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Cross-talk and decision making in MAP kinase pathways

Nature Genetics volume 39, pages 409–414 (2007)Cite this article

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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Figure 1: Different mechanisms for achieving specificity of two parallel signaling pathways yield different responses after exposure to both signals.
Figure 2: Pheromone and high-osmolarity pathways.
Figure 3: Cells costimulated with sorbitol and pheromone show mutually exclusive activation of the pheromone and the high-osmolarity response pathways.
Figure 4: Cells show history dependence in their response to pheromone.
Figure 5: Switch-like signaling behavior depends on pathway cross-inhibition.

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  • 14 March 2007

    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.

References

  1. Hunter, T. & Plowman, G.D. The protein kinases of budding yeast: six score and more. Trends Biochem. Sci. 22, 18–22 (1997).

    Article  CAS  Google Scholar 

  2. Posas, F., Takekawa, M. & Saito, H. Signal transduction by MAP kinase cascades in budding yeast. Curr. Opin. Microbiol. 1, 175–182 (1998).

    Article  CAS  Google Scholar 

  3. Banuett, F. Signalling in the yeasts: an informational cascade with links to the filamentous fungi. Microbiol. Mol. Biol. Rev. 62, 249–274 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Whitmarsh, A.J. & Davis, R.J. Structural organization of MAP-kinase signaling modules by scaffold proteins in yeast and mammals. Trends Biochem. Sci. 23, 481–485 (1998).

    Article  CAS  Google Scholar 

  5. Ferrell, J.E. Jr . & Machleder, E.M. The biochemical basis of an all-or-none switch in Xenopus oocytes. Science 280, 895–898 (1998).

    Article  CAS  Google Scholar 

  6. Schwartz, M.A. & Madhani, H.D. Principles of MAP kinase signaling specificity in Saccharomyces cerevisiae. Annu. Rev. Genet. 38, 725–748 (2004).

    Article  CAS  Google Scholar 

  7. Sprague, G.F. Jr . Control of MAP kinase signaling specificity or how not to go HOG wild. Genes Dev. 12, 2817–2820 (1998).

    Article  CAS  Google Scholar 

  8. Pryciak, P.M. & Huntress, F.A. Membrane recruitment of the kinase cascade scaffold protein Ste5 by the Gbetagamma complex underlies activation of the yeast pheromone response pathway. Genes Dev. 12, 2684–2697 (1998).

    Article  CAS  Google Scholar 

  9. Choi, K.Y., Satterberg, B., Lyons, D.M. & Elion, E.A. Ste5 tethers multiple protein kinases in the MAP kinase cascade required for mating in S. cerevisiae. Cell 78, 499–512 (1994).

    Article  CAS  Google Scholar 

  10. Posas, F. & Saito, H. Osmotic activation of the HOG MAPK pathway via Ste11p MAPKKK: scaffold role of Pbs2p MAPKK. Science 276, 1702–1705 (1997).

    Article  CAS  Google Scholar 

  11. Harris, K. et al. Role of scaffolds in MAP kinase pathway specificity revealed by custom design of pathway-dedicated signaling proteins. Curr. Biol. 11, 1815–1824 (2001).

    Article  CAS  Google Scholar 

  12. O'Rourke, S.M. & Herskowitz, I. The Hog1 MAPK prevents cross talk between the HOG and pheromone response MAPK pathways in Saccharomyces cerevisiae. Genes Dev. 12, 2874–2886 (1998).

    Article  CAS  Google Scholar 

  13. Posas, F. & Saito, H. Activation of the yeast SSK2 MAP kinase kinase kinase by the SSK1 two-component response regulator. EMBO J. 17, 1385–1394 (1998).

    Article  CAS  Google Scholar 

  14. Posas, F. et al. Yeast HOG1 MAP kinase cascade is regulated by a multistep phosphorelay mechanism in the SLN1–YPD1-SSK1 “two-component” osmosensor. Cell 86, 865–875 (1996).

    Article  CAS  Google Scholar 

  15. O'Rourke, S.M. & Herskowitz, I. Unique and redundant roles for HOG MAPK pathway components as revealed by whole-genome expression analysis. Mol. Biol. Cell 15, 532–542 (2004).

    Article  CAS  Google Scholar 

  16. Breitkreutz, A. & Tyers, M. MAPK signaling specificity: it takes two to tango. Trends Cell Biol. 12, 254–257 (2002).

    Article  CAS  Google Scholar 

  17. Tsien, R.Y. The green fluorescent protein. Annu. Rev. Biochem. 67, 509–544 (1998).

    Article  CAS  Google Scholar 

  18. Hagen, D.C., McCaffrey, G. & Sprague, G.F. Jr . Pheromone response elements are necessary and sufficient for basal and pheromone-induced transcription of the FUS1 gene of Saccharomyces cerevisiae. Mol. Cell. Biol. 11, 2952–2961 (1991).

    Article  CAS  Google Scholar 

  19. Campbell, R.E. et al. A monomeric red fluorescent protein. Proc. Natl. Acad. Sci. USA 99, 7877–7882 (2002).

    Article  CAS  Google Scholar 

  20. Rep, M., Krantz, M., Thevelein, J.M. & Hohmann, S. The transcriptional response of Saccharomyces cerevisiae to osmotic shock. Hot1p and Msn2p/Msn4p are required for the induction of subsets of high osmolarity glycerol pathway-dependent genes. J. Biol. Chem. 275, 8290–8300 (2000).

    Article  CAS  Google Scholar 

  21. Murray, J.D. Mathematical Biology (Springer, New York, 2002).

    Google Scholar 

  22. Hall, J.P. et al. The osmoregulatory pathway represses mating pathway activity in Saccharomyces cerevisiae: isolation of a FUS3 mutant that is insensitive to the repression mechanism. Mol. Cell. Biol. 16, 6715–6723 (1996).

    Article  CAS  Google Scholar 

  23. Xiong, W. & Ferrell, J.E. Jr . A positive-feedback-based bistable 'memory module' that governs cell fate decision. Nature 426, 460–465 (2003).

    Article  CAS  Google Scholar 

  24. Zhu, H. et al. Analysis of yeast protein kinases using protein chips. Nat. Genet. 26, 283–289 (2000).

    Article  CAS  Google Scholar 

  25. Philips, J. & Herskowitz, I. Osmotic balance regulates cell fusion during mating in Saccharomyces cerevisiae. J. Cell Biol. 138, 961–974 (1997).

    Article  CAS  Google Scholar 

  26. Gimeno, C.J., Ljungdahl, P.O., Styles, C.A. & Fink, G.R. Unipolar cell divisions in the yeast S. cerevisiae lead to filamentous growth: regulation by starvation and RAS. Cell 68, 1077–1090 (1992).

    Article  CAS  Google Scholar 

  27. Bhattacharyya, R.P. et al. The Ste5 scaffold allosterically modulates signaling output of the yeast mating pathway. Science 311, 822–826 (2006).

    Article  CAS  Google Scholar 

Download references

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).

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Authors and Affiliations

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

    Megan N McClean, Areez Mody & Sharad Ramanathan

  2. Division of Engineering and Applied Sciences, Harvard University, Cambridge, 02138, Massachusetts, USA

    Megan N McClean

  3. Department of Molecular Biology, Princeton University, Princeton, 08544, New Jersey, USA

    James R Broach

  4. Bell Laboratories, Lucent Technologies, Murray Hill, 07974, New Jersey, USA

    Sharad Ramanathan

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  1. Megan N McClean
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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.

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Correspondence to Sharad Ramanathan.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

The analysis of models. (PDF 887 kb)

Supplementary Fig. 2

Results from modeling. (PDF 525 kb)

Supplementary Fig. 3

Cell-to-cell variability. (PDF 732 kb)

Supplementary Fig. 4

Controls. (PDF 220 kb)

Supplementary Fig. 5

Protein blots. (PDF 290 kb)

Supplementary Fig. 6

Filamentous growth and pheromone response pathways and model. (PDF 494 kb)

Supplementary Fig. 7

Phase plot of pheromone and filamentous response as a function of the inputs. (PDF 384 kb)

Supplementary Methods (PDF 880 kb)

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McClean, M., Mody, A., Broach, J. et al. Cross-talk and decision making in MAP kinase pathways. Nat Genet 39, 409–414 (2007). https://doi.org/10.1038/ng1957

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