Integrin signaling through arg activates p190RhoGAP by promoting its binding to p120RasGAP and recruitment to the membrane
Integrin signaling through arg activates p190RhoGAP by promoting its binding to p120RasGAP and recruitment to the membrane
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DOI：
10.1091/mbc.e06-02-0132
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发表时间：
2006-11-01
影响因子：
3.3
通讯作者：
Koleske, Anthony J.
中科院分区：
文献类型：
--
作者：
Bradley, William D.;Hernandez, Samuel E.;Koleske, Anthony J.
Rho家族GTP酶RhoA(Rho)、Rac1和CDC42是整合素介导的细胞黏附和扩散的重要效应因子。促进局部粘连和肌动蛋白应激纤维形成的Rho活性在细胞初始附着时被抑制，以允许对新的粘连环境进行采样。AB1相关基因(Arg)酪氨酸激酶通过磷酸化和激活Rho抑制因子p190RhoGAP-A(P190)，介导对Rho的黏附依赖性抑制。P190的磷酸化促进其与p120RasGAP(P120)的结合。在这里，我们阐明了p120结合调节黏附后p190激活的机制。我们发现p190需要它的p120结合域在体内经历Arg依赖的激活。然而，在体外，P120结合并不激活p190RhoGAP的活性。相反，p190的激活需要向细胞外围募集。整合素介导的黏附促进再定位。P190和p120在野生型成纤维细胞中呈阳性表达，而在Arg(-/-)成纤维细胞中不表达。显性负性p120片段阻断p190：p120复合体的形成，阻止黏附激活p190，并破坏黏附依赖的p190向细胞外周的募集。我们的结果表明，通过Arg的整合素信号通过促进p190与p120的关联来激活p190，导致p190募集到细胞外周，在那里它抑制Rho。
The Rho family GTPases RhoA (Rho), Racl, and Cdc42 are essential effectors of integrin-mediated cell attachment and spreading. Rho activity, which promotes formation of focal adhesions and actin stress fibers, is inhibited upon initial cell attachment to allow sampling of the new adhesive environment. The Ab1-related gene (Arg) tyrosine kinase mediates adhesion-dependent inhibition of Rho through phosphorylation and activation of the Rho inhibitor p190RhoGAP-A (p190). p190 phosphorylation promotes its binding to p120RasGAP (p120). Here, we elucidate the mechanism by which p120 binding regulates p190 activation after adhesion. We show that p190 requires its p120-binding domain to undergo Arg-dependent activation in vivo. However, P120 binding does not activate p190RhoGAP activity in vitro. Instead, activation of p190 requires recruitment to the cell periphery. Integrin-mediated adhesion promotes relocalization. of p190 and p120 to the cell periphery in wild-type fibroblasts, but not in arg(-/-) fibroblasts. A dominant-negative p120 fragment blocks p190:p120 complex formation, prevents activation of p190 by adhesion, and disrupts the adhesion-dependent recruitment of p190 to the cell periphery. Our results demonstrate that integrin signaling through Arg activates p190 by promoting its association with p120, resulting in recruitment of p190 to the cell periphery where it inhibits Rho.