{"id":{"repo_id":"uiuc","oai_identifier":"oai:www.ideals.illinois.edu:2142/132621"},"canonical_url":"https://search.dev.ndltd.org/etd/uiuc/oai:www.ideals.illinois.edu:2142/132621","repository":{"repo_id":"uiuc","name":"University of Illinois - Urbana-Champaign","base_url":"https://www.ideals.illinois.edu/oai-pmh"},"display":{"title":"Epidermal growth factor receptor is an essential component in E-cadherin force-transduction complexes","abstract":"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.","abstract_html":"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.","abstract_has_math":false,"creators":["Zou, Yubo"],"institution":"University of Illinois Urbana-Champaign","degree_name":"Ph.D.","degree_level":"Dissertation","degree_discipline":"Biochemistry","degree_department":null,"school":null,"contributors":["Leckband, Deborah","Sokac, Anna","Brieher, William","Zhang, Kai"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2025,"date_issued":"2025-12","date_published":"2025-12","updated_at":"2026-07-22T22:25:07Z","subjects":["Epidermal growth factor receptor, E-cadherin, Mechanotransduction"],"languages":["en"],"rights":["Copyright 2025 Yubo Zou"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/2142/132621","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Leckband, Deborah","Sokac, Anna","Brieher, William","Zhang, Kai"]},{"key":"dc:creator","label":"Author","values":["Zou, Yubo"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2025-12","2025-09-29"]},{"key":"dc:type","label":"Dc Type","values":["text","Thesis"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Biochemistry"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Ph.D."]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["University of Illinois Urbana-Champaign"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Epidermal growth factor receptor, E-cadherin, Mechanotransduction"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en"]},{"key":"dc:rights","label":"Dc Rights","values":["Copyright 2025 Yubo Zou"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://hdl.handle.net/2142/132621"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["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.","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"]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Epidermal growth factor receptor is an essential component in E-cadherin force-transduction complexes"]}]}],"canonical_facts":{"dc:contributor":["Leckband, Deborah","Sokac, Anna","Brieher, William","Zhang, Kai"],"dc:creator":["Zou, Yubo"],"dc:date":["2025-12","2025-09-29"],"dc:description":["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.","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"],"dc:format":["application/pdf"],"dc:identifier":["https://hdl.handle.net/2142/132621"],"dc:language":["en"],"dc:rights":["Copyright 2025 Yubo Zou"],"dc:subject":["Epidermal growth factor receptor, E-cadherin, Mechanotransduction"],"dc:title":["Epidermal growth factor receptor is an essential component in E-cadherin force-transduction complexes"],"dc:type":["text","Thesis"],"thesis:degree_discipline":["Biochemistry"],"thesis:degree_level":["Dissertation"],"thesis:degree_name":["Ph.D."],"thesis:institution_name":["University of Illinois Urbana-Champaign"]},"updated_at":"2026-07-22T22:25:07Z"}