Systematic analysis of essential genes reveals new regulators of G protein signaling Public Deposited

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  • March 22, 2019
Creator
  • Cappell, Steven D.
    • Affiliation: School of Medicine, Department of Pharmacology
Abstract
  • Heterotrimeric G proteins are molecular switches that respond to a wide range of stimuli including light, neurotransmitters, small molecules and peptides. Due to their role in a variety of physiological responses, it is no surprise that over 50% of drugs modulate G protein signaling pathways. While many drugs function at the level of the G protein-coupled receptor, downstream signaling components are increasingly being investigated as drug targets. Therefore, discovery of new components and regulators will help identify new ways to exploit G protein-coupled signaling pathways for therapeutic utility. Previous attempts to systematically identify new components of G protein pathways have focused on genome-wide knockout screens including gene-deletion mutants. However, these methods are inherently limited because they exclude the essential genes. In this thesis, we present studies to identify new signaling components by systematically analyzing 870 essential genes using repressible-promoter strains. Specifically, we show that the SCFCdc4 E3 ubiquitin ligase complex regulates G protein turnover and catalyzes ubiquitination of the G protein [alpha] subunit, Gpa1. Also, we demonstrate that Pik1, a phosphatidylinositol (PtdIns) 4-kinase, regulates the mitogen-activated protein kinase (MAPK) cascade and helps maintain signaling fidelity. These findings reveal the essential-genome as an untapped resource for identifying new components and regulators of signal transduction pathways. Furthermore, work on this thesis has expanded our understanding of G protein signaling networks and could lead to future opportunities for drug discovery.
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  • In Copyright
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  • "... in partial fulfillment of the requirements for the degree of Doctorate of Philosophy in the Department of Pharmacology, School of Medicine."
Advisor
  • Dohlman, Henrik
Degree granting institution
  • University of North Carolina at Chapel Hill
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Place of publication
  • Chapel Hill, NC
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  • Open access
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