Tales of three signaling pathways: EGFR, TGFB, and WNT signaling in the GI tract

Abstract

My study of three signaling pathways in the context of three gastrointestinal diseases is presented here. Firstly, the epidermal growth factor receptor (EGFR) pathway and its role in the pathogenesis of the hypertrophic gastropathy Ménétrier's disease will be introduced. I will discuss the results of a clinical trial demonstrating that cetuximab, an EGFR pathway inhibitor, is the first effective medical therapy against Ménétrier's disease. I will then introduce the transforming growth factor-β (TGFB) pathway, and its role in the disorder juvenile polyposis syndrome (JPS). I will compare the clinico-pathological presentation of JPS to that of Ménétrier's disease, and suggest that there is a role for aberrant EGFR signaling in the pathogenesis of JPS. Finally, I will discuss my studies of the canonical WNT signaling pathway in the context of colorectal cancer (CRC). This part of the dissertation will center on my findings that the E3 ubiquitin ligase, NEDD4L, is a canonical WNT pathway inhibitor that is downregulated early in CRC, and may serve a tumor-suppressive role in CRC.