Force loading on molecular clutches governs the stability of cell lamellipodia

Abstract Cells can utilize the lamellipodia, a thin actin-rich membrane protrusion, to probe the mechanical properties of microenvironments. During the mechanosensing process, the lamellipodium usually exhibits instability in dynamics, i.e ., protrusion-retraction cycles. However, how mechanical instability arises in lamellipodia, along with the functional role of dynamic instability in mechanosensing, is poorly understood. Here, we develop a minimal mechanochemical model for lamellipodia dynamics that integrates membrane deformation, myosin contractility, and binding kinetics of adhesion molecules (molecular clutches). Through stochastic simulations and analytical mean-field analysis, we demonstrate that both force-loading rate and magnitude applied by myosin-driven retrograde flow mediate the clutch binding kinetics, governing lamellipodial stability and hence the mechanosensing. Specifically, a slow force loading rate allows the clutches to bind and traction to accumulate, while a high loading magnitude collapses the bound clutches, causing protrusion-retraction cycles (instability) in lamellipodia. Our model predicts that a stiffer substrate stabilizes the lamellipodia by increasing the force loading rate, consistence with previous experiments. Furthermore, our model predictions on the biphasic regulation effect of myosin perturbations have been quantitatively validated by experimental results. Overall, the theoretical framework highlights the force loading as the key mechanical input driving lamellipodial instability and cell mechanosensing, advancing our understanding of mechanotransduction’s role in cell behaviors. Significance Cell behavior can be highly dynamic, showing periodic protrusion and retraction at the leading edge, and this dynamic instability is key to migration, immune response, and cancer invasion. How such instability arises from mechanotransduction between intercellular components and extracellular matrices remains unclear. Here, through theoretical modeling, we identify the rate and magnitude of force loading on adhesion molecules (molecular clutches) as the key factors for controlling lamellipodial stability. We find that a slow loading rate enables more clutches to bind and traction to accumulate, while a high loading magnitude collapses the bound clutches, causing protrusion-retraction cycles in lamellipodia. This work reveals a physical mechanism of how cells sense mechanical cues and adapt their dynamics, offering insights into diverse biological processes.