Mechanotransduction at cell-cell contacts

For nearly 40 years, it was debated as to whether the differences in cadherin- dependent cell-cell adhesion energies could solely predict cell sorting. Although adhesion energies do influence cell sorting in vitro, recent studies suggested that that differences in cell adhesion, determined mainly by cadherin binding affinities and expression levels, were not sufficient to predict cell sorting. This result suggested that other factors contribute. Besides their adhesive function, cadherins are also signaling proteins. Naturally, the next question is whether differences in downstream signaling associated with differences in cadherin affinity might also contribute to cell segregation. Chapter 2 of this dissertation specifically therefore investigates the relationship between cadherin affinities and signaling by small Rho GTPases, which are cytoskeletal regulatory proteins that influence actin polymerization and myosin dependent contractility. Recent findings also suggested that adhesion energies and cell mechanics together influence cell sorting, but the link between the two parameters had not been established. Chapter 3 builds on recent findings that cadherin complexes are also force transducers, and addresses whether differences in cadherin affinity also differentially alter cell mechanics. Studies discovered a significant difference between force transduction triggered by homophilic versus heterophilic cadherin bonds that could differentially influence cell mechanics. I further investigated the mechanism of force transduction at cadherin junctions, as described in Chapter 4 of this thesis. Chapter 4 specifically focused on the role of α-catenin—a key component in cadherin complexes—as a critical force transducer at cell-cell adhesion