MassIVE MSV000088285

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CRAF dimerization with ARAF regulates KRAS driven tumors

Description

KRAS, mutated in ~30% of all cancers, activates the RAF-MEK-ERK signaling cascade. It has previously been shown that 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 rescued growth inhibition suggesting that dimerization but not kinase activity is required. Quantitative proteomics demonstrated enrichment of CRAF:ARAF dimers in KRAS mutant cells and depletion of both CRAF and ARAF rescued the CRAF loss phenotype. Mechanistically, CRAF depletion caused sustained ERK activation and induction of cell cycle arrest. Treatment with low dose MEK or ERK inhibitor rescued 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 dimerization or degrading CRAF may have therapeutic benefit. [doi:10.25345/C5527D] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: APMS ; affinity purification mass spectrometry ; CRAF ; IP ; ARAF ; KRAS

Contact

Principal Investigators:
(in alphabetical order)
Shiva Malek, Genentech, United States
Submitting User: hinklet
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