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Cross-talk and decision making in MAP kinase pathways

Nature Genetics volume 39, pages 409414 (2007) | Download Citation

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  • A Corrigendum to this article was published on 01 April 2007

This article has been updated

Abstract

Cells must respond specifically to different environmental stimuli in order to survive. The signal transduction pathways involved in sensing these stimuli often share the same or homologous proteins. Despite potential cross-wiring, cells show specificity of response. We show, through modeling, that the physiological response of such pathways exposed to simultaneous and temporally ordered inputs can demonstrate system-level mechanisms by which pathways achieve specificity. We apply these results to the hyperosmolar and pheromone mitogen-activated protein (MAP) kinase pathways in the yeast Saccharomyces cerevisiae. These two pathways specifically sense osmolar and pheromone signals1,2,3, despite sharing a MAPKKK, Ste11, and having homologous MAPKs (Fus3 and Hog1). We show that in a single cell, the pathways are bistable over a range of inputs, and the cell responds to only one stimulus even when exposed to both. Our results imply that these pathways achieve specificity by filtering out spurious cross-talk through mutual inhibition. The variability between cells allows for heterogeneity of the decisions.

NOTE: In the version of this article initially published,the strain referred to as FUS3D63S on pp.411-412 of the main text and in the figure legend for Figure 5c-f should instead read 5c-f should instead read 5c-f FUS3D317G.The error has been corrected in the PDF version of the article.

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  • 14 March 2007

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Acknowledgements

We thank J. Weiner, P. Houston, K. Thorn, K. Duevel, L. Schneper, E. Xu and P. Hersen for help with experiments, R. Tsien and E. Winters for reagents, A. Sengupta, A. Murray and M. Tyers for helpful discussions and A. Regev, L. Garwin, K. Vestrepen, P. Swain, E. O'Shea, I. Nachman, N. Barkai and A. Amon for comments on the manuscript. This work was supported by grants from the NIH (J.R.B.), GRPW fellowship, Lucent Technologies (M.N.M.), Keck Futures Initiative (S.R.) and the FAS Center for Systems Biology (S.R. and M.N.M.). Requests for materials should be addressed to S.R. (sharadr@alcatel-lucent.com).

Author information

Affiliations

  1. FAS Center for Systems Biology, Harvard University, Cambridge, Massachusetts 02138, USA.

    • Megan N McClean
    • , Areez Mody
    •  & Sharad Ramanathan
  2. Division of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts 02138, USA.

    • Megan N McClean
  3. Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA.

    • James R Broach
  4. Bell Laboratories, Lucent Technologies, Murray Hill, New Jersey 07974, USA.

    • Sharad Ramanathan

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Contributions

S.R., J.R.B. and M.M. designed the experiments; M.M. and A.M. did the modeling and J.R.B., M.M., A.M. and S.R. wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Sharad Ramanathan.

Supplementary information

PDF files

  1. 1.

    Supplementary Fig. 1

    The analysis of models.

  2. 2.

    Supplementary Fig. 2

    Results from modeling.

  3. 3.

    Supplementary Fig. 3

    Cell-to-cell variability.

  4. 4.

    Supplementary Fig. 4

    Controls.

  5. 5.

    Supplementary Fig. 5

    Protein blots.

  6. 6.

    Supplementary Fig. 6

    Filamentous growth and pheromone response pathways and model.

  7. 7.

    Supplementary Fig. 7

    Phase plot of pheromone and filamentous response as a function of the inputs.

  8. 8.

    Supplementary Methods

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DOI

https://doi.org/10.1038/ng1957

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