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eIF4F controls ERK MAPK signaling in melanomas with BRAF and NRAS mutations
B. Valcikova, N. Vadovicova, K. Smolkova, M. Zacpalova, P. Krejci, S. Lee, J. Rauch, W. Kolch, A. von Kriegsheim, A. Dorotikova, Z. Andrysik, R. Vichova, O. Vacek, K. Soucek, S. Uldrijan
Language English Country United States
Document type Journal Article
Grant support
LX22NPO5102
European Commission (EC)
18/SPP/3522
Science Foundation Ireland (SFI)
GA22-30397S
Grantová Agentura České Republiky (GAČR)
CZ.02.1.01/0.0/0.0/16_019/0000868
EC | European Regional Development Fund (ERDF)
208402/Z/17
Wellcome Trust (WT)
Wellcome Trust - United Kingdom
GA20-22984S
Grantová Agentura České Republiky (GAČR)
NLK
Free Medical Journals
from 1915 to 6 months ago
Freely Accessible Science Journals
from 1915 to 6 months ago
PubMed Central
from 1915 to 6 months ago
Europe PubMed Central
from 1915 to 6 months ago
Open Access Digital Library
from 1915-01-01
Open Access Digital Library
from 1915-01-15
- MeSH
- Eukaryotic Initiation Factor-4F * metabolism genetics MeSH
- Extracellular Signal-Regulated MAP Kinases metabolism MeSH
- Dual Specificity Phosphatase 6 metabolism genetics MeSH
- GTP Phosphohydrolases * metabolism genetics MeSH
- Humans MeSH
- MAP Kinase Signaling System * genetics MeSH
- Melanoma * genetics metabolism pathology MeSH
- Membrane Proteins * metabolism genetics MeSH
- Mutation * MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Proto-Oncogene Proteins B-raf * genetics metabolism MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
The eIF4F translation initiation complex plays a critical role in melanoma resistance to clinical BRAF and MEK inhibitors. In this study, we uncover a function of eIF4F in the negative regulation of the rat sarcoma (RAS)/rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) signaling pathway. We demonstrate that eIF4F is essential for controlling ERK signaling intensity in treatment-naïve melanoma cells harboring BRAF or NRAS mutations. Specifically, the dual-specificity phosphatase DUSP6/MKP3, which acts as a negative feedback regulator of ERK activity, requires continuous production in an eIF4F-dependent manner to limit excessive ERK signaling driven by oncogenic RAF/RAS mutations. Treatment with small-molecule eIF4F inhibitors disrupts the negative feedback control of MAPK signaling, leading to ERK hyperactivation and EGR1 overexpression in melanoma cells in vitro and in vivo. Furthermore, our quantitative analyses reveal a high spare signaling capacity in the ERK pathway, suggesting that eIF4F-dependent feedback keeps the majority of ERK molecules inactive under normal conditions. Overall, our findings highlight the crucial role of eIF4F in regulating ERK signaling flux and suggest that pharmacological eIF4F inhibitors can disrupt the negative feedback control of MAPK activity in melanomas with BRAF and NRAS activating mutations.
Department of Biology Faculty of Medicine Masaryk University Brno 62500 Czech Republic
Department of Experimental Biology Faculty of Science Masaryk University Brno 62500 Czech Republic
International Clinical Research Center St Anne's University Hospital Brno 60200 Czech Republic
School of Biomolecular and Biomedical Science University College Dublin Dublin D04 V1W8 Ireland
Systems Biology Ireland School of Medicine University College Dublin Dublin D04 V1W8 Ireland
References provided by Crossref.org
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