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Dissertation/Thesis Abstract

PI3K-C2α: Insights into Autophagy and Endocytosis
by Merrill, Nathan Michael, Ph.D., Van Andel Research Institute, 2017, 187; 10620555
Abstract (Summary)

The class II phosphoinositide 3-kinase PI3K-C2α is an enzyme that phosphorylates phosphatidylinositides at intracellular membranes. The most well characterized function of PI3K-C2α is in vesicular trafficking, having been shown to be functionally required for the fission of clathrin-coated vesicles, allowing their budding into the cell. Additionally, knockdown studies have identified PI3K-C2α as a potential modulator of the autophagy pathway. This dissertation summarizes my findings around PI3K-C2α in the endocytosis and autophagy pathways, elucidating the role of PI3K-C2α in each pathway. Using confocal microscopy, membrane fractionation, and co-immunoprecipitation, I show that PI3K-C2α interacts with markers of the endocytosis and autophagy pathways. I show that these interactions are dependent on proper function of distinct domains of the protein. Proper function of these distinct domains is additionally required for PI3K-C2α to positively modulate the autophagy pathway. I show that the interaction of PI3K-C2α with the pre-autophagosomal marker ATG9 is a critical interface linking the two pathways, as knockdown of either PI3K-C2α or ATG9 results in a deficit in maturation of clathrin-coated vesicles, downstream of vesicle fission. To further explore these functional consequences in human disease, I have identified two compounds that have the potential to inhibit the kinase activity of PI3K-C2α as high nM inhibitors. Overall, this dissertation summarizes my work on how PI3K-C2α links endocytosis and autophagy.

Indexing (document details)
Advisor: MacKeigan, Jeffrey
Commitee: Melcher, Karsten, Reiners, John, Thorburn, Andrew, Wu, Ning
School: Van Andel Research Institute
Department: Biomedical
School Location: United States -- Michigan
Source: DAI-B 79/01(E), Dissertation Abstracts International
Subjects: Molecular biology, Cellular biology, Biochemistry
Keywords: Autophagy, Class ii phosphoinositide 3-kinase, Endocytosis
Publication Number: 10620555
ISBN: 978-0-355-16838-9
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