Wild-type and mutant B-RAF activate C-RAF through distinct mechanisms involving heterodimerization

Mol Cell. 2005 Dec 22;20(6):963-9. doi: 10.1016/j.molcel.2005.10.022.


The protein kinase B-RAF is mutated in approximately 7% of human cancers. Most mutations are activating, but, surprisingly, a small number have reduced kinase activity. However, the latter can still stimulate cellular signaling through the MEK-ERK pathway because they activate the related family member C-RAF. We examine the mechanism underlying C-RAF activation by B-RAF. We show that C-RAF is activated in the cytosol in a RAS-independent manner that requires activation segment phosphorylation and binding of 14-3-3 to C-RAF. We show that wild-type B-RAF forms a complex with C-RAF in a RAS-dependent manner, whereas the mutants bind independently of RAS. Importantly, we show that wild-type B-RAF can also activate C-RAF. Our data suggest that B-RAF activates C-RAF through a mechanism involving 14-3-3 mediated heterooligomerization and C-RAF transphosphorylation. Thus, we have identified a B-RAF-C-RAF-MEK-ERK cascade that signals not only in cancer but also in normal cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 14-3-3 Proteins / metabolism
  • Autocrine Communication
  • Cytoplasm / enzymology
  • Dimerization
  • Enzyme Activation
  • Growth Substances / metabolism
  • Humans
  • Isoenzymes / chemistry
  • Isoenzymes / genetics
  • Isoenzymes / metabolism*
  • MAP Kinase Signaling System / physiology*
  • Models, Molecular
  • Multiprotein Complexes
  • Mutation
  • Neoplasms / enzymology
  • Protein Conformation*
  • 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*
  • ras Proteins / genetics
  • ras Proteins / metabolism


  • 14-3-3 Proteins
  • Growth Substances
  • Isoenzymes
  • Multiprotein Complexes
  • Proto-Oncogene Proteins B-raf
  • Proto-Oncogene Proteins c-raf
  • ras Proteins