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 and Michael A. White ()
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Sharon A. Matheny: UT Southwestern Medical Center
Chiyuan Chen: UT Southwestern Medical Center
Robert L. Kortum: University of Nebraska Medical Center
Gina L. Razidlo: University of Nebraska Medical Center
Robert E. Lewis: University of Nebraska Medical Center
Michael A. White: UT Southwestern Medical Center

Nature, 2004, vol. 427, issue 6971, 256-260

Abstract: 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 MEK1. 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.

Date: 2004
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DOI: 10.1038/nature02237

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