SH3BP1, an exocyst-associated RhoGAP, inactivates Rac1 at the front to drive cell motility.
SH3BP1, an exocyst-associated RhoGAP, inactivates Rac1 at the front to drive cell motility.
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DOI：
10.1016/j.molcel.2011.03.032
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发表时间：
2011-06-10
期刊：
影响因子：
16
通讯作者：
Camonis J
中科院分区：
文献类型：
--
作者：
Parrini MC;Sadou-Dubourgnoux A;Aoki K;Kunida K;Biondini M;Hatzoglou A;Poullet P;Formstecher E;Yeaman C;Matsuda M;Rossé C;Camonis J
参与细胞运动的几条通路的协调作用还知之甚少。在这里，我们确定了属于RhoGAP家族的SH3BP1是胞囊复合体的合作伙伴，并在两条运动驱动通路--Ral/Excyst和Rac信号通路之间建立了物理和功能上的联系。我们发现SH3BP1与外囊一起定位于运动细胞的前沿，并且SH3BP1通过其在rac1上的GAP活性来调节细胞的迁移。SH3BP1功能丧失导致在体内生物传感器观察到的前部异常高的rac1活性，以及细胞形态动力学分析揭示的无序和不稳定的突起。始终如一地，结构性活性的rac1模拟SH3BP1耗竭的表型：缓慢的迁移和异常的细胞形态动力学。我们的发现是SH3BP1下调了运动细胞前沿的rac1，这表明该位置的rac1失活以及被环境基金蛋白激活是细胞运动的基本要求。
The coordination of the several pathways involved in cell motility is poorly understood. Here, we identify SH3BP1, belonging to the RhoGAP family, as a partner of the exocyst complex, and establish a physical and functional link between two motility-driving pathways, the Ral/exocyst and Rac signaling pathways. We show that SH3BP1 localizes together with the exocyst to the leading edge of motile cells and that SH3BP1 regulates cell migration via its GAP activity upon Rac1. SH3BP1 loss-of-function induces abnormally high Rac1 activity at the front, as visualized by in vivo biosensors, and disorganized and instable protrusions, as revealed by cell morphodynamics analysis. Consistently, constitutively active Rac1 mimics the phenotype of SH3BP1 depletion: slow migration and aberrant cell morphodynamics. Our finding that SH3BP1 down-regulates Rac1 at the motile-cell front indicates that Rac1 inactivation in this location, as well as its activation by GEF proteins, is a fundamental requirement for cell motility.
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