Unfarnesylated transforming Ras mutant inhibits the Ras‐signaling pathway by forming a stable Ras·Raf complex in the cytosol

FEBS Letters

Kaziro, Yoshito¹  Miyake, Mika¹  Koide, Hiroshi¹  Mizutani, Shin¹ 

[1] Faculty of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta, Midori-ku, Yokohama 226, Japan

关键词: Ras;    Farnesylation;    Dominant-negative mutant;    Raf;    G12Ras-SVLS;    Ha-RasC186S;    VI2Ras-CVLS;    Ha-RasG12V;    VI2Ras-SVLS;    Ha-RasG12V;    C186S;    MAPK;    mitogen-activated protein kinase;    MEK;    MAPK kinase;    Raf-FH6;    Raf-1 with flag-epitope tag and six histidine residues in its C-terminus;   

DOI  :  10.1016/0014-5793(95)01416-0

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

Farnesyltransferase inhibitors cause the growth arrest of ras-transformed cells, but not that of normal cells. To elucidate the mechanism of this differential effect, we examined the effect of accumulation of unfarnesylated Ras in the cytosol by using Ras^G12V,C186S and Ras^C186S, which mimic unfarnesylated form of the oncogenic and the normal Ras, respectively. We found that Ras^G12,C186S inhibited activation and membrane translocation of Raf by forming a stable complex with Raf in the cytosol. In contrast, Ras^C186S showed inhibitory effect on neither Raf activation nor Raf translocation. These results indicate that unfarnesylated oncogenic Ras interacts with Raf in the cytosol and inhibits its membrane translocation, a crucial step for the Raf activation, while unfarnesylated normal Ras does not.

【 授权许可】

Unknown