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MAPK-mediated bimodal gene expression and adaptive gradient sensing in yeast


The mating pathway in Saccharomyces cerevisiae has been the focus of considerable research effort, yet many quantitative aspects of its regulation still remain unknown. Using an integrated approach involving experiments in microfluidic chips and computational modelling, we studied gene expression and phenotypic changes associated with the mating response under well-defined pheromone gradients. Here we report a combination of switch-like and graded pathway responses leading to stochastic phenotype determination in a specific range of pheromone concentrations. Furthermore, we show that these responses are critically dependent on mitogen-activated protein kinase (MAPK)-mediated regulation of the activity of the pheromone-response-specific transcription factor, Ste12, as well as on the autoregulatory feedback of Ste12. In particular, both the switch-like characteristics and sensitivity of gene expression in shmooing cells to pheromone concentration were significantly diminished in cells lacking Kss1, one of the MAP kinases activated in the mating pathway. In addition, the dynamic range of gradient sensing of Kss1-deficient cells was reduced compared with wild type. We thus provide unsuspected functional significance for this kinase in regulation of the mating response.

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Figure 1: Pheromone dose–response analysis using a microfluidic experimental setup.
Figure 2: Quantification of Fus1 protein and gene expression.
Figure 3: Computational modelling of transcriptional regulation in the pheromone response.
Figure 4: Role of Kss1 in regulating the pheromone response.
Figure 5: Quantification of pheromone gradient sensing.

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  1. Roberts, C. J. et al. Signaling and circuitry of multiple MAPK pathways revealed by a matrix of global gene expression profiles. Science 287, 873–880 (2000)

    Article  ADS  CAS  Google Scholar 

  2. Poritz, M. A., Malmstrom, S., Kim, M. K., Rossmeissl, P. J. & Kamb, A. Graded mode of transcriptional induction in yeast pheromone signalling revealed by single-cell analysis. Yeast 18, 1331–1338 (2001)

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  4. Jeon, N. L. et al. Neutrophil chemotaxis in linear and complex gradients of interleukin-8 formed in a microfabricated device. Nature Biotechnol. 20, 826–830 (2002)

    Article  CAS  Google Scholar 

  5. Moore, S. A. Comparison of dose–response curves for alpha factor-induced cell division arrest, agglutination, and projection formation of yeast cells. Implication for the mechanism of alpha factor action. J. Biol. Chem. 258, 13849–13856 (1983)

    CAS  PubMed  Google Scholar 

  6. Lee, T. I. et al. Transcriptional regulatory networks in Saccharomyces cerevisiae. Science 298, 799–804 (2002)

    Article  ADS  CAS  Google Scholar 

  7. Angeli, D., Ferrell, J. E. & Sontag, E. D. Detection of multistability, bifurcations, and hysteresis in a large class of biological positive-feedback systems. Proc. Natl Acad. Sci. USA 101, 1822–1827 (2004)

    Article  ADS  CAS  Google Scholar 

  8. Becskei, A., Seraphin, B. & Serrano, L. Positive feedback in eukaryotic gene networks: cell differentiation by graded to binary response conversion. EMBO J. 20, 2528–2535 (2001)

    Article  CAS  Google Scholar 

  9. Biggar, S. R. & Crabtree, G. R. Cell signaling can direct either binary or graded transcriptional responses. EMBO J. 20, 3167–3176 (2001)

    Article  CAS  Google Scholar 

  10. Ferrell, J. E. Self-perpetuating states in signal transduction: positive feedback, double-negative feedback and bistability. Curr. Opin. Cell Biol. 14, 140–148 (2002)

    Article  CAS  Google Scholar 

  11. Gardner, T. S., Cantor, C. R. & Collins, J. J. Construction of a genetic toggle switch in Escherichia coli. Nature 403, 339–342 (2000)

    Article  ADS  CAS  Google Scholar 

  12. Ninfa, A. J. & Mayo, A. E. Hysteresis vs. graded responses: the connections make all the difference. Sci. STKE 232, pe20 (2004)

    Google Scholar 

  13. Pomerening, J. R., Sontag, E. D. & Ferrell, J. E. Building a cell cycle oscillator: hysteresis and bistability in the activation of Cdc2. Nature Cell Biol. 5, 346–351 (2003)

    Article  CAS  Google Scholar 

  14. Sha, W. et al. From the cover: hysteresis drives cell-cycle transitions in Xenopus laevis egg extracts. Proc. Natl Acad. Sci. USA 100, 975–980 (2003)

    Article  ADS  CAS  Google Scholar 

  15. Ozbudak, E. M., Thattai, M., Lim, H. N., Shraiman, B. I. & Van Oudenaarden, A. Multistability in the lactose utilization network of Escherichia coli. Nature 427, 737–740 (2004)

    Article  ADS  CAS  Google Scholar 

  16. Bardwell, L., Cook, J. G., Zhu-Shimoni, J. X., Voora, D. & Thorner, J. Differential regulation of transcription: repression by unactivated mitogen-activated protein kinase Kss1 requires the Dig1 and Dig2 proteins. Proc. Natl Acad. Sci. USA 95, 15400–15405 (1998)

    Article  ADS  CAS  Google Scholar 

  17. Cook, J. G., Bardwell, L. & Thorner, J. Inhibitory and activating functions for MAPK Kss1 in the S. cerevisiae filamentous-growth signalling pathway. Nature 390, 85–88 (1997)

    Article  ADS  CAS  Google Scholar 

  18. Madhani, H. D., Styles, C. A. & Fink, G. R. MAP kinases with distinct inhibitory functions impart signaling specificity during yeast differentiation. Cell 91, 673–684 (1997)

    Article  CAS  Google Scholar 

  19. Colman-Lerner, A. et al. Regulated cell-to-cell variation in a cell-fate decision system. Nature 437, 699–706 (2005); erratum Nature 439, 502 (2006)

    Article  ADS  CAS  Google Scholar 

  20. Elion, E. A., Satterberg, B. & Kranz, J. E. FUS3 phosphorylates multiple components of the mating signal transduction cascade: evidence for STE12 and FAR1. Mol. Biol. Cell 4, 495–510 (1993)

    Article  CAS  Google Scholar 

  21. Farley, F. W., Satterberg, B., Goldsmith, E. J. & Elion, E. A. Relative dependence of different outputs of the Saccharomyces cerevisiae pheromone response pathway on the MAP kinase Fus3p. Genetics 151, 1425–1444 (1999)

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Matheos, D., Metodiev, M., Muller, E., Stone, D. & Rose, M. D. Pheromone-induced polarization is dependent on the Fus3p MAPK acting through the formin Bni1p. J. Cell Biol. 165, 99–109 (2004)

    Article  CAS  Google Scholar 

  23. Roberts, R. L. & Fink, G. R. Elements of a single MAP kinase cascade in Saccharomyces cerevisiae mediate two developmental programs in the same cell type: mating and invasive growth. Genes Dev. 8, 2974–2985 (1994)

    Article  CAS  Google Scholar 

  24. Bardwell, L. et al. Repression of yeast Ste12 transcription factor by direct binding of unphosphorylated Kss1 MAPK and its regulation by the Ste7 MEK. Genes Dev. 12, 2887–2898 (1998)

    Article  CAS  Google Scholar 

  25. Ma, D., Cook, J. G. & Thorner, J. Phosphorylation and localization of Kss1, a MAP kinase of the Saccharomyces cerevisiae pheromone response pathway. Mol. Biol. Cell 6, 889–909 (1995)

    Article  CAS  Google Scholar 

  26. Segall, J. E. Polarization of yeast cells in spatial gradients of alpha mating factor. Proc. Natl Acad. Sci. USA 90, 8332–8336 (1993)

    Article  ADS  CAS  Google Scholar 

  27. Janetopoulos, C., Ma, L., Devreotes, P. N. & Iglesias, P. A. Chemoattractant-induced phosphatidylinositol 3,4,5-trisphosphate accumulation is spatially amplified and adapts, independent of the actin cytoskeleton. Proc. Natl Acad. Sci. USA 101, 8951–8956 (2004)

    Article  ADS  CAS  Google Scholar 

  28. Isbister, C. M., Mackenzie, P. J., To, K. C. W. & O'Connor, T. P. Gradient steepness influences the pathfinding decisions of neuronal growth cones in vivo. J. Neurosci. 23, 193–202 (2003)

    Article  CAS  Google Scholar 

  29. Guthrie, C. & Fink, G. R. Methods in Enzymology. Guide to Yeast Genetics and Molecular Biology (Academic, San Diego, 1991)

    Google Scholar 

  30. Unger, M. A., Chou, H. P., Thorsen, T., Scherer, A. & Quake, S. R. Monolithic microfabricated valves and pumps by multilayer soft lithography. Science 288, 113–116 (2000)

    Article  ADS  CAS  Google Scholar 

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The authors would like to thank M. Piel from A. Murray’s laboratory (Harvard) for the initial suggestion of the possible importance of Kss1 in controlling bimodality of pheromone response. They also want to thank P. Sternberg, J. Bruck, M. Peter, A. Colman-Lerner, J. Boeke, L. Bardwell and S. Quake for intellectual and material support of the study. This work was supported by NIH and NSF grants.

Author Contributions S.P., A.G. and A.L. conceived the framework of and wrote the paper, and A.L. oversaw the complete project. A.G., K.C., S.P. and A.L. conceptualized the microfluidic device design and the experimental setup, and K.C. and A.G. fabricated the devices. S.P., P.A.I. and A.L. were involved in the mathematical model setup. Z.H., S.P. and A.L. designed the yeast strains used in the study. S.P. performed the experiments, analysis of results and mathematical model simulations.

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Correspondence to Alex Groisman or Andre Levchenko.

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Reprints and permissions information is available at The authors declare no competing financial interests.

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Supplementary Information

This file contains Supplementary Methods, Supplementary Discussions, Supplementary Table 1, Supplementary Figures S1-S17 with Legends and additional references. A list of the contents of this file is included on the first page. (PDF 3236 kb)

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Paliwal, S., Iglesias, P., Campbell, K. et al. MAPK-mediated bimodal gene expression and adaptive gradient sensing in yeast. Nature 446, 46–51 (2007).

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