Talin autoinhibition is required for normal hemostasis.

Abstract

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, Tln1^E1770A, therefore increases integrin activation and disrupts cell migration in fibroblasts. Here, we show that talin autoinhibition also plays an important role during hemostasis. Tln1^E1770A mutant mice display defective hemostasis when examined using a tail bleeding assay. Furthermore, platelets isolated from Tln1^E1770A 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.