“Molecular Mechanisms of Cellular Force Transduction"
Establishing molecular mechanisms by which cells sense and respond to mechanical forces is a major challenge in biology. This talk focuses on our investigations of biomolecular adhesion and force transduction at cell-cell contacts. We focus on cadherins—essential cell-to-cell adhesion proteins in all tissues—as models proteins for demonstrating biophysical approaches used to unravel the molecular mechanisms of force transduction in cells. Studies used mechanical probes and fluorescent protein biosensors to identify the rapid, early molecular events triggered by mechanically perturbing cadherin receptors on the cell surface. Our studies identified two related cadherin-mediated, force-transduction mechanisms in cells. The first involves a cytoplasmic, actin-binding protein, alpha catenin, which mechanically links cadherin complexes to actin. Alpha catenin is an autoinhibited protein that undergoes a force-dependent conformational change, to expose a cryptic site for actin binding proteins in the cell. Biophysical studies directly demonstrated that force fluctuations at cadherin-adhesions activate α-catenin, and an engineered protein based fluorescence reporter identified force-activated biomolecular changes in live cells. Steered MD simulations further identified key amino acids in the protein structure that appear to gate its mechanical response. In a second mechanism, cadherin force transduction activates a signaling cascade via the epidermal growth factor receptor (EGFR)—an integral membrane protein that associates with cadherin. Resulting EGFR signals trigger biochemical cascades that result in increased cell contractility and cytoskeletal remodelling. Together these findings reveal how protein nano machines sense force at cell-cell junctions, and trigger biochemical changes that both mechanically reinforce intercellular contacts and alter essential cell functions.