2. Academic Validation
  3. eIF4F controls ERK MAPK signaling in melanomas with BRAF and NRAS mutations

eIF4F controls ERK MAPK signaling in melanomas with BRAF and NRAS mutations

  • Proc Natl Acad Sci U S A. 2024 Oct 29;121(44):e2321305121. doi: 10.1073/pnas.2321305121.
Barbora Valcikova # 1 2,  Natalia Vadovicova # 1 2,  Karolina Smolkova 1 2,  Magdalena Zacpalova 1,  Pavel Krejci 1 2 3,  Shannon Lee 4,  Jens Rauch 4 5,  Walter Kolch 4 6,  Alexander von Kriegsheim 7,  Anna Dorotikova 1 2,  Zdenek Andrysik 1 8,  Rachel Vichova 9,  Ondrej Vacek 2 9 10,  Karel Soucek 2 9 10,  Stjepan Uldrijan 1 2
Affiliations

Affiliations

  • 1 Department of Biology, Faculty of Medicine, Masaryk University, Brno 62500, Czech Republic.
  • 2 International Clinical Research Center, St. Anne's University Hospital, Brno 60200, Czech Republic.
  • 3 Laboratory of Cell Signaling, Institute of Animal Physiology and Genetics of the Czech Academy of Sciences, Brno 60200, Czech Republic.
  • 4 Systems Biology Ireland, School of Medicine, University College Dublin, Dublin D04 V1W8, Ireland.
  • 5 School of Biomolecular and Biomedical Science, University College Dublin, Dublin D04 V1W8, Ireland.
  • 6 Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin D04 V1W8, Ireland.
  • 7 Cancer Research UK Scotland Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XR, United Kingdom.
  • 8 Department of Pharmacology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045.
  • 9 Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno 61200, Czech Republic.
  • 10 Department of Experimental Biology, Faculty of Science, Masaryk University, Brno 62500, Czech Republic.
  • # Contributed equally.
PMID: 39436655 DOI: 10.1073/pnas.2321305121
Abstract

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.

Keywords

DUSP6; ERK; MAP kinase; eIF4F; melanoma.

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