| Literature DB >> 35613620 |
Wenjing Su1, Radha Mukherjee1, Rona Yaeger2, Jieun Son3, Jianing Xu1, Na Na1, Neilawattie Merna Timaul1, Jaclyn Hechtman4, Viktoriya Paroder5, Mika Lin3, Marissa Mattar1, Juan Qiu1, Qing Chang1, Huiyong Zhao1, Jonathan Zhang1, Megan Little1, Yuta Adachi6, Sae-Won Han7, Barry S Taylor8, Hiromichi Ebi9, Omar Abdel-Wahab10, Elisa de Stanchina1, Charles M Rudin2, Pasi A Jänne3, Frank McCormick11, Zhan Yao12, Neal Rosen13.
Abstract
RAF protein kinases are effectors of the GTP-bound form of small guanosine triphosphatase RAS and function by phosphorylating MEK. We showed here that the 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.Entities:
Keywords: ARAF; ERK signaling; NF1; RAS-GTP; drug sensitivity; receptor tyrosine kinase inhibitor
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Year: 2022 PMID： 35613620 PMCID： PMC9271631 DOI： 10.1016/j.molcel.2022.04.034
Source DB: PubMed Journal: Mol Cell ISSN： 1097-2765 Impact factor: 19.328