CK2β regulates thrombopoiesis and Ca²⁺-triggered platelet activation in arterial thrombosis

Platelets, anucleated megakaryocyte (MK)-derived cells, play a major role in hemostasis and arterial thrombosis. Although protein kinase casein kinase 2 (CK2) is readily detected in MKs and platelets, the impact of CK2-dependent signaling on MK/platelet (patho-)physiology has remained elusive. The present study explored the impact of the CK2 regulatory β-subunit on platelet biogenesis and activation. MK/platelet-specific genetic deletion of CK2β (ck2β ) in mice resulted in a significant macrothrombocytopenia and an increased extramedullar megakaryopoiesis with an enhanced proportion of premature platelets. Although platelet life span was only mildly affected, ck2β MK displayed an abnormal microtubule structure with a drastically increased fragmentation within bone marrow and a significantly reduced proplatelet formation in vivo. In ck2β platelets, tubulin polymerization was disrupted, resulting in an impaired thrombopoiesis and an abrogated inositol 1,4,5-triphosphate receptor-dependent intracellular calcium (Ca²⁺) release. Presumably due to a blunted increase in the concentration of cytosolic Ca²⁺, activation-dependent increases of α and dense-granule secretion and integrin α_IIbβ₃ activation, and aggregation were abrogated in ck2β platelets. Accordingly, thrombus formation and stabilization under high arterial shear rates were significantly diminished, and thrombotic vascular occlusion in vivo was significantly blunted in ck2β mice, accompanied by a slight prolongation of bleeding time. Following transient middle cerebral artery occlusion, ck2β mice displayed significantly reduced cerebral infarct volumes, developed significantly less neurological deficits, and showed significantly better outcomes after ischemic stroke than ck2β mice. The present observations reveal CK2β as a novel powerful regulator of thrombopoiesis, Ca²⁺-dependent platelet activation, and arterial thrombosis in vivo.