The analysis of feedback regulation in yeast signal transduction pathways Public Deposited

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  • March 21, 2019
Creator
  • Hao, Nan
    • Affiliation: School of Medicine, Department of Biochemistry and Biophysics
Abstract
  • The feedback loop is a ubiquitous regulatory motif that allows biological systems to dynamically control the intensity, duration and specificity of signal transduction. In yeast there are three interconnected mitogen-activated protein kinase (MAPK) signal transduction pathways controlling the mating pheromone response, the invasive growth response and the high osmolarity glycerol (HOG) response respectively. These parallel signaling pathways involve distinct MAPKs although they share some upstream components. Here we studied feedback regulation in each of these three yeast signal transduction pathways with the combinatorial use of experimental and computational analysis. We identified a novel negative feedback loop in the yeast pheromone pathway and a novel negative feedback loop in the yeast high osmolarity glycerol (HOG) response pathway, both of which contribute to regulation of signal intensity and duration. The feedback loop we identified in the pheromone pathway involves pheromone-dependent transcriptional induction of a regulator of G protein signaling (RGS) protein, Sst2, that accelerates GTPase activity of the G protein and contributes to signal termination. The feedback loop we discovered in the HOG response pathway is mediated by feedback phosphorylation of the osmotic sensor Sho1 by mitogen-activated protein kinase (MAPK) Hog1. Both of these two feedback regulations lead to signal desensitization. We also found a novel feedback loop that contributes to control the signal specificity between the pheromone pathway and the invasive growth pathway. The pheromone and invasive growth pathways require distinct effector MAP kinases (Fus3 and Kss1, respectively) yet they are activated by a common set of upstream kinases (Ste11 and Ste7). We found that phosphorylation of an intermediary MAP kinase kinase (Ste7) by Fus3 leads to selective inhibition of Kss1 and thus prevents cross-activation of the invasive growth pathway by pheromone. The analysis of feedback regulation in yeast might provide insights into the mechanism of signal desensitization and signal specificity control in higher eukaryotic organisms. The combination of experimental and computational approaches employed in our study could also be applied to other signaling pathways and other organisms, and promises to improve our understanding of how cellular changes in disease states can be predicted and managed.
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  • In Copyright
Advisor
  • Dohlman, Henrik
Degree granting institution
  • University of North Carolina at Chapel Hill
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  • Open access
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