Oscillatory stress stimulation uncovers an Achilles’ heel of the yeast MAPK signaling network

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Science  11 Dec 2015:
Vol. 350, Issue 6266, pp. 1379-1383
DOI: 10.1126/science.aab0892

Altering timing perturbs cell signaling

Biological regulatory systems have been optimized by evolution to accommodate environmental variation. Yet these systems may also have fragile aspects that can be exposed by variation in the timing of signaling events. Mitchell et al. studied the properties of the yeast signaling system that allows cells to adapt to changing osmotic conditions. The same properties also made the system sensitive to hyperactivation and the consequent inhibition of cell growth if exposed to oscillations in osmotic conditions with a particular frequency. The identification of similar fragility in other regulatory pathways might prove useful in the development of therapeutic strategies against diseases in which signaling is perturbed, such as cancer and diabetes.

Science, this issue p. 1379


Cells must interpret environmental information that often changes over time. In our experiment, we systematically monitored the growth of yeast cells under various frequencies of oscillating osmotic stress. Growth was severely inhibited at a particular resonance frequency, at which cells show hyperactivated transcriptional stress responses. This behavior represents a sensory misperception: The cells incorrectly interpret oscillations as a staircase of ever-increasing osmolarity. The misperception results from the capacity of the osmolarity-sensing mitogen-activated protein kinase (MAPK) network to retrigger with sequential osmotic stresses. Although this feature is critical for coping with natural challenges, such as continually increasing osmolarity, it results in a trade-off of fragility to non-natural oscillatory inputs that match the retriggering time. These findings demonstrate the value of non-natural dynamic perturbations in exposing hidden sensitivities of cellular regulatory networks.

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