RAF protein-serine/threonine kinases: structure and regulation

Biochem Biophys Res Commun. 2010 Aug 27;399(3):313-7. doi: 10.1016/j.bbrc.2010.07.092. Epub 2010 Jul 30.

Abstract

A-RAF, B-RAF, and C-RAF are a family of three protein-serine/threonine kinases that participate in the RAS-RAF-MEK-ERK signal transduction cascade. This cascade participates in the regulation of a large variety of processes including apoptosis, cell cycle progression, differentiation, proliferation, and transformation to the cancerous state. RAS mutations occur in 15-30% of all human cancers, and B-RAF mutations occur in 30-60% of melanomas, 30-50% of thyroid cancers, and 5-20% of colorectal cancers. Activation of the RAF kinases requires their interaction with RAS-GTP along with dephosphorylation and also phosphorylation by SRC family protein-tyrosine kinases and other protein-serine/threonine kinases. The formation of unique side-to-side RAF dimers is required for full kinase activity. RAF kinase inhibitors are effective in blocking MEK1/2 and ERK1/2 activation in cells containing the oncogenic B-RAF Val600Glu activating mutation. RAF kinase inhibitors lead to the paradoxical increase in RAF kinase activity in cells containing wild-type B-RAF and wild-type or activated mutant RAS. C-RAF plays a key role in this paradoxical increase in downstream MEK-ERK activation.

Publication types

  • Review

MeSH terms

  • Humans
  • Mutation
  • Protein Conformation
  • Protein Multimerization
  • Proto-Oncogene Proteins A-raf / chemistry
  • Proto-Oncogene Proteins A-raf / genetics
  • Proto-Oncogene Proteins A-raf / metabolism*
  • Proto-Oncogene Proteins B-raf / chemistry
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins B-raf / metabolism*
  • Proto-Oncogene Proteins c-raf / chemistry
  • Proto-Oncogene Proteins c-raf / genetics
  • Proto-Oncogene Proteins c-raf / metabolism*

Substances

  • Proto-Oncogene Proteins A-raf
  • Proto-Oncogene Proteins B-raf
  • Proto-Oncogene Proteins c-raf