Coordination of Rho and Rac GTPase function via p190B RhoGAP.
Coordination of Rho and Rac GTPase function via p190B RhoGAP.
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DOI：
10.1016/j.cub.2008.09.019
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发表时间：
2008-10-28
期刊：
影响因子：
--
通讯作者：
Hansen SH
中科院分区：
文献类型：
--
作者：
Bustos RI;Forget MA;Settleman JE;Hansen SH
Rac GT3在广泛的生理环境和致癌转化中调节Rho信号传导。在这里，我们报告了一种新的机制，通过该机制实现了Rac和Rho GTP酶之间的串扰。活化的Rac1直接结合到p190B RhoGAP（GTdR活化蛋白），一种Rho信号传导的主要调节剂。p190B与组成型活性Rac1共定位于膜皱褶中。此外，活化的Rac1足以将p190 B募集到洗涤剂不溶性的膜部分中，这伴随着膜中GTP结合的RhoA的减少。p190 B被募集到质膜上以响应整合素的接合。我们证明，胶原I型，一个强大的诱导剂的Rac1依赖细胞运动的HeLa细胞，抵消细胞骨架崩溃导致过度表达野生型p190B，但不是一个p190B突变体，特别是缺乏Rac1结合序列。此外，该p190 B突变体表现出显著增强的RhoGAP活性，这与Rac1结合缓解p190 B RhoGAP功能自抑制的模型一致。总的来说，这些观察结果表明，激活Rac 1，通过与p190 B直接相互作用，调节亚细胞RhoGAP的定位和活性，从而提供了一种新的机制，Rac控制Rho信号在广泛的生理过程。
The Rac GTPase regulates Rho signaling in a broad range of physiological settings and in oncogenic transformation. Here, we report a novel mechanism by which cross-talk between Rac and Rho GTPases is achieved. Activated Rac1 binds directly to p190B RhoGAP (GTPase activating protein), a major modulator of Rho signaling. p190B co-localizes with constitutively active Rac1 in membrane ruffles. Moreover, activated Rac1 is sufficient to recruit p190B into a detergent-insoluble membrane fraction, which is accompanied by a decrease in GTP-bound RhoA from membranes. p190B is recruited to the plasma membrane in response to integrin engagement. We demonstrate that collagen type-I, a potent inducer of Rac1-dependent cell motility in HeLa cells, counteracts cytoskeletal collapse resulting from overexpression of wild-type p190B but not of a p190B mutant specifically lacking the Rac1-binding sequence. Furthermore, this p190B mutant exhibits dramatically enhanced RhoGAP activity consistent with a model whereby binding of Rac1 relieves autoinhibition of p190B RhoGAP function. Collectively, these observations establish that activated Rac1, through direct interaction with p190B, modulates subcellular RhoGAP localization and activity, thereby providing a novel mechanism for Rac to control Rho signaling in a broad range of physiological processes.
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