Metabolic stress regulates ERK activity by controlling KSR-RAF heterodimerization

0488412 - BFÚ 2018 RIV US eng J - Článek v odborném periodiku
Verlande, A. - Krafčíková, M. - Potěšil, D. - Trantírek, L. - Zdráhal, Z. - Elkalaf, M. - Trnka, J. - Souček, Karel - Rauch, N. - Rauch, J. - Kolch, W. - Uldrijan, S.
Metabolic stress regulates ERK activity by controlling KSR-RAF heterodimerization.
Embo Reports. Roč. 19, č. 2 (2018), s. 320-336. ISSN 1469-221X. E-ISSN 1469-3178
Institucionální podpora: RVO:68081707
Klíčová slova: cell-cycle arrest * 14-3-3 binding * kinase suppressor
Obor OECD: Biochemistry and molecular biology
Impakt faktor: 8.383, rok: 2018

Altered cell metabolism is a hallmark of cancer, and targeting specific metabolic nodes is considered an attractive strategy for cancer therapy. In this study, we evaluate the effects of metabolic stressors on the deregulated ERK pathway in melanoma cells bearing activating mutations of the NRAS or BRAF oncogenes. We report that metabolic stressors promote the dimerization of KSR proteins with CRAF in NRAS-mutant cells, and with oncogenic BRAF in BRAF(V600E)-mutant cells, thereby enhancing ERK pathway activation. Despite this similarity, the two genomic subtypes react differently when a higher level of metabolic stress is induced. In NRAS-mutant cells, the ERK pathway is even more stimulated, while it is strongly downregulated in BRAF(V600E)-mutant cells. We demonstrate that this is caused by the dissociation of mutant BRAF from KSR and is mediated by activated AMPK. Both types of ERK regulation nevertheless lead to cell cycle arrest. Besides studying the effects of the metabolic stressors on ERK pathway activity, we also present data suggesting that for efficient therapies of both genomic melanoma subtypes, specific metabolic targeting is necessary.
Trvalý link: http://hdl.handle.net/11104/0282992