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The intermediate-activity L597V BRAF mutant acts as an epistatic modifier of oncogenic RAS by enhancing signaling through the RAF/MEK/ERK pathway

2012; Cold Spring Harbor Laboratory Press; Volume: 26; Issue: 17 Linguagem: Inglês

10.1101/gad.193458.112

1549-5477

Catherine Andreadi, Lai-Kay Maggie Cheung, Susan Giblett, B. Patel, Hong Jin, Kathryn Mercer, Tamihiro Kamata, Pearl Lee, Alexander Williams, Martin McMahon, Richard Marais, Catrin Pritchard,

Protein Kinase Regulation and GTPase Signaling

L597V BRAF mutations are acquired somatically in human cancer samples and are frequently coincident with RAS mutations. Germline L597V BRAF mutations are also found in several autosomal dominant developmental conditions known as RASopathies, raising the important question of how the same mutation can contribute to both pathologies. Using a conditional knock-in mouse model, we show that endogenous expression of L597V Braf leads to approximately twofold elevated Braf kinase activity and weak activation of the Mek/Erk pathway. This is associated with induction of RASopathy hallmarks including cardiac abnormalities and facial dysmorphia but is not sufficient for tumor formation. We combined L597V Braf with G12D Kras and found that L597V Braf modified G12D Kras oncogenesis such that fibroblast transformation and lung tumor development were more reminiscent of that driven by the high-activity V600E Braf mutant. Mek/Erk activation levels were comparable with those driven by V600E Braf in the double-mutant cells, and the gene expression signature was more similar to that induced by V600E Braf than G12D Kras. However, unlike V600E Braf, Mek/Erk pathway activation was mediated by both Craf and Braf, and ATP-competitive RAF inhibitors induced paradoxical Mek/Erk pathway activation. Our data show that weak activation of the Mek/Erk pathway underpins RASopathies, but in cancer, L597V Braf epistatically modifies the transforming effects of driver oncogenes.