eIF4F controls ERK MAPK signaling in melanomas with BRAF and NRAS mutations
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985904%3A_____%2F24%3A00602073" target="_blank" >RIV/67985904:_____/24:00602073 - isvavai.cz</a>
Alternative codes found
RIV/68081707:_____/24:00602073 RIV/00216224:14110/24:00137752 RIV/00159816:_____/24:00081597
Result on the web
<a href="https://www.pnas.org/doi/10.1073/pnas.2321305121" target="_blank" >https://www.pnas.org/doi/10.1073/pnas.2321305121</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1073/pnas.2321305121" target="_blank" >10.1073/pnas.2321305121</a>
Alternative languages
Result language
angličtina
Original language name
eIF4F controls ERK MAPK signaling in melanomas with BRAF and NRAS mutations
Original language description
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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30204 - Oncology
Result continuities
Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2024
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Proceedings of the National Academy of Sciences of the United States of America
ISSN
0027-8424
e-ISSN
1091-6490
Volume of the periodical
121
Issue of the periodical within the volume
44
Country of publishing house
US - UNITED STATES
Number of pages
12
Pages from-to
e2321305121
UT code for WoS article
001349500800002
EID of the result in the Scopus database
2-s2.0-85206962127