Clustering of α 5 β 1 integrins determines adhesion strength whereas α v β 3 and talin enable mechanotransduction

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Abstract
A key molecular link between cells and the extracellular matrix is the binding between fibronectin and integrins α 5 β 1 and α v β 3 . However, the roles of these different integrins in establishing adhesion remain unclear. We tested the adhesion strength of fibronectin-integrin-cytoskeleton linkages by applying physiological nanonewton forces to fibronectin-coated magnetic beads bound to cells. We report that the clustering of fibronectin domains within 40 nm led to integrin α 5 β 1 recruitment, and increased the ability to sustain force by over six-fold. This force was supported by α 5 β 1 integrin clusters. Importantly, we did not detect a role of either integrin α v β 3 or talin 1 or 2 in maintaining adhesion strength. Instead, these molecules enabled the connection to the cytoskeleton and reinforcement in response to an applied force. Thus, high matrix forces are primarily supported by clustered α 5 β 1 integrins, while less stable links to α v β 3 integrins initiate mechanotransduction, resulting in reinforcement of integrin-cytoskeleton linkages through talin-dependent bonds.