| First Author | Münzer P | Year | 2017 |
| Journal | Blood | Volume | 130 |
| Issue | 25 | Pages | 2774-2785 |
| PubMed ID | 28928125 | Mgi Jnum | J:262171 |
| Mgi Id | MGI:6120443 | Doi | 10.1182/blood-2017-05-784413 |
| Citation | Munzer P, et al. (2017) CK2beta regulates thrombopoiesis and Ca(2+)-triggered platelet activation in arterial thrombosis. Blood 130(25):2774-2785 |
| abstractText | 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 beta-subunit on platelet biogenesis and activation. MK/platelet-specific genetic deletion of CK2beta (ck2beta(-/-) ) 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, ck2beta(-/-) MK displayed an abnormal microtubule structure with a drastically increased fragmentation within bone marrow and a significantly reduced proplatelet formation in vivo. In ck2beta(-/-) 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 alpha and dense-granule secretion and integrin alphaIIbbeta3 activation, and aggregation were abrogated in ck2beta(-/-) platelets. Accordingly, thrombus formation and stabilization under high arterial shear rates were significantly diminished, and thrombotic vascular occlusion in vivo was significantly blunted in ck2beta(-/-) mice, accompanied by a slight prolongation of bleeding time. Following transient middle cerebral artery occlusion, ck2beta(-/-) mice displayed significantly reduced cerebral infarct volumes, developed significantly less neurological deficits, and showed significantly better outcomes after ischemic stroke than ck2beta(fl/fl) mice. The present observations reveal CK2beta as a novel powerful regulator of thrombopoiesis, Ca(2+)-dependent platelet activation, and arterial thrombosis in vivo. |
