RAS-dependent RAF-MAPK hyperactivation by pathogenic RIT1 is a therapeutic target in Noonan syndrome-associated cardiac hypertrophy.
Journal
Science advances
ISSN: 2375-2548
Titre abrégé: Sci Adv
Pays: United States
ID NLM: 101653440
Informations de publication
Date de publication:
14 07 2023
14 07 2023
Historique:
medline:
17
7
2023
pubmed:
14
7
2023
entrez:
14
7
2023
Statut:
ppublish
Résumé
RIT1 is a RAS guanosine triphosphatase (GTPase) that regulates different aspects of signal transduction and is mutated in lung cancer, leukemia, and in the germline of individuals with Noonan syndrome. Pathogenic RIT1 proteins promote mitogen-activated protein kinase (MAPK) hyperactivation; however, this mechanism remains poorly understood. Here, we show that RAF kinases are direct effectors of membrane-bound mutant RIT1 necessary for MAPK activation. We identify critical residues in RIT1 that facilitate interaction with membrane lipids and show that these are necessary for association with RAF kinases and MAPK activation. Although mutant RIT1 binds to RAF kinases directly, it fails to activate MAPK signaling in the absence of classical RAS proteins. Consistent with aberrant RAF/MAPK activation as a driver of disease, we show that pathway inhibition alleviates cardiac hypertrophy in a mouse model of
Identifiants
pubmed: 37450595
doi: 10.1126/sciadv.adf4766
pmc: PMC10348673
doi:
Substances chimiques
Mitogen-Activated Protein Kinases
EC 2.7.11.24
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
eadf4766Subventions
Organisme : NCI NIH HHS
ID : 75N91019D00024
Pays : United States
Organisme : NCI NIH HHS
ID : F31 CA265066
Pays : United States
Organisme : NCI NIH HHS
ID : R00 CA245122
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA197709
Pays : United States
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