Ritt Daniel A, Abreu-Blanco María T, Bindu Lakshman, Durrant David E, Zhou Ming, Specht Suzanne I, Stephen Andrew G, Holderfield Matthew, Morrison Deborah K
Laboratory of Cell and Developmental Signaling, NCI-Frederick, Frederick, MD 21702, USA.
NCI-Ras Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Frederick, MD 21702, USA.
Mol Cell. 2016 Dec 1;64(5):875-887. doi: 10.1016/j.molcel.2016.10.029. Epub 2016 Nov 23.
Ras pathway signaling plays a critical role in cell growth control and is often upregulated in human cancer. The Raf kinases selectively interact with GTP-bound Ras and are important effectors of Ras signaling, functioning as the initiating kinases in the ERK cascade. Here, we identify a route for the phospho-inhibition of Ras/Raf/MEK/ERK pathway signaling that is mediated by the stress-activated JNK cascade. We find that key Ras pathway components, the RasGEF Sos1 and the Rafs, are phosphorylated on multiple S/TP sites in response to JNK activation and that the hyperphosphorylation of these sites renders the Rafs and Sos1 unresponsive to upstream signals. This phospho-regulatory circuit is engaged by cancer therapeutics, such as rigosertib and paclitaxel/Taxol, that activate JNK through mitotic and oxidative stress as well as by physiological regulators of the JNK cascade and may function as a signaling checkpoint to suppress the Ras pathway during conditions of cellular stress.
Ras信号通路在细胞生长控制中起着关键作用，在人类癌症中常常上调。Raf激酶选择性地与结合GTP的Ras相互作用，是Ras信号的重要效应器，作为ERK级联反应中的起始激酶发挥作用。在此，我们确定了一条由应激激活的JNK级联介导的对Ras/Raf/MEK/ERK信号通路进行磷酸化抑制的途径。我们发现，关键的Ras信号通路成分，即Ras鸟嘌呤核苷酸交换因子Sos1和Rafs，在响应JNK激活时在多个S/TP位点被磷酸化，并且这些位点的过度磷酸化使Rafs和Sos1对上游信号无反应。这种磷酸化调节回路被癌症治疗药物（如rigosertib和紫杉醇/泰素）所激活，这些药物通过有丝分裂和氧化应激激活JNK，同时也被JNK级联的生理调节因子所激活，并且可能作为一个信号检查点，在细胞应激条件下抑制Ras信号通路。
