Coordination of G Protein and Mitogen-Activated Protein Kinase Signaling Pathways by Branched-Chain Amino Acid Metabolite Second Messengers during Osmotic Stress Public Deposited

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  • March 20, 2019
Creator
  • Shellhammer, James
    • Affiliation: School of Medicine, Department of Pharmacology
Abstract
  • Cells experience a variety of environmental signals, often simultaneously. These signals may encode opposing effects, so the response must be coordinated in a manner that promotes cell and organismal well-being. The expression of surface receptors, such as G protein-coupled receptors (GPCRs), aids in the detection of bioactive molecules. Once perceived by the cell, the signal is transduced to intracellular signaling components that carry out the appropriate response. Mitogen-activated protein kinase (MAPK) cascades are commonly activated in response to external stimuli that range from growth factors to environmental stresses. The budding yeast S. cerevisiae employs MAPK pathways to respond to mating pheromones and environmental stresses. The pheromone response pathway is a MAPK pathway regulated by a GPCR, and the high osmolarity glycerol (HOG) pathway is a parallel MAPK pathway that shares some components with the pheromone response pathway. Signal fidelity is maintained during simultaneous activation of these and other MAPK pathways through mechanisms including signal strength and duration, feedback regulation, and cross-pathway inhibition. In this dissertation, I identify a new means by which parallel MAPK pathways are regulated. I show that activation of the HOG pathway promotes the production of second messenger molecules derived from branched-chain amino acids. These new second messengers promote phosphorylation of the Gα subunit regulating the pheromone response pathway, and lead to reduced downstream transcriptional output. I also compare conventional and recently developed methods for analyzing MAPK activation and gene transcription. This work adds to our understanding of how signaling pathway cross-talk can maintain signal fidelity, and provides an update on the methods that can be used to best study these pathways for future discoveries.
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Rights statement
  • In Copyright
Advisor
  • Brenman, Jay
  • Nicholas, Robert
  • Emanuele, Michael
  • Graves, Lee
  • Dohlman, Henrik
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2017
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