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A rate threshold mechanism regulates MAPK stress signaling and survival

Significance Signaling pathways must decide how to respond to extracellular stimulation patterns that vary widely in vivo. However, most experiments only explore how cells respond to one stimulation variable: concentration. By probing the model yeast osmostress mitogen-activated protein kinase pathway with diverse stimulation gradients we explore cellular sensitivity to multiple stimulation variables. We identify a rate threshold required for signaling and show that the timing of signaling initiation depends on both stimulation rate and concentration in finite-rate treatments. We connect our discovered limit on cell sensitivity to stimulation rate with a phenotype and molecular mechanism, demonstrating its biological relevance. Our results provide motivation and a blueprint for the dissection of other major stimulation-rate-dependent mechanisms in a variety of systems. Cells are exposed to changes in extracellular stimulus concentration that vary as a function of rate. However, how cells integrate information conveyed from stimulation rate along with concentration remains poorly understood. Here, we examined how varying the rate of stress application alters budding yeast mitogen-activated protein kinase (MAPK) signaling and cell behavior at the single-cell level. We show that signaling depends on a rate threshold that operates in conjunction with stimulus concentration to determine the timing of MAPK signaling during rate-varying stimulus treatments. We also discovered that the stimulation rate threshold and stimulation rate-dependent cell survival are sensitive to changes in the expression levels of the Ptp2 phosphatase, but not of another phosphatase that similarly regulates osmostress signaling during switch-like treatments. Our results demonstrate that stimulation rate is a regulated determinant of cell behavior and provide a paradigm to guide the dissection of major stimulation rate dependent mechanisms in other systems.