endogenous GIT2 in repression of lamellipodial extension and FA turnover by Rac1- and Cdc42-dependent signaling pathways, respectively. Moreover, we show that the SH2-SH3 adaptor protein Crk is an essential target of GIT2 inhibition. Unexpectedly, we find that bPIX is dispensable for the effects elicited by knockdown of GIT2. Finally, we show that loss of GIT2 is sufficient to induce migration of the nontransformed epithelial cell line MCF10A. These results suggest that inactivation of GIT2 function is a required step for induction of cell motility and that GIT2 may be a target of oncogenic signaling pathways that regulate cell migration.