The Role of Akt in Platelet Activation
thesisposted on 2013-02-21, 00:00 authored by Kelly A. O'Brien
Platelet activation is critical for the maintenance of hemostasis. Under pathological conditions, platelets also play a critical role in thrombosis, a leading cause of heart attack and stroke. Therefore, understanding the mechanisms of platelet activation may aid in the development of novel anti-thrombotic agents. PI3 Kinases (PI3Ks) have been shown to be a common and key signal mediator in platelet activation. The most well known effector of PI3Ks is Akt. Akt is a family of serine threonine kinases with 3 isoforms: Akt1, Akt2, and Akt3. In this study, we have identified Akt3 expression in platelets and that Akt3 plays an important role in platelet function and thrombosis. Furthermore, the role of Akt3 in platelets is different from the previously characterized Akt1 and Akt2 in that Akt3 selectively plays a stimulatory role in the signaling pathways of two Gq/G13 coupled receptors (thrombin receptors PAR4 and TXA2 receptor), but is not required in the signaling pathways mediated by collagen, ADP, and VWF receptor. Therefore, different isoforms of Akt have distinct and shared roles in platelet activation. In addition, we show that Akt (specifically Akt3) plays an important role in integrin outside-in signaling and is important in promoting platelet spreading on integrin ligands. The role of Akt provides a mechanism why PI3K is important for cell spreading in platelets and other cell types. In addition, we have shown that a major mechanism by which Akt3 mediates platelet activation signaling is its phosphorylation and inhibition of GSK-3β. This is different from the major mechanisms responsible for the roles of Akt1 and Akt2, which are to stimulate the cGMP-dependent protein kinase pathway. Furthermore, GSK-3β plays an inhibitory role in thrombin-induced platelet activation and a novel role in negatively regulating platelet spreading, which is regulated by Akt3. Finally, we have shown that full activation of Src/PI3K/Akt pathway during integrin outside-in signaling requires integrin-mediated ADP secretion and ADP signaling through P2Y12/P2Y1 receptors. This provides a mechanism to explain the importance of ADP secretion in platelet spreading. Taken together, these studies have identified a novel role for Akt3 in platelet activation, thrombosis, and integrin outside-in signaling.