Ota Takahide, Maeda Masayo, Murakami Manabu, Takegami Tsutomu, Suto Shiho, Tatsuka Masaaki
Division of Molecular Oncology and Virology, Medical Research Institute, Kanazawa Medical University, Daigaku, Uchinada, Ishikawa 920-0293, Japan.
Cell Biol Int. 2007 Jan;31(1):92-6. doi: 10.1016/j.cellbi.2006.09.002. Epub 2006 Sep 10.
Rho-guanine nucleotide dissociation inhibitor-beta (RhoGDIbeta), a regulator for Rho GTPases, is implicated in cancer cell progression. We reported that C-terminal truncated RhoGDIbeta (DeltaC(166-201)-RhoGDIbeta) promoted metastasis through activating Rac1 signaling pathway in ras-transformed fibroblast cells. To better understand the mechanism of Rac1 activation by DeltaC(166-201)-RhoGDIbeta during metastasis, the amount of GTP-bound Rac1 was measured as the activation level of Rac1 in cells expressing various mutant RhoGDIbeta with sequential C-terminal deletions. Three C-terminal hydrophobic amino acid residues (Trp191, Leu193, and Ile195) supposed to interact with isoprenyl groups of Rac1, was indispensable for a proper regulation of Rac1 activation/inhibition. Deletion of this region led RhoGDIbeta to continuously associate with GTP-bound Rac1, provoking constitutive activation of Rac1. Thus, impaired interaction of RhoGDIbeta with Rac1 isoprenyl groups possibly makes RhoGDIbeta function as a positive regulator for Rac1 during metastasis.
Rho鸟嘌呤核苷酸解离抑制剂β（RhoGDIβ）是Rho GTP酶的一种调节剂，与癌细胞进展有关。我们报道，C末端截短的RhoGDIβ（DeltaC(166 - 201)-RhoGDIβ）通过激活ras转化的成纤维细胞中的Rac1信号通路促进转移。为了更好地理解DeltaC(166 - 201)-RhoGDIβ在转移过程中激活Rac1的机制，我们测定了表达各种具有连续C末端缺失的突变型RhoGDIβ的细胞中与GTP结合的Rac1的量，以此作为Rac1的激活水平。三个C末端疏水氨基酸残基（Trp191、Leu193和Ile195）被认为与Rac1的异戊二烯基相互作用，对于正确调节Rac1的激活/抑制是必不可少的。该区域的缺失导致RhoGDIβ持续与结合GTP的Rac1结合，并引发Rac1的组成型激活。因此，RhoGDIβ与Rac1异戊二烯基之间相互作用受损可能使RhoGDIβ在转移过程中作为Rac1的正向调节剂发挥作用。
