Superoxide inhibits guanine nucleotide exchange factor (GEF) action on Ras, but not on Rho, through desensitization of Ras to GEF.
Superoxide inhibits guanine nucleotide exchange factor (GEF) action on Ras, but not on Rho, through desensitization of Ras to GEF.
复制标题
DOI：
10.1021/bi401528n
复制
发表时间：
2014-01-28
期刊：
影响因子：
2.9
通讯作者：
Heo J
中科院分区：
文献类型：
--
作者：
Wey M;Phan V;Yepez G;Heo J
Ras和Rho gtpase是各种重要细胞信号通路的分子开关。这些gtpase的过度激活通常会导致癌症的发展。鸟嘌呤核苷酸交换因子（GEFs）和氧化剂通过促进这些gtpase的鸟嘌呤核苷酸交换（GNE）来上调这些gtpase。然而，氧化剂对GEF功能的影响，或反之亦然，尚不清楚。我们发现，通过靶向Ras Cys51，一种氧化剂抑制了cdc25 （rasgefs的催化结构域）对Ras的催化作用。然而，不管Cdc25是否存在，氧化剂对Ras GNE的增强作用仍在继续。通过氧化剂限制RasGEF的作用可以防止RasGEF和氧化剂同时存在时Ras的病理生理过度激活。Ras持续暴露于一氧化氮及其衍生物中可形成s-亚硝化Ras （Ras- sno）。本研究还表明，氧化剂不仅抑制了Cdc25对Ras-SNO的催化作用，而且不能增强Ras-SNO的GNE。这种增强的缺失会在细胞中填充具有生物活性的Ras- sno，其功能可能是阻止Ras病理生理反应的持续氧化还原信号传导。最后，本研究还表明，与rasgef不同，氧化剂不会抑制RhoGEF-Vav或dbs对Rho gtpase（如Rac1、RhoA、RhoC和Cdc42）的催化作用。这一结果解释了之前的研究结果，即尽管存在氧化剂，Dbs在细胞中的催化作用继续增强RhoC GNE。
Ras and Rho GTPases are molecular switches for various vital cellular signaling pathways. Overactivation of these GTPases often causes development of cancer. Guanine nucleotide exchange factors (GEFs) and oxidants function to upregulate these GTPases through facilitation of guanine nucleotide exchange (GNE) of these GTPases. However, the effect of oxidants on GEF functions, or vice versa, has not been known. We show that, via targeting Ras Cys51, an oxidant inhibits the catalytic action of Cdc25—the catalytic domain of RasGEFs—on Ras. However, the enhancement of Ras GNE by an oxidant continues regardless of the presence of Cdc25. Limiting RasGEF action by an oxidant may function to prevent the pathophysiological overactivation of Ras in the presence of both RasGEFs and oxidants. The continuous exposure of Ras to nitric oxide and its derivatives can form S-nitrosated Ras (Ras-SNO). This study also shows that an oxidant not only inhibits the catalytic action of Cdc25 on Ras-SNO but also fails to enhance Ras-SNO GNE. This lack of enhancement then populates the biologically inactive Ras-SNO in cells, which may function to prevent the continued redox signaling of the Ras pathophysiological response. Finally, this study also demonstrates that, unlike the case with RasGEFs, an oxidant does not inhibit the catalytic action of RhoGEF—Vav or Dbs—on Rho GTPases such as Rac1, RhoA, RhoC, and Cdc42. This result explains the results of the previous study in which, despite the presence of an oxidant, the catalytic action of Dbs in cells continued to enhance RhoC GNE.