The Rho family of GTPases are inactivated in a cell context-dependent manner by Rho-GTPase-activating proteins (Rho-GAPs), but their signaling mechanisms are poorly understood. Here we demonstrate that ARHGAP4, the Rho-GAPs, forms a complex with SEPT2 and SEPT9 via its Rho-GAP domain and SH3 domain to enable both up- and down-modulation of integrin-mediated focal adhesions (FAs). We show that silencing ARHGAP4 as well as overexpressing its two mutually independent upstream regulators SEPT2 and SEPT9 all induce reorganization of FAs to newly express Integrin Beta 1 and also enhance both cell migration and invasion. Interestingly, even if these cell migration/invasion-associated phenotypic changes are induced upon perturbations to the complex, it does not necessarily cause enhanced clustering of FAs. Instead, its extent depends on whether the microenvironment contains ligands suitable for the upregulated Integrin Beta 1. These results provide novel insights to cell migration, invasion, and microenvironment-dependent phenotypic changes regulated by the newly identified complex.

Rho GTPase 家族被 Rho-GTPase 激活蛋白 (Rho-GAPs) 以依赖于细胞环境的方式灭活，但对其信号传导机制知之甚少。在这里，我们证明 ARHGAP4，即 Rho-GAP，通过其 Rho-GAP 结构域和 SH3 结构域与 SEPT2 和 SEPT9 形成复合物，以实现整合素介导的粘着斑 (FAs) 的上调和下调。我们表明，沉默 ARHGAP4 以及过表达其两个相互独立的上游调节因子 SEPT2 和 SEPT9 都会诱导 FA 重组以新表达 Integrin Beta 1，并增强细胞迁移和侵袭。有趣的是，即使这些细胞迁移/侵袭相关的表型变化是在对复合物的扰动时引起的，它也不一定会导致 FAs 的聚集增强。反而，