Integrin-mediated adhesion regulates cell polarity and membrane protrusion through the Rho family of GTPases
Integrin-mediated adhesion regulates cell polarity and membrane protrusion through the Rho family of GTPases
复制标题
DOI：
10.1091/mbc.12.2.265
复制
发表时间：
2001-02-01
影响因子：
3.3
通讯作者：
Huttenlocher, A
中科院分区：
文献类型：
--
作者：
Cox, EA;Sastry, SK;Huttenlocher, A
整合素介导的粘附是细胞迁移的关键调节因子。在这里，我们证明了整合素介导的粘附高浓度的纤连蛋白诱导细胞迁移的停止信号，通过抑制细胞极化和突起。在纤连蛋白上，终止信号通过α 5 β 1整联蛋白介导的信号传导至Rho家族的GTP酶而产生。具体而言，Cdc42和Rac 1激活表现出对纤连蛋白浓度的双相依赖性，其平行于最佳细胞极化和突起。相反，RhoA活性随着底物浓度的增加而增加。我们发现，Cdc42和Rac1之间的串扰是需要基质刺激突起，而RhoA活性是抑制性的。我们还表明，Cdc42活性受到Rac1激活的抑制，这表明Rac1活性可能下调Cdc42活性，并促进形成稳定的，而不是短暂的突出。此外，RhoA的表达下调Cdc42和Rac1活性，提供了RhoA可以抑制细胞极化和突起的机制。这些发现暗示粘附依赖性信号传导作为通过经由GTP酶的Rho家族调节细胞极性和突起来阻止细胞迁移的机制。
Integrin-mediated adhesion is a critical regulator of cell migration. Here we demonstrate that integrin-mediated adhesion to high fibronectin concentrations induces a stop signal for cell migration by inhibiting cell polarization and protrusion. On fibronectin, the stop signal is generated through alpha5 beta1 integrin-mediated signaling to the Rho family of GTPases. Specifically, Cdc42 and Rac1 activation exhibits a biphasic dependence on fibronectin concentration that parallels optimum cell polarization and protrusion. In contrast, RhoA activity increases with increasing substratum concentration. We find that cross talk between Cdc42 and Rac1 is required for substratum-stimulated protrusion, whereas RhoA activity is inhibitory. We also show that Cdc42 activity is inhibited by Rac1 activation, suggesting that Rac1 activity may down-regulate Cdc42 activity and promote the formation of stabilized rather than transient protrusion. Furthermore, expression of RhoA down-regulates Cdc42 and Rac1 activity, providing a mechanism whereby RhoA may inhibit cell polarization and protrusion. These findings implicate adhesion-dependent signaling as a mechanism to stop cell migration by regulating cell polarity and protrusion via the Rho family of GTPases.