ArticleGenes & development2012
The intermediate-activity (L597V)BRAF mutant acts as an epistatic modifier of oncogenic RAS by enhancing signaling through the RAF/MEK/ERK pathway.
Article in Genes & development, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 65 citations in OpenAlex.
- Identification of a novel HER3 activating mutation homologous to EGFR-L858R in lung cancer.Oncotarget · 2016Trial
- Aberrant ERK signaling in astrocytes impairs learning and memory in RASopathy-associated BRAF mutant mouse models.The Journal of clinical investigation · 2025Article
- RASopathies - what they reveal about RAS/MAPK signaling in skeletal muscle development.Disease models & mechanisms · 2024Review
- An Assessment of the Therapeutic Landscape for the Treatment of Heart Disease in the RASopathies.Cardiovascular drugs and therapy · 2023Review
- Allosteric site variants affect GTP hydrolysis on Ras.Protein science : a publication of the Protein Society · 2023Article
- The seventh international RASopathies symposium: Pathways to a cure-expanding knowledge, enhancing research, and therapeutic discovery.American journal of medical genetics. Part A · 2022Article
- The RASopathies: from pathogenetics to therapeutics.Disease models & mechanisms · 2022Review
- Review
- Article
- Review
- The impact of RASopathy-associated mutations on CNS development in mice and humans.Molecular brain · 2019Review
- Development of Allosteric BRAF Peptide Inhibitors Targeting the Dimer Interface of BRAF.ACS chemical biology · 2019Article
- The Noonan Syndrome-linked Raf1L613V mutation drives increased glial number in the mouse cortex and enhanced learning.PLoS genetics · 2019Article
- Early detection of pre-malignant lesions in a KRASDisease models & mechanisms · 2019Article
- Over-expressed, N-terminally truncated BRAF is detected in the nucleus of cells with nuclear phosphorylated MEK and ERK.Heliyon · 2018Article
- Classifying BRAF alterations in cancer: new rational therapeutic strategies for actionable mutations.Oncogene · 2018Review
- Article
- Ras Signaling Regulates Stem Cells and Amelogenesis in the Mouse Incisor.Journal of dental research · 2017Article
- Article
- KRASBlood · 2017Article
Corrections and comments
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Authors and funding
12 authors at 4 institutions in 2 countries.
Funding
Abstract
(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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.