1. ARAF protein kinase activates RAS by antagonizing its binding to RASGAP NF1
- Author
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Wenjing Su, Radha Mukherjee, Rona Yaeger, Jieun Son, Jianing Xu, Na Na, Neilawattie Merna Timaul, Jaclyn Hechtman, Viktoriya Paroder, Mika Lin, Marissa Mattar, Juan Qiu, Qing Chang, Huiyong Zhao, Jonathan Zhang, Megan Little, Yuta Adachi, Sae-Won Han, Barry S. Taylor, Hiromichi Ebi, Omar Abdel-Wahab, Elisa de Stanchina, Charles M. Rudin, Pasi A. Jänne, Frank McCormick, Zhan Yao, and Neal Rosen
- Subjects
ErbB Receptors ,Neurofibromin 1 ,ras GTPase-Activating Proteins ,Humans ,Guanosine Triphosphate ,Cell Biology ,Proto-Oncogene Proteins A-raf ,Molecular Biology ,Article ,Protein Binding ,Signal Transduction - Abstract
RAF protein kinases are effectors of the GTP-bound form of the small guanosine triphosphatase RAS and function by phosphorylating MEK. We showed here that expression of ARAF activated RAS in a kinase-independent manner. Binding of ARAF to RAS displaced the GTPase-activating protein NF1 and antagonized NF1-mediated inhibition of RAS. This reduced ERK-dependent inhibition of RAS and increased RAS-GTP. By this mechanism, ARAF regulated the duration and consequences of RTK-induced RAS activation and supported the RAS output of RTK-dependent tumor cells. In human lung cancers with EGFR mutation, amplification of ARAF was associated with acquired resistance to EGFR inhibitors, which was overcome by combining EGFR inhibitors with an inhibitor of the protein tyrosine phosphatase SHP2 to enhance inhibition of nucleotide exchange and RAS activation.
- Published
- 2022