RKIP regulates MAP kinase signaling in cells with defective B-Raf activity

Cell Signal. 2013 May;25(5):1156-65. doi: 10.1016/j.cellsig.2013.02.005. Epub 2013 Feb 14.


MAP kinase (MAPK) signaling results from activation of Raf kinases in response to external or internal stimuli. Here, we demonstrate that Raf kinase inhibitory protein (RKIP) regulates the activation of MAPK when B-Raf signaling is defective. We used multiple models including mouse embryonic fibroblasts (MEFs) and primary keratinocytes from RKIP- or Raf-deficient mice as well as allografts in mice to investigate the mechanism. Loss of B-Raf protein or activity significantly reduces MAPK activation in these cells. We show that RKIP depletion can rescue the compromised ERK activation and promote proliferation, and this rescue occurs through a Raf-1 dependent mechanism. These results provide formal evidence that RKIP is a bona fide regulator of Raf-1. We propose a new model in which RKIP plays a key role in regulating the ability of cells to signal through Raf-1 to ERK in B-Raf compromised cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation
  • Cells, Cultured
  • Enzyme Activation
  • MAP Kinase Signaling System
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Mitogen-Activated Protein Kinases / metabolism*
  • Phosphatidylethanolamine Binding Protein / antagonists & inhibitors
  • Phosphatidylethanolamine Binding Protein / genetics
  • Phosphatidylethanolamine Binding Protein / metabolism*
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins B-raf / metabolism*
  • Proto-Oncogene Proteins c-raf / antagonists & inhibitors
  • Proto-Oncogene Proteins c-raf / genetics
  • Proto-Oncogene Proteins c-raf / metabolism
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Signal Transduction


  • Phosphatidylethanolamine Binding Protein
  • RNA, Small Interfering
  • Raf kinase inhibitory protein, mouse
  • Proto-Oncogene Proteins B-raf
  • Proto-Oncogene Proteins c-raf
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases