Thesis
Cell death signaling mediated by dependence receptors EphA4 and EphB3 following induced stress
Master of Science (M.S.), Drexel University
Jun 2021
DOI:
https://doi.org/10.17918/00000785
Abstract
Dependence receptors are a category of transmembrane receptors which carry out an alternative cell death pathway. In the presence of their respective ligand, these receptors carry out their positive downstream signals, whereas in the absence of ligand they mediate cell death. More than a dozen receptors have been classified as dependence receptors, including EphA4 and EphB3, which have been demonstrated to mediate cell death following central nervous system (CNS) injuries. In this study we demonstrate that EphA4 and EphB3 mediate cell death through a pre-assembled pro-death complex consisting of FHL2, TUCAN, caspase-9. In addition, we demonstrate the novel association of tumor suppressor p53 with both EphA4 and EphB3, and that the activity of p53 was necessary for proper induction of cell death. Furthermore, we demonstrate that the complex assembles on Eph receptors classified as dependence receptors, as testing with EphB1, a receptor unable to elicit cell death in our model, we were unable to demonstrate the association of the pro-death complex with the receptor. Lastly, we investigated the role of the DART motif, a shared consensus sequence within the transmembrane domain of dependence receptors. Mutating the DART domain of EphB3 we did not observe disruptions in the mediation of cell death nor in the stimulation of the receptor by ephrinB3. Yet, we find that regulated intramembrane proteolysis of EphA4 and EphB3 likely plays a role in the proper induction of cell death, as by inhibiting gamma secretase, a secretase responsible for cleavage within transmembrane domains, cell death is ameliorated in cells overexpressing either EphA4 or EphB3. Together, our results demonstrate the assembly of a pro-death complex similar to the complex demonstrated for the receptor Patched, as well as demonstrating a novel function for p53.
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Details
- Title
- Cell death signaling mediated by dependence receptors EphA4 and EphB3 following induced stress
- Creators
- Dmytro Klitchyk
- Contributors
- Jerome J. Ricard (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Master of Science (M.S.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- vi, 63 pages
- Resource Type
- Thesis
- Language
- English
- Academic Unit
- Biology; College of Arts and Sciences; Drexel University
- Other Identifier
- 991015241382004721