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 journalArticle

16 Citations (Scopus)

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

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Inosine Monophosphate
MAP Kinase Signaling System
Mitogen-Activated Protein Kinase Kinases
Chemical activation
Proto-Oncogene Proteins c-raf
Oligomerization
Phosphotransferases
MAP Kinase Kinase Kinases
Ubiquitin-Protein Ligases
Oligomers
Resistors
Modulation
Substrates

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

IMP modulates KSR1-dependent multivalent complex formation to specify ERK1/2 pathway activation and response thresholds. / Chen, Chiyuan; Lewis, Robert E; White, Michael A.

In: Journal of Biological Chemistry, Vol. 283, No. 19, 09.05.2008, p. 12789-12796.

Research output: Contribution to journalArticle

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