IMP modulates KSR1-dependent multivalent complex formation to specify ERK1/2 pathway activation and response thresholds

J Biol Chem. 2008 May 9;283(19):12789-96. doi: 10.1074/jbc.M709305200. Epub 2008 Mar 10.

Abstract

The Ras effector and ubiquitin-protein isopeptide ligase family member IMP acts as a steady-state resistor within the Raf-MEK-ERK kinase module. IMP concentrations are regulated by Ras through induction of autodegradation and can modulate signal/response thresholds by directly limiting the assembly of functional KSR1-dependent Raf.MEK complexes. Here, we show that the capacity of IMP to inhibit signal propagation through Raf to MEK is a consequence of disrupting KSR1 homooligomerization and B-Raf/c-Raf hetero-oligomerization. This impairs both the recruitment of MEK to activated Raf family members and the contribution of Raf oligomers to c-Raf kinase activation. Our observations indicate that human KSR1 proteins promote assembly of multivalent Raf.MEK complexes that are required for c-Raf kinase activation and functional coupling of active kinases to downstream substrates. This property is engaged by IMP for modulation of signal amplitude.

Publication types

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

MeSH terms

  • Cell Line
  • Enzyme Activation
  • Humans
  • MAP Kinase Signaling System*
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mitosis
  • Protein Binding
  • Protein Kinases / genetics
  • Protein Kinases / metabolism*
  • Sensitivity and Specificity
  • Ubiquitin-Protein Ligases / classification
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • raf Kinases / metabolism

Substances

  • BRAP protein, human
  • Ubiquitin-Protein Ligases
  • Protein Kinases
  • KSR-1 protein kinase
  • raf Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinase Kinases