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eIF4F controls ERK MAPK signaling in melanomas with BRAF and NRAS mutations.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Oct 29; Vol. 121 (44), pp. e2321305121. Date of Electronic Publication: 2024 Oct 22. - Publication Year :
- 2024
-
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.<br />Competing Interests: Competing interests statement:The authors declare no competing interest.
- Subjects :
- Humans
Cell Line, Tumor
Animals
Mice
Dual Specificity Phosphatase 6 metabolism
Dual Specificity Phosphatase 6 genetics
Extracellular Signal-Regulated MAP Kinases metabolism
Proto-Oncogene Proteins B-raf genetics
Proto-Oncogene Proteins B-raf metabolism
Melanoma genetics
Melanoma metabolism
Melanoma pathology
GTP Phosphohydrolases metabolism
GTP Phosphohydrolases genetics
MAP Kinase Signaling System genetics
Mutation
Membrane Proteins metabolism
Membrane Proteins genetics
Eukaryotic Initiation Factor-4F metabolism
Eukaryotic Initiation Factor-4F genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 121
- Issue :
- 44
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 39436655
- Full Text :
- https://doi.org/10.1073/pnas.2321305121