Michiels F, Habets G G, Stam J C, van der Kammen R A, Collard J G
The Netherlands Cancer Institute, Division of Cell Biology, Amsterdam.
Nature. 1995 May 25;375(6529):338-40. doi: 10.1038/375338a0.
Rho-like GTPases have been implicated in the regulation of the actin cytoskeleton which controls the morphology, adhesion and motility of cells. Like Ras proteins, they become activated when bound GDP is exchanged for GTP, a process catalysed by GDP-dissociation stimulator (GDS) proteins. Several GDS proteins specific for Rho-like GTPases have been identified. Most of these contain a conserved catalytic domain, the DBL-homology (DH) domain, and activate Cdc42 or Rho but not Rac. We have isolated the invasion-inducing Tiam1 gene, which also encodes a protein with a DH domain. Here we show that Tiam1 is a GDS protein for Rho-like GTPases in vitro. In fibroblasts, Tiam1 induces a similar phenotype as constitutively activated (V12)Rac1, including membrane ruffling, and this is inhibited by dominant negative (N17)Rac1. Moreover, T-lymphoma cells expressing V12Rac1 become invasive, indicating that the Tiam1-Rac signalling pathway could be operating in the invasion and metastasis of tumour cells.
Rho样GTP酶参与肌动蛋白细胞骨架的调节，而肌动蛋白细胞骨架控制着细胞的形态、黏附及运动。与Ras蛋白相似，当结合的GDP被GTP替换时它们被激活，这一过程由GDP解离刺激因子（GDS）蛋白催化。已鉴定出几种对Rho样GTP酶具有特异性的GDS蛋白。其中大多数含有保守的催化结构域，即DBL同源（DH）结构域，可激活Cdc42或Rho，但不激活Rac。我们分离出了诱导侵袭的Tiam1基因，该基因也编码一种具有DH结构域的蛋白。在此我们表明，Tiam1在体外是一种针对Rho样GTP酶的GDS蛋白。在成纤维细胞中，Tiam1诱导出与组成型激活的（V12）Rac1相似的表型，包括膜皱褶，而这被显性负性（N17）Rac1抑制。此外，表达V12Rac1的T淋巴瘤细胞具有侵袭性，这表明Tiam1-Rac信号通路可能在肿瘤细胞的侵袭和转移中发挥作用。
