Year: 2010
Type: article
Abstract: Wounding disrupts the primary function of an epithelium, which is to provide a barrier to the outside environment. The longer the epithelial defect remains unhealed, the greater the risks of morbidity and mortality from infection, loss of tissue homeostasis, and fibrosis. Normally, epithelial cells restore barrier function by becoming highly motile and migrating to cover the defect, but in many situations cells do not move fast enough to prevent tissue malfunction. This is especially true in the cornea, where even minor wounds can impair vision. Therefore, there is considerable therapeutic interest in identifying signals that induce epithelial migration. Activation of the epidermal growth factor receptor (EGFR) is a key signaling event that promotes cells to move and cover wounds in many epithelia. The broad goal of this dissertation research was to identify mechanisms of wound-induced EGFR activation so that therapies may be developed to improve normal and pathological healing.I hypothesized that mechanisms of EGFR activation may differ with respect to distance from the wound, so I developed wounding models to analyze signaling specifically in cells near to or far from "wounds" in a human corneal epithelial cell line. I have examined the involvement of extracellular ATP, phospholipase D, Src-family kinases (SFKs), and the focal adhesion kinase Pyk2, all of which are signals that have been hypothesized to be stimulated by environmental cues related to wounding and to activate the EGFR.I have found that the proximal mechanism of EGFR activation is the proteolytic release of membrane-bound ligands, which is regulated by activation of SFKs. After wounding, multiple pathways converge on SFKs to regulate EGFR activation and cell motility. In one pathway, extracellular ATP transactivates the EGFR through phospholipase D2. In a distinct pathway that functions specifically near the wound edge, Pyk2 triggers SFK and EGFR activation. Finally, my data suggest the presence of a third distinct pathway that promotes SFK and EGFR activation in response to a physically unconstrained edge. By delineating signaling pathways that stimulate EGFR activation, I have identified potential therapeutic targets for modulating EGFR signaling and cell motility in wound healing and other pathologies.
Author: Ethan R. Block
Language: English
Topic: HER2/EGFR in Cancer Research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W12629940