Specific isoprenoid modification is required for function of normal, but not oncogenic, Ras protein.

摘要: While the Ras C-terminal CAAX sequence signals modification by a 15-carbon farnesyl isoprenoid, majority of isoprenylated proteins in mammalian cells are modified instead 20-carbon geranylgeranyl moiety. To determine structural and functional basis for specific isoprenoid group, we have generated chimeric containing sequences (CVLL CAIL) from geranylgeranyl-modified Krev-1 protein H-Ras (CVLS). Our results demonstrate that both oncogenic transforming activity antagonism can be promoted either or modification. Similarly, normal [Ras(WT)CVLL], when overexpressed, exhibited same level as authentic farnesyl-modified protein. Therefore, moieties functionally interchangeable these biological activities. In contrast, expression moderate levels inhibited growth untransformed NIH 3T3 cells. This inhibition was overcome coexpression mutant with Raf, but not Src Ras. The similar growth-inhibiting activities Ras(WT)CVLL previously described Ras(17N) dominant inhibitory suggest may exert its action perturbing endogenous function. These function specifically require farnesyl, geranylgeranyl, isoprenoid.