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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.

References

  1. Nguyen, A. et al. Kinase suppressor of Ras (KSR) is a scaffold which facilitates mitogen-activated protein kinase activation in vivo. Mol. Cell. Biol. 22, 3035–3045 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Jensen, K., Shiels, C. & Freemont, P. S. PML protein isoforms and the RBCC/TRIM motif. Oncogene 20, 7223–7233 (2001)

    Article  CAS  Google Scholar 

  3. Li, S. et al. Identification of a novel cytoplasmic protein that specifically binds to nuclear localization signal motifs. J. Biol. Chem. 273, 6183–6189 (1998)

    Article  CAS  PubMed  Google Scholar 

  4. White, M. A. et al. Multiple Ras functions can contribute to mammalian cell transformation. Cell 80, 533–541 (1995)

    Article  CAS  PubMed  Google Scholar 

  5. Bruder, J. T., Heidecker, G. & Rapp, U. R. Serum-, TPA-, and Ras-induced expression from Ap-1/Ets-driven promoters requires Raf-1 kinase. Genes Dev. 6, 545–556 (1992)

    Article  CAS  PubMed  Google Scholar 

  6. Diaz, B. et al. Phosphorylation of Raf-1 serine 338/serine 339 is an essential regulatory event for Ras-dependent activation and biological signalling. Mol. Cell. Biol. 17, 4509–4516 (1997)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Joazeiro, C. A. & Weissman, A. M. RING finger proteins: mediators of ubiquitin ligase activity. Cell 102, 549–552 (2000)

    Article  CAS  Google Scholar 

  8. Yeung, K. et al. Suppression of Raf-1 kinase activity and MAP kinase signalling by RKIP. Nature 401, 173–177 (1999)

    Article  ADS  CAS  Google Scholar 

  9. Muller, J. S. O., Copeland, T., Piwnica-Worms, H. & Morrison, D. K. C-TAK1 regulates Ras signalling by phosphorylating the MAPK scaffold, KSR1. Mol. Cell 8, 983–993 (2001)

    Article  CAS  PubMed  Google Scholar 

  10. Roy, F., Laberge, G., Douziech, M., Ferland-McCollough, D. & Therrien, M. KSR is a scaffold required for activation of the ERK/MAPK module. Genes Dev. 16, 427–438 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Brennan, J. A., Volle, D. J., Chaika, O. V. & Lewis, R. E. Phosphorylation regulates the nucleocytoplasmic distribution of kinase suppressor of Ras. J. Biol. Chem. 277, 5369–5377 (2002)

    Article  CAS  PubMed  Google Scholar 

  12. Sundaram, M. & Han, M. The C. elegans KSR-1 gene encodes a novel Raf-related kinase involved in Ras-mediated signal transduction. Cell 83, 889–901 (1995)

    Article  CAS  PubMed  Google Scholar 

  13. Stewart, S. et al. Kinase suppressor of Ras forms a multiprotein signalling complex and modulates MEK localization. Mol. Cell. Biol. 19, 5523–5534 (1999)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Clemens, J. C. et al. Use of double-stranded RNA interference in Drosophila cell lines to dissect signal transduction pathways. Proc. Natl Acad. Sci. USA 97, 6499–6503 (2000)

    Article  ADS  CAS  Google Scholar 

  15. Elbashir, S. M. et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411, 494–498 (2001)

    Article  ADS  CAS  Google Scholar 

  16. Chien, Y. & White, M. A. RAL GTPases are linchpin modulators of human tumour-cell proliferation and survival. EMBO Rep. 4, 800–806 (2003)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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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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