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  • Title: The β isoform of the catalytic subunit of protein phosphatase 2B restrains platelet function by suppressing outside-in αII b β3 integrin signaling.
    Author: Khatlani T, Pradhan S, Da Q, Gushiken FC, Bergeron AL, Langlois KW, Molkentin JD, Rumbaut RE, Vijayan KV.
    Journal: J Thromb Haemost; 2014 Dec; 12(12):2089-101. PubMed ID: 25330904.
    Abstract:
    BACKGROUND: Calcium-dependent signaling mechanisms play a critical role in platelet activation. Unlike calcium-activated protease and kinase, the contribution of calcium-activated protein serine/threonine phosphatase in platelet activation is poorly understood. OBJECTIVE: To assess the role of catalytic subunit of protein phosphatase 2B (PP2B) or calcineurin in platelet function. RESULTS: Here, we showed that an increase in PP2B activity was associated with agonist-induced activation of human and murine platelets. Pharmacological inhibitors of the catalytic subunit of protein phosphatase 2B (PP2B-A) such as cyclosporine A or tacrolimus (FK506) potentiated aggregation of human platelets. Murine platelets lacking the β isoform of PP2B-A (PP2B-Aβ(-/-) ) displayed increased aggregation with low doses of agonist concentrations. Loss of PP2B-Aβ did not affect agonist-induced integrin αII b β3 inside-out signaling, but increased basal Src activation and outside-in αII b β3 signaling to p38 mitogen-activated protein kinase (MAPK), with a concomitant enhancement in platelet spreading on immobilized fibrinogen and greater fibrin clot retraction. Fibrinogen-induced increased p38 activation in PP2B-Aβ(-/-) platelets were blocked by Src inhibitor. Both PP2B-Aβ(-/-) platelets and PP2B-Aβ-depleted human embryonal kidney 293 αII b β3 cells displayed increased adhesion to immobilized fibrinogen. Filamin A, an actin crosslinking phosphoprotein that is known to associate with β3 , was dephosphorylated on Ser(2152) in fibrinogen-adhered wild-type but not in PP2B-Aβ(-/-) platelets. In a FeCl3 injury thrombosis model, PP2B-Aβ(-/-) mice showed decreased time to occlusion in the carotid artery. CONCLUSION: These observations indicate that PP2B-Aβ by suppressing outside-in αII b β3 integrin signaling limits platelet response to vascular injury.
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