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,
• 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
• Names of Substances
• BRAF protein, human MeSH Browser
• DUSP6 protein, human MeSH Browser
• EIF4E protein, human MeSH Browser
• Eukaryotic Initiation Factor-4F * MeSH
• Extracellular Signal-Regulated MAP Kinases MeSH
• Dual Specificity Phosphatase 6 MeSH
• GTP Phosphohydrolases * MeSH
• Membrane Proteins * MeSH
• NRAS protein, human MeSH Browser
• Proto-Oncogene Proteins B-raf * MeSH