Apr 21, 2020

Model-driven experimental design identifies counter-acting feedback regulation in the osmotic stress response of yeast

BioRxiv : the Preprint Server for Biology
S. K. SuzukiTimothy C Elston

Abstract

Cells rely on mitogen-activated protein kinases (MAPKs) to survive environmental stress. In yeast, activation of the MAPK Hog1 is known to mediate the response to high osmotic conditions. Recent studies of Hog1 revealed that its temporal activity is subject to both negative and positive feedback regulation, yet the mechanisms of feedback remain unclear. By designing mathematical models of increasing complexity for the Hog1 MAPK cascade, we identified pathway circuitry sufficient to capture Hog1 dynamics observed in vivo. We used these models to optimize experimental designs for distinguishing potential feedback loops. Performing experiments based on these models revealed mutual inhibition between Hog1 and its phosphatases as the likely positive feedback mechanism underlying switch-like, dose-dependent MAPK activation. Importantly, our findings reveal a new signaling function for MAPK phosphatases. More broadly, they demonstrate the value using mathematical models to infer targets of feedback regulation in signaling pathways.

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Mentioned in this Paper

Metabolic Process, Cellular
Study
Hypoxia-Inducible Factor Prolyl Hydroxylase 2
Enzymes, antithrombotic
Malate Dehydrogenase
Endothelial PAS domain-containing protein 1
Isocitrate
Alpha Ketoglutarate
Hypoxia-inducible factor-1alpha Signaling Pathway
Neoplasms

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