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

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, ck2 β −/− 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 (Ca 2+ ) release. Presumably due to a blunted increase in the concentration of cytosolic Ca 2+ , activation-dependent increases of α and dense-granule secretion and integrin α IIb β 3 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 fl/fl mice. The present observations reveal CK2β as a novel powerful regulator of thrombopoiesis, Ca 2+ -dependent platelet activation, and arterial thrombosis in vivo.