Advertisement

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

Patrick Münzer, Britta Walker-Allgaier, Sascha Geue, Friederike Langhauser, Eva Geuss, David Stegner, Katja Aurbach, Daniela Semeniak, Madhumita Chatterjee, Irene Gonzalez Menendez, Melanie Märklin, Leticia Quintanilla-Martinez, Helmut R. Salih, David W. Litchfield, Thierry Buchou, Christoph Kleinschnitz, Florian Lang, Bernhard Nieswandt, Irina Pleines, Harald Schulze, Meinrad Gawaz and Oliver Borst

Key Points

  • CK2β is critically required for thrombopoiesis by regulating tubulin polymerization, MK fragmentation, and proplatelet formation.

  • CK2β facilitates inositol triphosphate–mediated increase of cytosolic Ca2+ and is essential for platelet activation in arterial thrombosis in vivo.

Publisher's Note: There is an Inside Blood Commentary on this article in this issue.

Abstract

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 αIIbβ3 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 ck2βfl/fl mice. The present observations reveal CK2β as a novel powerful regulator of thrombopoiesis, Ca2+-dependent platelet activation, and arterial thrombosis in vivo.

  • Submitted May 12, 2017.
  • Accepted September 12, 2017.
View Full Text