Epidermal growth factor receptor is an essential component in E-cadherin force transduction complexes

Area of Science:

• Cell Biology
• Biophysics
• Molecular Signaling

Background:

• Epithelial (E)-cadherin is vital for cell-cell adhesion and tissue integrity.
• Epidermal growth factor receptor (EGFR) signaling regulates cell growth and survival.
• Mechanical forces at cell junctions influence cellular behavior.

Purpose of the Study:

• To investigate the role of E-cadherin and EGFR association in force transduction signaling.
• To identify the specific domains involved in the mechanical activation of EGFR by E-cadherin.
• To elucidate the interplay between cadherin-EGFR complexes, integrins, and cytoskeletal dynamics.

Main Methods:

• Utilized engineered E-cadherin mutants to disrupt E-cadherin/EGFR co-immunoprecipitation.
• Employed co-localization studies to assess hetero-receptor complex formation at intercellular junctions.
• Investigated the rescue of cytoskeletal reinforcement by integrin activation and tension.
• Analyzed EGFR-mediated proliferation in response to extracellular matrix stiffness.

Main Results:

• E-cadherin and EGFR associate at cell surfaces, and tension on E-cadherin activates EGFR signaling.
• The extracellular domain 4 (EC4) of E-cadherin is essential for hetero-receptor complex formation and mechanical signaling.
• Integrin activation and tension can rescue cytoskeletal reinforcement at cadherin adhesions.
• The E-cadherin-EGFR complex regulates growth factor-dependent epithelial proliferation, particularly under matrix stiffening.

Conclusions:

• E-cadherin forms a force-transducing complex with EGFR at cell-cell contacts.
• This complex acts as a mechano-switch, coupling mechanical forces to EGFR signaling and cellular responses.
• The findings highlight a direct link between physical forces, cell adhesion molecules, and mitogenic signaling pathways.