Integrin Catch Bond Kinetics Mediate Mechanosensing during Cell Spreading

Abstract

Cell spreading and polarization are morphogenetic responses to extracellular matrix adhesion. Cultured fibroblasts polarize when plated on rigid, but not compliant substrates. In this study, we demonstrate that fibroblasts have increased spread area on compliant substrates when integrins are directly activated via manganese (Mn2+), even upon inhibition of myosin motor activity. Integrin activation is primarily regulated by changes in tertiary and quaternary structure and Mn2+ treatments enhance the lifetime of integrin/ligand bonds. The decrease of integrin/ligand unbinding rate under tension suggests a mechanosensing role of activated integrins in regulating adhesion formation. Using a combination of atomistic molecular dynamics and coarse grain Brownian dynamics simulations, we identify integrin intermediates along the activation pathway and show that modulation of integrin catch bond kinetics upon Mn2+-activation promotes integrin binding on compliant substrates. Combining experiments with simulations, our results support the idea that different regimes of ligand binding and cell spreading result from variations in integrin catch bond kinetics. This suggests an alternative mechanosensing pathway based on integrin activity and independent of myosin activity.