PLATELETS AND THROMBOPOIESIS An important role for Akt3 in platelet activation and thrombosis

The Akt family of serine/threonine kinases includes Akt1, Akt2, and Akt3 isoforms. Prior studies have reported that Akt1 and Akt2, but not Akt3, are expressed in platelets. Here, we show that Akt3 is expressed in substantial amounts in platelets. Akt3 / mouse platelets selectively exhibit impaired platelet aggregation and secretion in response to low concentrations of thrombin receptor agonists and thromboxane A2 (TXA2), but not collagen or VWF. In contrast, platelets from Akt1 / or Akt2 / mice are defective in platelet activation induced by thrombin, TXA2, and VWF, but only Akt1 / platelets show significant defects in response to collagen, indicating differences among Akt isoforms. Akt3 / platelets exhibit a significant reduction in thrombin-induced phosphorylation of glycogen synthase kinase 3 (GSK-3 ) at Ser9, which is known to inhibit GSK-3 function. Thus, Akt3 is important in inhibiting GSK-3 . Accordingly, treatment of Akt3 / platelets with a GSK-3 inhibitor rescued the defect of Akt3 / platelets in thrombin-induced aggregation, suggesting that negatively regulating GSK-3 may be a mechanism by which Akt3 promotes platelet activation. Importantly, Akt3 / mice showed retardation in FeCl3-induced carotid artery thrombosis in vivo. Thus, Akt3 plays an important and distinct role in platelet activation and in thrombosis. (Blood. 2011;118(15): 4215-4223)