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

Kód výsledku v 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>

Nalezeny alternativní kódy

RIV/68081707:_____/24:00602073 RIV/00216224:14110/24:00137752 RIV/00159816:_____/24:00081597

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30204 - Oncology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2024

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Proceedings of the National Academy of Sciences of the United States of America

ISSN

0027-8424

e-ISSN

1091-6490

Svazek periodika

121

Číslo periodika v rámci svazku

44

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

12

Strana od-do

e2321305121

Kód UT WoS článku

001349500800002

EID výsledku v databázi Scopus

2-s2.0-85206962127