1. Department of Biomedical Engineering and Whitaker Institute of Biomedical Engineering, and,
2. Department of Electrical Engineering and Computer Engineering, The Johns Hopkins University, Baltimore, Maryland 21218, USA
3. Department of Physics, University of California, San Diego, La Jolla, California 92093, USA

Correspondence to: Alex Groisman³Andre Levchenko¹ Correspondence and requests for materials should be addressed to A.L. (Email: alev@jhu.edu) and A.G. (Email: agroisman@ucsd.edu).

Abstract

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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