R-Ras is regulated by activators and effectors distinct from those that control Ras function
R-Ras is regulated by activators and effectors distinct from those that control Ras function
复制标题
DOI：
10.1038/sj.onc.1200815
复制
发表时间：
1997-01-16
期刊：
影响因子：
8
通讯作者：
Der, CJ
中科院分区：
文献类型：
--
作者：
Huff, SY;Quilliam, LA;Der, CJ
与Ras一样，Ras相关蛋白R-Ras的组成型激活突变体引起NIH 3 T3细胞的致瘤性转化。然而，由于R-Ras引起的转化表型不同于Ras诱导的转化表型，因此R-Ras控制的信号传导途径和细胞过程可能不同于Ras调节的信号传导途径和细胞过程。为了解决这种可能性，我们确定了R-Ras是否受到与调节Ras功能的那些不同的激活剂和效应剂的调节。我们观察到Ras鸟嘌呤核苷酸交换因子未能在体内激活R-Ras，表明R-Ras被不同的GEF激活。与此一致，具有类似于Ras（15 A）/（17 N）显性失活蛋白的突变的R-Ras突变体不拮抗Ras GEF功能，并且缺乏这些突变体Ras蛋白所见的生长抑制活性。因此，R-Ras，而不是Ras，对MIH 3 T3细胞的生存力不利。最后，尽管组成型激活的Ras可以通过Raf-dependent和-independent活性克服Ras（17 N）显性负性蛋白的生长抑制作用，但R-Ras的转化突变体未能做到这一点。这种无能是一致的，我们的观察，Ras，但不是R-Ras转化，NIH 3 T3细胞具有组成性上调Raf激酶活性。因此，R-Ras和Ras是不同信号传导途径和细胞过程的调节剂。
Like Ras, constitutively activated mutants of the Ras-related protein R-Ras cause tumorigenic transformation of NIH3T3 cells. However, since R-Ras causes a transformed phenotype distinct from that induced by Ras, it is likely that R-Ras controls signaling pathways and cellular processes distinct from those regulated by Ras. To address this possibility, we determined if R-Ras is regulated by activators and effecters distinct from those that regulate Ras function, We observed that Ras guanine nucleotide exchange factors failed to activate R-Ras in vivo, indicating that R-Ras is activated by distinct GEFs. Consistent with this, mutants of R-Ras with mutations analogous to the Ras(15A)/(17N) dominant negative proteins did not antagonize Ras GEF function and lacked the growth inhibitory activity seen with these mutant Ras proteins, Thus, R-Ras, but not Ras, is dispensable for the viability of MIH3T3 cells. Finally, whereas constitutively activated Ras can overcome the growth inhibitory action of the Ras(17N) dominant negative protein via Raf-dependent and -independent activities, transforming mutants of R-Ras failed to do so. This inability was consistent with our observation that Ras-, but not R-Ras-transformed, NIH3T3 cells possessed constitutively upregulated Raf kinase activities. Thus, R-Ras and Ras are regulators of distinct signaling pathways and cellular processes.