Signaling threshold regulation by the Ras effector IMP

J Biol Chem. 2009 Apr 24;284(17):11007-11. doi: 10.1074/jbc.R800082200. Epub 2008 Dec 17.


The Ras effector and E3 ligase family member IMP (impedes mitogenic signal propagation) acts as a steady-state resistor within the Raf-MEK-ERK kinase module. IMP concentrations are directly regulated by Ras, through induction of autoubiquitination, to permit productive Raf-MEK complex assembly. Inhibition of Raf-MEK pathway activation by IMP occurs through the inactivation of KSR, a scaffold/adapter protein that couples activated Raf to its substrate MEK1. The capacity of IMP to inhibit signal propagation through Raf to MEK is, in part, a consequence of disrupting KSR1 homo-oligomerization and c-Raf-B-Raf hetero-oligomerization. These observations suggest that IMP functions as a threshold modulator, controlling sensitivity of the cascade to stimulus by directly limiting the assembly of functional KSR1-dependent Raf-MEK complexes.

Publication types

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

MeSH terms

  • Animals
  • Dimerization
  • Humans
  • MAP Kinase Kinase 1 / metabolism
  • Models, Biological
  • Protein Binding
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins B-raf / metabolism
  • Proto-Oncogene Proteins c-raf / metabolism
  • Signal Transduction*
  • Substrate Specificity
  • Ubiquitin-Protein Ligases / metabolism*
  • ras Proteins / metabolism*


  • BRAP protein, human
  • Ubiquitin-Protein Ligases
  • Proto-Oncogene Proteins B-raf
  • Proto-Oncogene Proteins c-raf
  • MAP Kinase Kinase 1
  • ras Proteins