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RAF Inhibitor-Induced KSR1/B-RAF Binding and Its Effects on ERK Cascade Signaling

  1. Author:
    McKay, M. M. M. M. M.
    Ritt, D. A.
    Morrison, D. K.

  2. Author Address

    [McKay, MM McKay, MM; Ritt, DA; Morrison, DK] NCI, Lab Cell & Dev Signaling, Ctr Canc Res, Frederick, MD 21702 USA;Morrison, DK (reprint author), NCI, Lab Cell & Dev Signaling, Ctr Canc Res, Frederick, MD 21702 USA;morrisod@mail.nih.gov
    1. Year: 2011
    2. Date: Apr
  2. Journal: Current Biology
    1. 21
    2. 7
    3. Pages: 563-568
  4. Type of Article: Article
  5. ISSN: 0960-9822
  1. Abstract:

    RAF kinase inhibitors can induce ERK cascade signaling by promoting dimerization of RAF family members in the presence of oncogenic or normally activated RAS [1-3]. 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) [4,5]. 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.

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External Sources

  1. View Full Text
  2. DOI: 10.1016/j.cub.2011.02.033
  3. View record in Web of Science®
  4. WOS: 000289662600018

Library Notes

  1. Fiscal Year: FY2010-2011
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