Date of Award

2018

Document Type

Open Access Dissertation

Department

Chemistry and Biochemistry

Sub-Department

College of Arts and Sciences

First Advisor

Mythreye Karthikeyan

Abstract

During tumor progression, cancer cells undergo a number of alterations to evade tumor inhibitory mechanisms, proliferate, invade surrounding tissues and metastasize to distant sites. These properties reflect changes in their cell signaling pathways that, in normal cells, control aberrant cell proliferation, motility, and survival. Over the past few decades, hyperactive Wnt/β-catenin signaling has been linked to the formation of multiple cancers, including malignant ovarian cancer, making identification of molecules regulating Wnt/β-catenin signaling crucial to the development of early detection methods and cancer treatment strategies. Proteoglycans, which regulate transmission of cellular signals, are implicated in the pathophysiology of diseases, including cancer, where signals and tissue interactions malfunction. These cell surface molecules consist of a core protein decorated extracellularly with covalently linked heparan sulfate (HS), chondroitin sulfate (CS), dermatan sulfate and/or keratan sulfate glycosaminoglycan (GAG) chain modifications. A small group of proteoglycans that contain the two most common GAG chain attachments, HS and CS chains, span the cell membrane to regulate signal transduction and are hereby referred to as dually modified transmembrane proteoglycans (DMTPs). Two examples of DMTPs are betaglycan (TβRIII) and syndecan-1 (SDC1). These DMTPs play important roles in modulating key cell signaling pathways to affect epithelial cell biology and cancer progression. The overall goal of my dissertation research was to determine the impact of betaglycan, a well-established TGFβ co-receptor, on Wnt/β-catenin signaling. To this end, my work has revealed new roles for betaglycan

in Wnt signaling. Specifically, depending on its GAG chain modification, betaglycan can either enhance or suppress canonical Wnt/β-catenin signaling. My findings implicate interactions between Wnt and betaglycan’s HS chains in inhibiting Wnt signaling, likely via Wnt sequestration, while the CS GAG chains on betaglycan promote Wnt signaling. My studies reveal a novel, dual role for TβRIII/betaglycan and define a key requirement for the balance between CS and HS chains in dictating ligand responses. Ultimately, my findings will help unravel the complex roles that DMTPs and their GAG chains play in regulating ligand availability and cell signal transduction during disease progression.

Rights

© 2018, Laura M. Jenkins

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