Date of Award

2014

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Alan Diehl

Abstract

Cells constantly encounter changing environments that challenge the ability to adapt

and survive. Signal transduction networks enable cells to appropriately sense and respond

to these changes, and are often mediated through the activity of protein kinases. Protein

kinases are a class of enzyme responsible for regulating a broad spectrum of cellular

functions by transferring phosphate groups from ATP to substrate proteins, thereby

altering substrate activity and function. PERK is a resident kinase of the endoplasmic

reticulum, and is responsible for sensing perturbations in the protein folding capacity of

the ER. When the influx of unfolded, nascent proteins exceeds the folding capacity of the

ER, PERK initiates a cascade of signaling events that enable cell adaptation and ER

stress resolution. These signaling pathways are not only essential for the survival of

normal cells undergoing ER stress, but are also co-opted by tumor cells in order to

survive the oxygen and nutrient-restricted conditions of the tumor microenvironment. Not

surprisingly, PERK signaling is known to influence a variety of pro-tumorigenic

processes. Therefore, from a purely biological standpoint as well as from a clinical

perspective, it is important to understand this critical cell adaptive pathway in greater

detail through identifying its interacting partners and thereby elucidating additional

downstream signaling branches.

Prior to the work described herein, only three direct PERK substrates had been

identified. Using chemical-genetic screening techniques, we have generated a significant

list of putative PERK substrates, several of which have been confirmed as PERK

substrates in vitro. These preliminary results suggest new connections between known

UPR pathways, as well as entirely novel signaling branches downstream of PERK. This

work will provide a solid foundation for launching future PERK-related discovery

studies.

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