USING A SYSTEMS BIOLOGY APPROACH TO STUDY DIFFERENTIAL REGULATION OF MAPK DYNAMICS BY PHOSPHATASES IN YEAST

Date of Award

2017

Document Type

Thesis

Degree Name

Bachelors

Department

Natural Sciences

First Advisor

Walstrom, Katherine

Area of Concentration

Biochemistry

Abstract

Yeast cells secrete pheromones to signal mating through activation of an extensively studied cellular signaling pathway called the pheromone response pathway, which is arguably one of the best-characterized eukaryotic pathways. The pathway involves a G-protein coupled receptor-initiated MAPK cascade. On pathway activation, the phosphorylated active Fus3 first phosphorylates and activates the protein phosphatases Ptp3 and Msg5, but only transcriptionally up-regulates Msg5. The active forms of both phosphatases then dephosphorylate and inactivate Fus3, providing two distinct regulatory negative feedback mechanisms. To better understand the necessity of having two distinct phosphatases deactivating Fus3 and the differential roles they play in controlling the signal, a mathematical model was developed with parameters estimated by fitting the models to published experimental data for Fus3 dynamics. Numerical simulation and analysis of the model suggests that Msg5 negatively regulates Fus3 more effectively for stronger signals, and mostly at later times after the activation of the pathway by pheromone. Conversely, Ptp3 inhibits Fus3 for the weaker signals seen during early times after signal exposure and is not dependent on the signal profile. Furthermore, while stochastic simulation of the model suggests that while Ptp3 reduces the variability in Fus3 abundance at earlier times than it does at later times, it also suggests that Msg5 increases such variation all times.

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