ARAF protein kinase activates RAS by antagonizing its binding to RASGAP NF1 Journal Article
| Authors: | Su, W.; Mukherjee, R.; Yaeger, R.; Son, J.; Xu, J.; Na, N.; Timaul, N. M.; Hechtman, J.; Paroder, V.; Lin, M.; Mattar, M.; Qiu, J.; Chang, Q.; Zhao, H.; Zhang, J.; Little, M.; Adachi, Y.; Han, S. W.; Taylor, B. S.; Ebi, H.; Abdel-Wahab, O.; de Stanchina, E.; Rudin, C. M.; Jänne, P. A.; McCormick, F.; Yao, Z.; Rosen, N. |
| Article Title: | ARAF protein kinase activates RAS by antagonizing its binding to RASGAP NF1 |
| 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. © 2022 The Author(s) |
| Keywords: | signal transduction; genetics; raf protein; metabolism; protein kinases; epidermal growth factor receptor; protein binding; guanosine triphosphatase activating protein; guanosine triphosphate; drug sensitivity; protein kinase; raf kinases; nf1; receptor tyrosine kinase inhibitor; erbb receptors; humans; human; erk signaling; ras-gtp; ras gtpase-activating proteins; araf |
| Journal Title: | Molecular Cell |
| Volume: | 82 |
| Issue: | 13 |
| ISSN: | 1097-2765 |
| Publisher: | Cell Press |
| Date Published: | 2022-07-07 |
| Start Page: | 2443 |
| End Page: | 2457.e7 |
| Language: | English |
| DOI: | 10.1016/j.molcel.2022.04.034 |
| PUBMED: | 35613620 |
| PROVIDER: | scopus |
| PMCID: | PMC9271631 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 August 2022 -- Source: Scopus |
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