Signaling threshold regulation by the Ras effector IMP.
The Ras effector and E3 ligase family member IMP (impedes mitogenic signal propagation) acts as a steady-state resistor within the Raf-MEK-ERK kinase module. IMP concentrations are directly regulated by Ras, through induction of autoubiquitination, to permit productive Raf-MEK complex assembly. Inhibition of Raf-MEK pathway activation by IMP occurs through the inactivation of KSR, a scaffold/adapter protein that couples activated Raf to its substrate MEK1. The capacity of IMP to inhibit signal propagation through Raf to MEK is, in part, a consequence of disrupting KSR1 homo-oligomerization and c-Raf-B-Raf hetero-oligomerization. These observations suggest that IMP functions as a threshold modulator, controlling sensitivity of the cascade to stimulus by directly limiting the assembly of functional KSR1-dependent Raf-MEK complexes.
Matheny
Sharon A
SA
Zimmer Biologics, Austin, Texas 78729, USA.
White
Michael A
MA
D000818:Animals; D019281:Dimerization; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D008954:Models, Biological; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D015398:Signal Transduction; D013379:Substrate Specificity; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*
C111164:BRAP protein, human; D044767:Ubiquitin-Protein Ligases; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf; D048369:MAP Kinase Kinase 1; D018631:ras Proteins