(339g) Investigations of Mechanisms of Force Transduction in Tissues

This talk focuses on our investigations of mechanisms of force transduction in tissues. Specifically, I will describe our recent identification of a mechano-transduction cascade that integrates intercellular adhesion proteins, cadherins, growth factor receptor signaling, and integrins to regulate tissue functions in response to mechanical stimuli. Integrins are well-known force-transducing adhesion proteins that regulate cell spreading and contractility on compliant matrices. However, cadherins—crucial adhesion proteins at cell-cell contacts—also form mechanically responsive adhesion complexes. Cadherin mediated force-transduction impinges on a range of tissue functions, including the maintenance of tissue barrier integrity, the shear alignment of vascular endothelial cells, tissue morphogenesis, and cell proliferation. One identified cadherin-mediated force-transduction mechanism involves an actin binding protein, alpha-catenin, that associates with cadherin complexes at the plasma membrane. We and others showed that alpha-catenin undergoes a conformational change in response to force on cadherin receptors, to facilitate cytoskeletal remodelling, which mechanically reinforces perturbed cadherin adhesions. However, in more recent studies using mechanical probes and live cell imaging, we identified a second, cadherin-mediated, force transduction mechanism that activates epidermal growth factor receptor signalling and integrins in a global, mechano-sensitive signalling cascade. These findings reveal an integrated signalling network in cells that coordinately regulates cell and tissue mechanics. Furthermore, matrix rigidity modulates both integrin and cadherin-mediated force transduction through this integrated network. These results suggest a mechanism underlying the growth factor sensitivity of epithelial cells cultured on rigid versus soft matrices.