Deborah Leckband

Professor, Chemical and Biomolecular Engineering

We discovered a novel intercellular force transduction mechanism in epithelial cells through which mechanically stimulated cadherins—indispensable adhesion proteins at cell-cell junctions—activate epidermal growth factor signaling to stimulate global cell contractility1. Although integrins are well-known force transducers, our research demonstrated that cadherins are also force transduction loci in tissues. Initial studies identified an essential protein in cadherin complexes, alpha catenin as a force transducing protein2. By combining mechanical probes and high resolution imaging, we identified a second cadherin-mediated pathway that activates a kinase cascade via the epidermal growth factor receptor. We further demonstrated that this kinase cascade also activates integrins, which stimulate cell contractility.  Findings demonstrated that the resulting integrin-mediated cell contractility also depends on matrix rigidity.  Our results thus link cadherins and integrins in a force-sensitive signaling network that regulates global cell mechanics and activates pro-proliferative signals. These findings account for increased growth factor sensitivity of epithelial tissues cultured on stiff matrices. They also suggest a mechanism by which cancer-linked growth factor receptor mutations may contribute to disease progression.

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