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Co-Ordinated Regulation Of Autophagy By Mtorc1 And Protein Phosphatase 2A

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Abstract

Autophagy is a cellular catabolic process critical for cell viability and homeostasis. As a membrane trafficking pathway, it is closely related to endocytosis and shares many points of convergence with endocytosis. In the first part of this dissertation, I find that although the two pathways are closely related, autophagosome fusion with lysosomes is governed by a distinct molecular mechanism from endosomal fusion with lysosomes. In recent years, the discovery of autophagy-essential-genes has accelerated research into the molecular mechanisms governing autophagy. For example, inhibition of mammalian target of rapamycin (mTOR) complex-1 (mTORC1) activates autophagy by relieving its inhibitory effects on autophagy essential gene, ULK1- a mTORC1 substrate whose dephosphorylation is required for autophagy induction. Puzzlingly, I observe that amino acid starvation triggers more rapid autophagy than pharmacological inhibition of mTORC1, although they both block mTORC1 activity with similar kinetics. Here I find that in addition to mTORC1 inactivation, starvation also causes a stimulation in phosphatase activity toward ULK1. In the second part of this dissertation, I identify the starvation-stimulated phosphatase for ULK1 as the PP2A-B55? complex and attempt to elucidate the mechanism of phosphatase stimulation during starvation. I find that treatment of cells with starvation but not mTORC1 inhibitors triggers dissociation of PP2A from its inhibitor Alpha4. Furthermore, pancreatic ductal adenocarcinoma cells (PDACs), whose growth depends on high basal autophagy, possess stronger basal phosphatase activity toward ULK1 and require ULK1 for sustained anchorage-independent growth. Taken together, these results suggest that concurrent mTORC1 inactivation and PP2A-B55? stimulation fuel ULK1-dependent autophagy.

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2015

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Autophagy; Cancer; Cell Signaling; Phosphatase; ULK1

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Cell & Developmental Biology

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Doctor of Philosophy

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Government Document

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Attribution-NonCommercial-NoDerivatives 4.0 International

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dissertation or thesis

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