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eIF4F controls ERK MAPK signaling in melanomas with BRAF and NRAS mutations
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SYSNO ASEP 0602073 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title eIF4F controls ERK MAPK signaling in melanomas with BRAF and NRAS mutations Author(s) Valčíková, B. (CZ)
Vadovičová, N. (CZ)
Smolková, K. (CZ)
Zacpalová, M. (CZ)
Krejčí, Pavel (UZFG-Y) ORCID
Lee, S. (IE)
Rauch, J. (DE)
Kolch, W. (IE)
von Kriegsheim, A. (GB)
Dorotíková, A. (CZ)
Andrysík, Z. (CZ)
Víchová, Ráchel (BFU-R)
Vacek, Ondřej (BFU-R) ORCID
Souček, Karel (BFU-R) RID, ORCID
Uldrijan, S. (CZ)Article number e2321305121 Source Title Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences - ISSN 0027-8424
Roč. 121, č. 44 (2024)Number of pages 12 s. Publication form Print - P Language eng - English Country US - United States Keywords melanoma ; ERK ; MAP kinase OECD category Oncology R&D Projects GA20-22984S GA ČR - Czech Science Foundation (CSF) LX22NPO5102 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Method of publishing Open access Institutional support UZFG-Y - RVO:67985904 ; BFU-R - RVO:68081707 UT WOS 001349500800002 EID SCOPUS 85206962127 DOI https://doi.org/10.1073/pnas.2321305121 Annotation 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- na & iuml,ve 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. Workplace Institute of Animal Physiology and Genetics Contact Jana Zásmětová, knihovna@iapg.cas.cz, Tel.: 315 639 554 Year of Publishing 2025 Electronic address https://www.pnas.org/doi/10.1073/pnas.2321305121
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