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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

. 2024 ; 121 (44) : e2321305121. [pub] 20241022

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc25003778

Grantová podpora
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)

E-zdroje Online Plný text

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Open Access Digital Library od 1915-01-01

Odkazy

PubMed 39436655
DOI 10.1073/pnas.2321305121
Knihovny.cz E-zdroje

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.

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