Integrin force loading rate in mechanobiology: From model to molecular measurement.

Integrins are critical transmembrane receptors that connect the extracellular matrix (ECM) to the intracellular cytoskeleton, playing a central role in mechanotransduction - the process by which cells convert mechanical stimuli into biochemical signals. The dynamic assembly and disassembly of integrin-mediated adhesions enable cells to adapt continuously to changing mechanical cues, regulating essential processes such as adhesion, migration, and proliferation. In this review, we explore the molecular clutch model as a framework for understanding the dynamics of integrin - ECM interactions, emphasizing the critical importance of force loading rate. We discuss how force loading rate bridges internal actomyosin-generated forces and ECM mechanical properties like stiffness and ligand density, determining whether sufficient force is transmitted to mechanosensitive proteins such as talin. This force transmission leads to talin unfolding and activation of downstream signalling pathways, ultimately influencing cellular responses. We also examine recent advances in single-molecule DNA tension sensors that have enabled direct measurements of integrin loading rates, refining the range to approximately 0.5-4 pN/s. These findings deepen our understanding of force-mediated mechanotransduction and underscore the need for improved sensor designs to overcome current limitations.