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

Research output: Contribution to journalArticle

147 Citations (Scopus)

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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Mitogen-Activated Protein Kinase Kinases
raf Kinases
Mitogen-Activated Protein Kinases
Proteins
MAP Kinase Kinase Kinases
ras Proteins
Ubiquitin-Protein Ligases
Psychological Adaptation
Cues
Signal Transduction

ASJC Scopus subject areas

  • General

Cite this

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

Ras regulates assembly of mitogenic signalling complexes through the effector protein IMP. / Matheny, Sharon A.; Chen, Chiyuan; Kortum, Robert L.; Razidlo, Gina L.; Lewis, Robert E; White, Michael A.

In: Nature, Vol. 427, No. 6971, 15.01.2004, p. 256-260.

Research output: Contribution to journalArticle

Matheny, SA, Chen, C, Kortum, RL, Razidlo, GL, Lewis, RE & White, MA 2004, 'Ras regulates assembly of mitogenic signalling complexes through the effector protein IMP', Nature, vol. 427, no. 6971, pp. 256-260. https://doi.org/10.1038/nature02237
Matheny, Sharon A. ; Chen, Chiyuan ; Kortum, Robert L. ; Razidlo, Gina L. ; Lewis, Robert E ; White, Michael A. / Ras regulates assembly of mitogenic signalling complexes through the effector protein IMP. In: Nature. 2004 ; Vol. 427, No. 6971. pp. 256-260.
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