Integrin-mediated Adhesion Regulates Cell Polarity and Membrane Protrusion through the Rho Family of GTPases

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 α5β1 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.

整合素（Integrin）介导的黏附是细胞迁移的关键调控因子。本研究证实，整合素介导的对高浓度纤连蛋白（fibronectin）的黏附，可通过抑制细胞极化与细胞突起形成，触发细胞迁移的停止信号。在纤连蛋白基质上，该停止信号通过α5β1整合素（α5β1 integrin）介导的信号通路作用于Rho家族GTP酶（Rho family GTPases）得以产生。具体而言，Cdc42与Rac1的激活对纤连蛋白浓度呈现双相依赖性，这一变化趋势与最佳状态下的细胞极化及突起形成相匹配。与之相反，RhoA的活性随基质浓度升高而持续增强。研究发现，Cdc42与Rac1之间的交叉对话是基质刺激突起形成所必需的，而RhoA活性则发挥抑制作用。此外，本研究还表明，Rac1激活会抑制Cdc42的活性，这提示Rac1活性可能下调Cdc42活性，进而促进稳定而非瞬时的细胞突起形成。进一步研究显示，RhoA的表达可下调Cdc42与Rac1的活性，这为RhoA如何抑制细胞极化与突起形成提供了潜在机制。上述研究结果表明，黏附依赖性信号通路可通过调控Rho家族GTP酶来影响细胞极性与突起形成，从而实现对细胞迁移的终止。