IMP modulates KSR1-dependent multivalent complex formation to specify ERK1/2 pathway activation and response thresholds.
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.
Mesh Terms:
Cell Line, Enzyme Activation, Humans, MAP Kinase Signaling System, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinase Kinases, Mitosis, Protein Binding, Protein Kinases, Sensitivity and Specificity, Ubiquitin-Protein Ligases, raf Kinases
Cell Line, Enzyme Activation, Humans, MAP Kinase Signaling System, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinase Kinases, Mitosis, Protein Binding, Protein Kinases, Sensitivity and Specificity, Ubiquitin-Protein Ligases, raf Kinases
J. Biol. Chem.
Date: May. 09, 2008
PubMed ID: 18332145
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