Talin autoinhibition is required for normal hemostasis.

The integrin family of extracellular matrix (ECM) adhesion receptors plays a central role in platelet function, including adhesion and aggregation. In resting platelets, integrins exist in a low-affinity state for their ligands, and are activated upon ligand binding to the extracellular domain or binding of cytoplasmic proteins such as talin to the intracellular β-tail. Talin function is regulated through autoinhibition, which reduces its integrin-activating function. A point mutation that blocks talin autoinhibition, Tln1E1770A, therefore increases integrin activation and disrupts cell migration in fibroblasts. Here, we show that talin autoinhibition also plays an important role during hemostasis. Tln1E1770A mutant mice display defective hemostasis when examined using a tail bleeding assay. Furthermore, platelets isolated from Tln1E1770A mice exhibit disrupted aggregation and delayed clot retraction, indicating a defect in integrin signaling. However, integrin activation was not increased in platelets with defective talin autoinhibition, suggesting a different role for talin in platelets, distinct from inside-out integrin signaling. Taken together, our data shows that talin autoinhibition is an important regulatory mechanism in platelets during hemostasis.