Epidermal growth factor receptor is an essential component in E-cadherin force-transduction complexes
Zou, Yubo
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https://hdl.handle.net/2142/132621
Description
Title
Epidermal growth factor receptor is an essential component in E-cadherin force-transduction complexes
Author(s)
Zou, Yubo
Issue Date
2025-09-29
Director of Research (if dissertation) or Advisor (if thesis)
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.
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