Focal adhesion kinase is a reversible molecular mechanosensor

Sensors are the first element of signalling pathways that control the response of cells to their environment. Protein complexes that produce or enable a chemical signal in response to a mechanical stimulus are called ‘‘mechanosensors’’. Here we develop a theoretical model describing the physical mechanism of a reversible single-molecule sensor of mechanical stiffness of extracellular matrix, and apply it to focal adhesion kinase (FAK), which initiates the chemical signal in its active phosphorylated conformation, but can spontaneously return to its closed folded conformation. We find how the rates of conformation changes depend on the substrate stiffness and the pulling force applied from the cell cytoskeleton. We find the sensor is homeostatic, spontaneously self-adjusting to reach a state where its range of maximum sensitivity matches the substrate stiffness. We then consider several signalling pathways, via different Rho GTPases, leading to morphological changes in cytoskeleton, and to changes in cell motility, and compare with the detailed kinetics of experiments on cell spreading on different substrates. The results compare well with the phenotype observations of cells, allow to estimate the FAK activation energy, and suggest that the shortest pathway has 5 steps.