K128 ubiquitination constrains RAS activity by expanding its binding interface with GAP proteins

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00843989%3A_____%2F24%3AE0111040" target="_blank" >RIV/00843989:_____/24:E0111040 - isvavai.cz</a>

Výsledek na webu

<a href="https://www.embopress.org/doi/full/10.1038/s44318-024-00146-w" target="_blank" >https://www.embopress.org/doi/full/10.1038/s44318-024-00146-w</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/s44318-024-00146-w" target="_blank" >10.1038/s44318-024-00146-w</a>

Jazyk výsledku

angličtina

Název v původním jazyce

K128 ubiquitination constrains RAS activity by expanding its binding interface with GAP proteins

Popis výsledku v původním jazyce

The RAS pathway is among the most frequently activated signaling nodes in cancer. However, the mechanisms that alter RAS activity in human pathologies are not entirely understood. The most prevalent post-translational modification within the GTPase core domain of NRAS and KRAS is ubiquitination at lysine 128 (K128), which is significantly decreased in cancer samples compared to normal tissue. Here, we found that K128 ubiquitination creates an additional binding interface for RAS GTPase-activating proteins (GAPs), NF1 and RASA1, thus increasing RAS binding to GAP proteins and promoting GAP-mediated GTP hydrolysis. Stimulation of cultured cancer cells with growth factors or cytokines transiently induces K128 ubiquitination and restricts the extent of wild-type RAS activation in a GAP-dependent manner. In KRAS mutant cells, K128 ubiquitination limits tumor growth by restricting RAL/ TBK1 signaling and negatively regulating the autocrine circuit induced by mutant KRAS. Reduction of K128 ubiquitination activates both wild-type and mutant RAS signaling and elicits a senescence-associated secretory phenotype, promoting RAS-driven pancreatic tumorigenesis.

Název v anglickém jazyce

K128 ubiquitination constrains RAS activity by expanding its binding interface with GAP proteins

Popis výsledku anglicky

The RAS pathway is among the most frequently activated signaling nodes in cancer. However, the mechanisms that alter RAS activity in human pathologies are not entirely understood. The most prevalent post-translational modification within the GTPase core domain of NRAS and KRAS is ubiquitination at lysine 128 (K128), which is significantly decreased in cancer samples compared to normal tissue. Here, we found that K128 ubiquitination creates an additional binding interface for RAS GTPase-activating proteins (GAPs), NF1 and RASA1, thus increasing RAS binding to GAP proteins and promoting GAP-mediated GTP hydrolysis. Stimulation of cultured cancer cells with growth factors or cytokines transiently induces K128 ubiquitination and restricts the extent of wild-type RAS activation in a GAP-dependent manner. In KRAS mutant cells, K128 ubiquitination limits tumor growth by restricting RAL/ TBK1 signaling and negatively regulating the autocrine circuit induced by mutant KRAS. Reduction of K128 ubiquitination activates both wild-type and mutant RAS signaling and elicits a senescence-associated secretory phenotype, promoting RAS-driven pancreatic tumorigenesis.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

<a href="/cs/project/GA22-26981S" target="_blank" >GA22-26981S: Studium regulačních komponent translace imunoglobulinu u mnohočetného myelomu jako nový terapeutický cíl</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2024

Kód důvěrnosti údajů

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

Název periodika

The EMBO journal

ISSN

0261-4189

e-ISSN

1460-2075

Svazek periodika

43

Číslo periodika v rámci svazku

14

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

16

Strana od-do

2862-2877

Kód UT WoS článku

001242788300001

EID výsledku v databázi Scopus

2-s2.0-85195493518