C-Raf inhibits MAPK activation and transformation by B-Raf(V600E)

Mol Cell. 2009 Nov 13;36(3):477-86. doi: 10.1016/j.molcel.2009.10.017.

Abstract

Activating B-Raf mutations that deregulate the MAPK pathway commonly occur in cancer. Whether additional proteins modulate the enzymatic activity of oncogenic B-Raf is unknown. Here we show that the proto-oncogene C-Raf paradoxically inhibits B-Raf(V600E) kinase activity through the formation of B-Raf(V600E)-C-Raf complexes. Although all Raf family members associate with oncogenic B-Raf, this inhibitory effect is specific to C-Raf. Indeed, a B-Raf(V600E) isoform with impaired ability to interact with C-Raf exhibits elevated oncogenic potential. Human melanoma cells expressing B-Raf(V600E) display a reduced C-Raf:B-Raf ratio, and further suppression of C-Raf increases MAPK activation and proliferation. Conversely, ectopic C-Raf expression lowers ERK phosphorylation and proliferation. Moreover, both oncogenic Ras and Sorafenib stabilize B-Raf(V600E)-C-Raf complexes, thereby impairing MAPK activation. This inhibitory function of C-Raf on B-Raf(V600E)-mediated MAPK activation may explain the lack of co-occurrence of B-Raf(V600E) and oncogenic Ras mutations, and influence the successful clinical development of small molecule inhibitors for B-Raf(V600E)-driven cancers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzenesulfonates / pharmacology
  • Blotting, Western
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics
  • Enzyme Activation
  • Humans
  • Immunoprecipitation
  • MAP Kinase Signaling System*
  • Melanoma / genetics
  • Melanoma / metabolism
  • Melanoma / pathology
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism*
  • Mutation
  • NIH 3T3 Cells
  • Niacinamide / analogs & derivatives
  • Phenylurea Compounds
  • Phosphorylation
  • Protein Binding / drug effects
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins B-raf / metabolism*
  • Proto-Oncogene Proteins c-raf / genetics
  • Proto-Oncogene Proteins c-raf / metabolism*
  • Pyridines / pharmacology
  • Sorafenib
  • Transfection
  • ras Proteins / genetics
  • ras Proteins / metabolism

Substances

  • Benzenesulfonates
  • Phenylurea Compounds
  • Protein Kinase Inhibitors
  • Pyridines
  • Niacinamide
  • Sorafenib
  • Proto-Oncogene Proteins B-raf
  • Proto-Oncogene Proteins c-raf
  • Mitogen-Activated Protein Kinases
  • ras Proteins