Targeting and activation of Rac1 are mediated by the exchange factor beta-Pix.
Targeting and activation of Rac1 are mediated by the exchange factor beta-Pix.
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DOI：
10.1083/jcb.200509096
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发表时间：
2006-02-27
期刊：
影响因子：
--
通讯作者：
Hordijk PL
中科院分区：
文献类型：
--
作者：
ten Klooster JP;Jaffer ZM;Chernoff J;Hordijk PL
Rho鸟苷三磷酸酶(GTP酶)是细胞骨架动力学的重要调节因子，控制着细胞的黏附、扩散、迁移和分裂等复杂功能。人们普遍认为，尽管控制Rho GTP酶靶向的分子机制尚不清楚，但GTP酶的局部激活是正确启动下游信号事件所必需的。在这项研究中，我们发现Rho GTPase rac1通过其COOH端的一个脯氨酸延伸，直接与Cdc42/Rac激活剂β-Pix(p21-激活的激酶[Pak]-相互作用的交换因子)的SH3结构域结合。与β-Pix的相互作用是不依赖于核苷酸的，并且是Rac1重新募集到膜褶皱和局部粘连的必要条件和充分条件。此外，Rac1-β-Pix的相互作用是β-Pix激活Rac1以及Rac1介导的传播所必需的。最后，利用缺失β-PIX结合蛋白的细胞，我们证明了Pak1调节Rac1-β-PIX的相互作用，并控制细胞的扩散和黏附诱导的Rac1的激活。这些数据为Rac1通过其交换因子β-Pix在细胞内的靶向和局部激活提供了一个模型。
Rho guanosine triphosphatases (GTPases) are critical regulators of cytoskeletal dynamics and control complex functions such as cell adhesion, spreading, migration, and cell division. It is generally accepted that localized GTPase activation is required for the proper initiation of downstream signaling events, although the molecular mechanisms that control targeting of Rho GTPases are unknown. In this study, we show that the Rho GTPase Rac1, via a proline stretch in its COOH terminus, binds directly to the SH3 domain of the Cdc42/Rac activator β-Pix (p21-activated kinase [Pak]–interacting exchange factor). The interaction with β-Pix is nucleotide independent and is necessary and sufficient for Rac1 recruitment to membrane ruffles and to focal adhesions. In addition, the Rac1–β-Pix interaction is required for Rac1 activation by β-Pix as well as for Rac1-mediated spreading. Finally, using cells deficient for the β-Pix–binding kinase Pak1, we show that Pak1 regulates the Rac1–β-Pix interaction and controls cell spreading and adhesion-induced Rac1 activation. These data provide a model for the intracellular targeting and localized activation of Rac1 through its exchange factor β-Pix.
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