Ridley A J, Allen W E, Peppelenbosch M, Jones G E
Ludwig Institute for Cancer Research, University College London, U.K.
Biochem Soc Symp. 1999;65:111-23.
The GTP-binding proteins Rho, Rac and Cdc42 are known to regulate actin organization: Rho induces the assembly of contractile actin-based filaments such as stress fibres, Rac regulates the formation of lamellipodia and membrane ruffles, while Cdc42 is required for filopodium extension. All three proteins can also regulate the assembly of integrin-containing focal adhesion complexes. Cell migration involves co-ordinated and dynamic changes in the actin cytoskeleton and cell adhesion, and we have therefore investigated the roles of Rho family proteins in migration, using two model cell systems. First, in the macrophage cell line Bac1, Rho and Rac were found to be required for colony-stimulating factor-1 (CSF-1)-induced cell migration. In contrast, inhibition of Cdc42 does not prevent macrophages migrating in response to CSF-1, but does prevent recognition of a CSF-1 concentration gradient, so that cells now migrate randomly rather than up the gradient. This implies that Cdc42, and probably filopodia, are required for gradient sensing and cell polarization. Secondly, in the Madin-Darby canine kidney (MDCK) epithelial cell line, Rho and Rac are also essential for migration induced by hepatocyte growth factor/scatter factor. Rac is required for lamellipodium formation and is apparently activated via Ras. Interestingly, however, Rac does not induce lamellipodium formation in unstimulated MDCK cells, indicating that Rac signals differently in epithelial cells compared with fibroblasts or macrophages. Our results point to central roles for Rho, Rac and Cdc42 in co-ordinating cell migration.
已知GTP结合蛋白Rho、Rac和Cdc42可调节肌动蛋白的组织：Rho诱导基于肌动蛋白的收缩性细丝组装，如应力纤维；Rac调节片状伪足和膜皱褶的形成；而丝状伪足的延伸则需要Cdc42。这三种蛋白还均可调节含整合素的粘着斑复合物的组装。细胞迁移涉及肌动蛋白细胞骨架和细胞粘附的协调及动态变化，因此我们利用两种模型细胞系统研究了Rho家族蛋白在迁移中的作用。首先，在巨噬细胞系Bac1中，发现Rho和Rac是集落刺激因子-1（CSF-1）诱导的细胞迁移所必需的。相比之下，抑制Cdc42并不妨碍巨噬细胞对CSF-1作出反应而迁移，但确实会阻止其识别CSF-1浓度梯度，这样细胞现在就会随机迁移而不是顺着梯度向上迁移。这意味着Cdc42，可能还有丝状伪足，是梯度传感和细胞极化所必需的。其次，在Madin-Darby犬肾（MDCK）上皮细胞系中，Rho和Rac对于肝细胞生长因子/分散因子诱导的迁移也至关重要。Rac是片状伪足形成所必需的，并且显然是通过Ras激活的。然而，有趣的是，Rac在未受刺激的MDCK细胞中并不诱导片状伪足形成，这表明与成纤维细胞或巨噬细胞相比，Rac在上皮细胞中的信号传导方式有所不同。我们的结果表明Rho、Rac和Cdc42在协调细胞迁移中起核心作用。
