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 language | English (US) |
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Pages (from-to) | 12789-12796 |
Number of pages | 8 |
Journal | Journal of Biological Chemistry |
Volume | 283 |
Issue number | 19 |
DOIs | |
State | Published - May 9 2008 |
ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Cell Biology