title: Inhibition of Ras/Raf/MEK/ERK Pathway Signaling by a Stress-Induced Phospho-Regulatory Circuit.
abstract: 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.
authors.affiliation: Laboratory of Cell and Developmental Signaling, NCI-Frederick, Frederick, MD 21702, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Ritt
authors.affiliation: NCI-Ras Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Frederick, MD 21702, USA.
authors.forename: María T
authors.initials: MT
authors.lastname: Abreu-Blanco
authors.affiliation: NCI-Ras Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Frederick, MD 21702, USA.
authors.forename: Lakshman
authors.initials: L
authors.lastname: Bindu
authors.affiliation: Laboratory of Cell and Developmental Signaling, NCI-Frederick, Frederick, MD 21702, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Durrant
authors.affiliation: NCI-Ras Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Frederick, MD 21702, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Laboratory of Cell and Developmental Signaling, NCI-Frederick, Frederick, MD 21702, USA.
authors.forename: Suzanne I
authors.initials: SI
authors.lastname: Specht
authors.affiliation: NCI-Ras Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Frederick, MD 21702, USA.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Stephen
authors.affiliation: NCI-Ras Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Frederick, MD 21702, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Holderfield
authors.affiliation: Laboratory of Cell and Developmental Signaling, NCI-Frederick, Frederick, MD 21702, USA. Electronic address: morrisod@mail.nih.gov.
authors.forename: Deborah K
authors.initials: DK
authors.lastname: Morrison
mesh_terms: D004789:Enzyme Activation / Q000187:drug effects; D005998:Glycine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D018384:Oxidative Stress; D017239:Paclitaxel / Q000493:pharmacokinetics / Q000494:pharmacology; D010766:Phosphorylation; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D013450:Sulfones / Q000493:pharmacokinetics / Q000494:pharmacology; D018631:ras Proteins / Q000378:metabolism
chemical_list: D013450:Sulfones; C507134:ON 01910; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf; D048031:JNK Mitogen-Activated Protein Kinases; D018631:ras Proteins; D017239:Paclitaxel; D005998:Glycine
keywords: ERK cascade; JNK cascade; Raf; Ras; Ras pathway; Sos; phosphorylation; rigosertib