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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 A? (TXA?), but not collagen or VWF. In contrast, platelets from Akt1(-/-) or Akt2(-/-) mice are defective in platelet activation induced by thrombin, TXA?, 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 FeCl?-induced carotid artery thrombosis in vivo. Thus, Akt3 plays an important and distinct role in platelet activation and in thrombosis.

SUBMITTER: O'Brien KA

PROVIDER: S-EPMC3204738 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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An important role for Akt3 in platelet activation and thrombosis.

O'Brien Kelly A KA Stojanovic-Terpo Aleksandra A Hay Nissim N Du Xiaoping X

Blood 20110805 15

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(- ...[more]

PMID: 21821713

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Project description:Essentials Signaling by Gas6 through Tyro3/Axl/Mer receptors is essential for stable platelet aggregation. UNC2025 is a small molecule inhibitor of the Mer tyrosine kinase. UNC2025 decreases platelet activation in vitro and thrombus formation in vivo. UNC2025's anti-platelet effect is synergistic with inhibition of the ADP receptor, P2Y12 . SUMMARY:Background Growth arrest-specific protein 6 signals through the TAM (TYRO-3-AXL-MERTK) receptor family, mediating platelet activation and thrombus formation via activation of the aggregate-stabilizing ?IIb ?3 integrin. Objective To describe the antithrombotic effects mediated by UNC2025, a small-molecule MERTK tyrosine kinase inhibitor. Methods MERTK phosphorylation and downstream signaling were assessed by immunoblotting. Light transmission aggregometry, flow cytometry and microfluidic analysis were used to evaluate the impact of MERTK inhibition on platelet activation and stability of aggregates in vitro. The effects of MERTK inhibition on arterial and venous thrombosis, platelet accumulation at microvascular injury sites and tail bleeding times were determined with murine models. The effects of combined treatment with ADP-P2Y1&12 pathway antagonists and UNC2025 were also evaluated. Results and Conclusions Treatment with UNC2025 inhibited MERTK phosphorylation and downstream activation of AKT and SRC, decreased platelet activation, and protected animals from pulmonary embolism and arterial thrombosis without increasing bleeding times. The antiplatelet effect of UNC2025 was enhanced in combination with ADP-P2Y1&12 pathway antagonists, and a greater than additive effect was observed when these two agents with different mechanisms of inhibition were coadministered. TAM kinase signaling represents a potential therapeutic target, as inhibition of this axis, especially in combination with ADP-P2Y pathway antagonism, mediates decreased platelet activation, aggregate stability, and thrombus formation, with less hemorrhagic potential than current treatment strategies. The data presented here also demonstrate antithrombotic activity mediated by UNC2025, a novel translational agent, and support the development of TAM kinase inhibitors for clinical applications.

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An important role for Akt3 in platelet activation and thrombosis.

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An important role for Akt3 in platelet activation and thrombosis.

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