RAF inhibitor-induced KSR1/B-RAF binding and its effects on ERK cascade signaling

Curr Biol. 2011 Apr 12;21(7):563-8. doi: 10.1016/j.cub.2011.02.033. Epub 2011 Mar 31.


RAF kinase inhibitors can induce ERK cascade signaling by promoting dimerization of RAF family members in the presence of oncogenic or normally activated RAS. This interaction is mediated by a dimer interface region in the RAF kinase domain that is conserved in members of the ERK cascade scaffold family, kinase suppressor of RAS (KSR). In this study, we find that most RAF inhibitors also induce the binding of KSR1 to wild-type and oncogenic B-RAF proteins, including V600E B-RAF, but promote little complex formation between KSR1 and C-RAF. The inhibitor-induced KSR1/B-RAF interaction requires direct binding of the drug to B-RAF and is dependent on conserved dimer interface residues in each protein, but, unexpectedly, is not dependent on binding of B-RAF to activated RAS. Inhibitor-induced KSR/B-RAF complex formation can occur in the cytosol and is observed in normal mouse fibroblasts, as well as a variety of human cancer cell lines. Strikingly, we find that KSR1 competes with C-RAF for inhibitor-induced binding to B-RAF and, as a result, alters the effect of the inhibitors on ERK cascade signaling.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Carcinoma, Non-Small-Cell Lung
  • Cell Line, Tumor
  • Dimerization
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Humans
  • MAP Kinase Signaling System / drug effects*
  • Melanoma
  • Mice
  • Protein Binding
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinases / genetics
  • Protein Kinases / metabolism*
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins B-raf / metabolism*
  • Pyridines / metabolism
  • Pyridines / pharmacology
  • raf Kinases / antagonists & inhibitors*
  • raf Kinases / metabolism


  • L-779,450
  • Protein Kinase Inhibitors
  • Pyridines
  • Protein Kinases
  • KSR-1 protein kinase
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • raf Kinases
  • Extracellular Signal-Regulated MAP Kinases