CRAF dimerization with ARAF regulates KRAS-driven tumor growth.
Cell Rep
; 38(6): 110351, 2022 02 08.
Article
en En
| MEDLINE
| ID: mdl-35139374
ABSTRACT
KRAS, which is mutated in â¼30% of all cancers, activates the RAF-MEK-ERK signaling cascade. CRAF is required for growth of KRAS mutant lung tumors, but the requirement for CRAF kinase activity is unknown. Here, we show that subsets of KRAS mutant tumors are dependent on CRAF for growth. Kinase-dead but not dimer-defective CRAF rescues growth inhibition, suggesting that dimerization but not kinase activity is required. Quantitative proteomics demonstrates increased levels of CRAFARAF dimers in KRAS mutant cells, and depletion of both CRAF and ARAF rescues the CRAF-loss phenotype. Mechanistically, CRAF depletion causes sustained ERK activation and induction of cell-cycle arrest, while treatment with low-dose MEK or ERK inhibitor rescues the CRAF-loss phenotype. Our studies highlight the role of CRAF in regulating MAPK signal intensity to promote tumorigenesis downstream of mutant KRAS and suggest that disrupting CRAF dimerization or degrading CRAF may have therapeutic benefit.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Proteínas Proto-Oncogénicas p21(ras)
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Dimerización
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Carcinogénesis
Límite:
Animals
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Humans
Idioma:
En
Revista:
Cell Rep
Año:
2022
Tipo del documento:
Article
País de afiliación:
Estados Unidos