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

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.

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Figure 1: IMP is a Ras effector.
Figure 2: IMP impedes signal transmission from Raf to MEK.
Figure 3: IMP is a Ras-sensitive RING-H2 E3 ubiquitin ligase.
Figure 4: IMP inactivates KSR.

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Acknowledgements

This work was supported by grants from the National Cancer Institute (to M.A.W. and to R.E.L.) and the Welch Foundation, and by an Idea Development award (to M.A.W.).

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Correspondence to Michael A. White.

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Matheny, S., Chen, C., Kortum, R. et al. Ras regulates assembly of mitogenic signalling complexes through the effector protein IMP. Nature 427, 256–260 (2004). https://doi.org/10.1038/nature02237

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