Date

November 2008

Document Type

Dissertation

Degree Name

Ph.D.

Institution

Oregon Health & Science University

Abstract

Eukaryotic cells are distinguished by an elaborate endomembrane system that regulates cellular and organismal homeostasis. While this system of membrane-bound organelles coordinates the proper functioning, proliferation and survival of cells, a mechanism of programmed self-destruction, apoptosis, emerges from the endomembrane system in times of damage and stress or during specific developmental stages to eliminate unneeded cells. Several details of how intracellular regulators manage either homeostasis or apoptosis are now understood. However, the manner in which such factors communicate with one another or share functions is unknown. In this dissertation I describe PACS-2, a sorting protein that regulates the trafficking of factors throughout the endomembrane system to medicate cellular homeostasis, interorganellar communication and apoptosis. PACS-2 coordinates communication between the endoplasmic reticulum and mitochondria to regulate calcium signaling, ER homeostasis and apoptosis. In response to apoptotic induction by chemotherapeutic agents such as Apo2L/TRAIL, PACS-2 is required to translocate Bid to mitochondria to initiate the activation of caspases to mediate cell death in vitro in cancer cell lines as well as in vivo in hepatocytes. PACS-2 is phosphorylated at Ser437 by the pro-survival kinase Akt to establish a docking site for 14- 3-3 proteins. Apoptotic induction triggers dephosphorylation of Ser437, reprogramming PACS-2 to promote apoptosis rather than the trafficking of cargo. Together, these studies describe the phosphorylation state of PACS-2 Ser437 as a molecular switch that regulates interorganellar communication, cellular homeostasis and apoptosis.

Identifier

doi:10.6083/M4XW4GRB

Division

Neuroscience Graduate Program

School

School of Medicine

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