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

Chiyuan Chen, Robert E. Lewis, Michael A. White

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

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 homo-oligomerization 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.

Original languageEnglish (US)
Pages (from-to)12789-12796
Number of pages8
JournalJournal of Biological Chemistry
Volume283
Issue number19
DOIs
StatePublished - May 9 2008

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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