Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.781358
Title: The regulation of E-cadherin turnover at the cell surface by p120-catenin
Author: Greig, Joshua
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2019
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Abstract:
E-cadherin (E-cad) is the primary cell adhesion molecule in epithelial tissue. It has multiple levels of regulation to mediate correct expression and localization in space and time within the cell and tissue. Intracellularly the C-terminus of E-cad interacts with the catenin protein family which mediate all intracellular functions. This family comprises three members: -catenin which is a component of the Wnt signalling pathway, -catenin which binds actin, and p120-catenin (p120ctn). Prior work established that p120ctn is the master regulator of E-cad levels at the cell surface, but the precise manner of this regulation and the downstream effectors were unknown. In this work I show that p120ctn acts via a clathrin-mediated mechanism to both promote and inhibit E-cad endocytosis by recruiting and activating two GTPases: Rho and Arf1. Rho has been known to regulate cortical actin and adhesion dynamics, and I demonstrate that p120ctn acts on this pathway to prevent E-cad internalization and stabilize its surface levels. At the same time, p120ctn interacts with Arf1, which has been traditionally viewed as being resident at the Golgi, which I found has a functional role at the plasma membrane. Through the Arf1 pathway p120ctn promotes E-cad internalization and targets it for endosomal recycling. I further dissect how these two signalling pathways operate in a hierarchical fashion with Rho predominating over Arf1, an effect which is dependent on the levels of p120ctn. In parallel, I describe a novel function of p120ctn in regulating the tension present at the cell surface and thus, show that p120ctn is a mechanotransducer. Finally, I characterize the wider implications of altered E-cad internalization and p120ctn expression on the endocytic and intracellular trafficking machinery. Altogether, this work elucidates the signalling pathways which are downstream of p120ctn and how they interact to modulate the levels of E-cad at the cell surface.
Supervisor: Bulgakova, Natalia Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.781358  DOI: Not available
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