Journal article

Publication year: 2014

Journal: Science Signaling

Volume number: 7

Issue number: 337

ISSN: 1945-0877

eISSN: 1937-9145

DOI Link: https://doi.org/10.1126/scisignal.2005484

Publisher: American Association for the Advancement of Science

Abstract: 
The RAF family of kinases mediates RAS signaling, and RAF inhibitors can be effective for treating tumors with BRAF(V600E) mutant protein. However, RAF inhibitors paradoxically accelerate metastasis in RAS-mutant tumors and become ineffective in BRAF(V600E) tumors because of reactivation of downstream mitogen-activated protein kinase (MAPK) signaling. We found that the RAF isoform ARAF has an obligatory role in promoting MAPK activity and cell migration in a cell type-dependent manner. Knocking down ARAF prevented the activation of MAPK kinase 1 (MEK1) and extracellular signal-regulated kinase 1 and 2 (ERK1/2) and decreased the number of protrusions from tumor cell spheroids in three-dimensional culture that were induced by BRAF(V600E)-specific or BRAF/CRAF inhibitors (GDC-0879 and sorafenib, respectively). RAF inhibitors induced the homodimerization of ARAF and the heterodimerization of BRAF with CRAF and the scaffolding protein KSR1. In a purified protein solution, recombinant proteins of the three RAF isoforms competed for binding to MEK1. In cells in culture, over-expressing mutants of ARAF that could not homodimerize impaired the interaction between ARAF and endogenous MEK1 and thus prevented the subsequent activation of MEK1 and ERK1/2. Our findings reveal a new role for ARAF in directly activating the MAPK cascade and promoting tumor cell invasion and suggest a new therapeutic target for RAS- and RAF-mediated cancers.

Harvard Citation style: Mooz, J., Oberoi-Khanuja, T., Harms, G., Wang, W., Jaiswal, B., Seshagiri, S., et al. (2014) Dimerization of the kinase ARAF promotes MAPK pathway activation and cell migration, Science Signaling, 7(337), Article ra73. https://doi.org/10.1126/scisignal.2005484

APA Citation style: Mooz, J., Oberoi-Khanuja, T., Harms, G., Wang, W., Jaiswal, B., Seshagiri, S., Tikkanen, R., & Rajalingam, K. (2014). Dimerization of the kinase ARAF promotes MAPK pathway activation and cell migration. Science Signaling. 7(337), Article ra73. https://doi.org/10.1126/scisignal.2005484