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Title:Mechanism of E-cadherin dimerization at the plasma membrane
Author(s):Vu, Vinh
Director of Research:Leckband, Deborah
Doctoral Committee Chair(s):Leckband, Deborah
Doctoral Committee Member(s):Zhang, Kai; Das, Aditi; Breiher, Bill
Department / Program:Biochemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
Subject(s):cadherin, fluorescence, dimerization, oligomerization
Abstract:Cadherins are essential intercellular adhesion proteins that regulate tissue cohesion and paracellular permeability by assembling dense adhesion plaques at cell-to-cell contacts. This thesis addresses two aspects of cadherin adhesion and force transduction. The first portion of this thesis addresses the mechanisms of E-cadherin dimerization at the plasma membrane and its impact on cadherin trans binding and on cadherin-mediated cell adhesion. Full-spectrum imaging fluorescence resonance energy transfer (FSI-FRET) measurements directly demonstrate that epithelial-cadherin (E-cadherin) forms constitutive lateral (cis) dimers at the plasma membrane. Studies further show that this requires the intracellular domain and binding to p120 catenin. Quantitative cell binding measurements and fluorescence imaging demonstrate that p120 catenin binding to the cadherin intracellular domain enhances the trans cadherin binding affinity, cell adhesion, and the assembly of macroscopic cadherin clusters at intercellular adhesions. Single-molecule tracking studies of engineered mutants of the E-cadherin ectodomain mutants on supported bilayers showed that the extracellular domain also clusters in the absence of the trans interaction or the intracellular domain, but the cis bonds between ectodomains are much weaker than those involving p120ctn. The second portion of this thesis described in Chapter 3 is on cadherin-based mechanotransduction and the role of homophilic vs heterophilic cadherin ligation on force transduction cascades. Studies demonstrate that cadherin force transduction requires homophilic cadherin ligation and cadherin association with specific receptor tyrosine kinases on the same cell. By contrast, heterophilic ligands fail to activate force transduction signaling. Studies further demonstrate that this mechano-selectivity regulates cadherin-dependent signaling cascades that reinforce cell adhesion strength and the extent of cell spreading on cadherin substrates. Overall, these studies provide novel insights into the assembly of cadherin adhesions, and the regulation of cadherin binding affinities, cell adhesion, and mechanotransduction.
Issue Date:2021-03-26
Rights Information:Copy right 2021 Vinh Vu
Date Available in IDEALS:2021-09-17
Date Deposited:2021-05

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