• What is BRAF?
  • BRAF in GIST
  • Clinical Trials

BRAF

BRAF belongs to a family of serine-threonine protein kinases that includes ARAF, BRAF, and CRAF (RAF1). RAF kinases are central mediators in the MAP kinase signaling cascade and exert their effect predominantly through phosphorylation and activation of MEK. This occurs following the dimerization (hetero- or homo-) of the RAF molecules. As part of the MAP kinase pathway, RAF is involved in many cellular processes, including cell proliferation, differentiation, and transcriptional regulation.

Mutant BRAF has been implicated in the pathogenesis of several cancers, including melanoma, non-small cell lung cancer, colorectal cancer, papillary thyroid cancer, and ovarian cancer (Davies et al. 2002). Mutant BRAF has been observed in these cancers as well as glioma and gastrointestinal stromal tumor (GIST).

mapk-pk13.png

Figure 1. Schematic of the MAPK and PI3K pathways. Growth factor binding to receptor tyrosine kinase results in activation of the MAPK signaling pathway (RAS-RAF-MEK-ERK) and the PI3K pathway (PI3K-AKT-mTOR). The letter "K" within the schema denotes the tyrosine kinase domain.

Related Pathways

Contributors: Christine M. Lovly, M.D., Ph.D., Leora Horn, M.D., M.Sc., William Pao, M.D., Ph.D. (through April 2014)

Suggested Citation: Lovly, C., L. Horn, W. Pao. 2015. BRAF. My Cancer Genome https://www.padiracinnovation.org/content/disease/gist/braf/?tab=0 (Updated December 7).

Last Updated: December 7, 2015

BRAF in GIST

Somatic mutations in BRAF have been found in <1% of GIST (Agaimy et al. 2009), and are similar to those seen in melanoma. In particular, the most common BRAF mutations are missense mutations which introduce an amino acid substitution at valine 600, in particular V600E (valine to glutamic acid). The result of these mutations is enhanced BRAF kinase activity and increased phosphorylation of downstream targets, particularly MEK (Hubbard 2004).

As in melanoma, BRAF mutations in GIST are non-overlapping with other oncogenic mutations found in GIST (e.g., KIT or PDGFRA mutations). BRAF mutations appear to be associated with a high risk of malignancy and resistance to presently available KIT/PDGFRA tyrosine kinase inhibitors (Agaram et al. 2008).

Contributors: Robert G. Maki, M.D., Ph.D., FACP, Vicki Keedy, M.D., M.S.C.I.

Suggested Citation: Maki, R., V. Keedy. 2015. BRAF in GIST. My Cancer Genome https://www.padiracinnovation.org/content/disease/gist/braf/ (Updated June 18).

Last Updated: June 18, 2015

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