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. Inhi...

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Bibliographic Details
Published in:The Journal of biological chemistry 2009-04, Vol.284 (17), p.11007-11011
Main Authors: Matheny, Sharon A., White, Michael A.
Format: Article
Language:English
Subjects:
Animals
Dimerization
Humans
MAP Kinase Kinase 1 - metabolism
Minireviews
Models, Biological
Protein Binding
Protein Structure, Tertiary
Proto-Oncogene Proteins B-raf - metabolism
Proto-Oncogene Proteins c-raf - metabolism
ras Proteins - metabolism
Signal Transduction
Substrate Specificity
Ubiquitin-Protein Ligases - metabolism
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Summary: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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.R800082200