2026-09-18T18:55:40Z https://www.ideals.illinois.edu/oai-pmh

oai:www.ideals.illinois.edu:2142/132621 2026-03-24 col_2142_5131 col_2142_14795 com_2142_5130 com_2142_14794 com_2142_14793 com_2142_8903

application/pdf en text Submission published under a 24 month embargo labeled 'U of I Access', the embargo will last until 2027-12-01 The student, Yubo Zou, accepted the attached license on 2025-09-09 at 14:51. The student, Yubo Zou, submitted this Dissertation for approval on 2025-09-09 at 14:57. This Dissertation was approved for publication on 2025-09-29 at 09:15. DSpace SAF Submission Ingestion Package generated from Vireo submission #22793 on 2026-02-19 at 18:45:23 Epidermal growth factor receptor is an essential component in E-cadherin force-transduction complexes Zou, Yubo 2025-09-29 Leckband, Deborah Leckband, Deborah Sokac, Anna Brieher, William Zhang, Kai Epidermal growth factor receptor, E-cadherin, Mechanotransduction eng This thesis focuses on the structural functional analysis of E-cadherin and EGFR interaction and their role in mediating E-cadherin mechanotransduction. E-cadherin serves as molecular Velcro in epithelial cells to maintain epithelial homeostasis. Despite passively bearing mechanical stress at cell-cell junctions, E-cadherin has been shown to actively respond to force to reinforce junction stability. However, classical E-cadherin mechanotransduction lacks sufficient information for force-induced biochemical signaling. In this dissertation, I focus on the role of E-cadherin/EGFR complexes in mediating force-responsive biochemical signaling in regulating junctional reinforcement. In Chapter 2, I focus on investigating the necessary region on E-cadherin required for EGFR binding. Studies revealed that the intracellular and transmembrane regions of E-cadherin were insufficient for EGFR binding. Further Co-IP and super-resolution results identified the extracellular domain 4 (EC4) as a critical binding domain for EGFR. Supporting these, Gastric cancer germline E-cadherin missense mutations near the EC4 domain impaired EGFR binding. Chapter 3 addressed the fundamental question of whether E-cadherin could initiate mechanotransduction signaling without EGFR physical complexes. Well-characterized E-cadherin mechanotransduction signatures, including adaptive cell stiffening, actin and vinculin recruitment at stressed junctions, were analyzed with E-cadherin mutants. The results demonstrated that without E-cadherin/EGFR physical complexes, cells were unable to activate EGFR and integrin in response to force, resulting in a lack of cellular stiffening and actin and vinculin remodeling at stressed junctions. Importantly, activation of integrin in E-cadherin mutant cells rescued E-cadherin mechanotransduction features, indicating a downstream role of integrin in the E-cadherin mechano-signaling pathway. In dense cultures, E-cadherin suppresses EGFR-mediated proliferation. I also studied how the hetero receptor regulates epithelial proliferation. Results revealed that E-cadherin mutants that uncouple EGFR displayed less effective inhibition of EGFR at confluency when treated with EGF. Notably, WT E-cadherin expressing cells displayed tension-dependent proliferation such that increased substrate rigidity correlated with higher proliferation rates. In contrast, cells expressing EGFR uncoupling E-cadherin mutants displayed higher proliferation than wild-type E-cadherin cells at all EGFR concentrations. Moreover, the substrate had no significant influence on proliferation for these mutant cells. These results provide direct evidence that E-cadherin and EGFR associate through extracellular domains to form a force-sensitive switch that regulates tension-dependent cell proliferation and intercellular junction mechanics. 2025-12 Thesis https://hdl.handle.net/2142/132621 Copyright 2025 Yubo Zou Biochemistry Biochemistry University of Illinois Urbana-Champaign Ph.D. Dissertation