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.
Chen
Chiyuan
C
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Lewis
Robert E
RE
White
Michael A
MA
D002460:Cell Line; D004789:Enzyme Activation; D006801:Humans; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D008938:Mitosis; D011485:Protein Binding; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D012680:Sensitivity and Specificity; D044767:Ubiquitin-Protein Ligases / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D048490:raf Kinases / Q000378:metabolism
C111164:BRAP protein, human; D044767:Ubiquitin-Protein Ligases; D011494:Protein Kinases; C097199:KSR-1 protein kinase; D048490:raf Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases