Ras regulates assembly of mitogenic signalling complexes through the effector protein IMP

Sharon A. Matheny, Chiyuan Chen, Robert L. Kortum, Gina L. Razidlo, Robert E. Lewis, Michael A. White

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Abstract

The signal transduction cascade comprising Raf, mitogen-activated protein (MAP) kinase kinase (MEK) and MAP kinase is a Ras effector pathway that mediates diverse cellular responses to environmental cues and contributes to Ras-dependent oncogenic transformation. Here we report that the Ras effector protein Impedes Mitogenic signal Propagation (IMP) modulates sensitivity of the MAP kinase cascade to stimulus-dependent activation by limiting functional assembly of the core enzymatic components through the inactivation of KSR, a scaffold/adaptor protein that couples activated Raf to its substrate MEK. IMP is a Ras-responsive E3 ubiquitin ligase that, on activation of Ras, is modified by auto-polyubiquitination, which releases the inhibition of Raf-MEK complex formation. Thus, Ras activates the MAP kinase cascade through simultaneous dual effector interactions: induction of Raf kinase activity and derepression of Raf-MEK complex formation. IMP depletion results in increased stimulus-dependent MEK activation without alterations in the timing or duration of the response. These observations suggest that IMP functions as a threshold modulator, controlling sensitivity of the cascade to stimulus and providing a mechanism to allow adaptive behaviour of the cascade in chronic or complex signalling environments.

Original languageEnglish (US)
Pages (from-to)256-260
Number of pages5
JournalNature
Volume427
Issue number6971
DOIs
StatePublished - Jan 15 2004

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Matheny, S. A., Chen, C., Kortum, R. L., Razidlo, G. L., Lewis, R. E., & White, M. A. (2004). Ras regulates assembly of mitogenic signalling complexes through the effector protein IMP. Nature, 427(6971), 256-260. https://doi.org/10.1038/nature02237