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Mol Cell. 2016 Dec 1;64(5):875-887. doi: 10.1016/j.molcel.2016.10.029. Epub 2016 Nov 23.

Inhibition of Ras/Raf/MEK/ERK Pathway Signaling by a Stress-Induced Phospho-Regulatory Circuit.

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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.
Laboratory of Cell and Developmental Signaling, NCI-Frederick, Frederick, MD 21702, USA. Electronic address:


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.


ERK cascade; JNK cascade; Raf; Ras; Ras pathway; Sos; phosphorylation; rigosertib

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