title: An important role for Akt3 in platelet activation and thrombosis.
abstract: 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 3β (GSK-3β) at Ser9, which is known to inhibit GSK-3β function. Thus, Akt3 is important in inhibiting GSK-3β. Accordingly, treatment of Akt3(-/-) platelets with a GSK-3β inhibitor rescued the defect of Akt3(-/-) platelets in thrombin-induced aggregation, suggesting that negatively regulating GSK-3β 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.
authors.affiliation: Department of Pharmacology, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: O'Brien
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Stojanovic-Terpo
authors.forename: Nissim
authors.initials: N
authors.lastname: Hay
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Du
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000201:enzymology*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000235:genetics; D010974:Platelet Aggregation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D013917:Thrombin / Q000235:genetics / Q000378:metabolism; D013927:Thrombosis / Q000201:enzymology* / Q000235:genetics; D013928:Thromboxane A2 / Q000235:genetics / Q000378:metabolism; D014841:von Willebrand Factor / Q000235:genetics / Q000378:metabolism
chemical_list: D014841:von Willebrand Factor; D013928:Thromboxane A2; C491754:AKT3 protein, human; C491753:Akt3 protein, mouse; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D013917:Thrombin