MAPK feedback encodes a switch and timer for tunable stress adaptation in yeast

Signaling pathways can behave as switches or rheostats, generating binary or graded responses to a given cell stimulus. We evaluated whether a single signaling pathway can simultaneously encode a switch and a rheostat. We found that the kinase Hog1 mediated a bifurcated cellular response: Activation and commitment to adaptation to osmotic stress are switchlike, whereas protein induction and the resolution of this commitment are graded. Through experimentation, bioinformatics analysis, and computational modeling, we determined that graded recovery is encoded through feedback phosphorylation and a gene induction program that is both temporally staggered and variable across the population. This switch-to-rheostat signaling mechanism represents a versatile stress adaptation system, wherein a broad range of inputs generate an "all-in" response that is later tuned to allow graded recovery of individual cells over time.