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

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 IP3-mediated [Ca2+]i increase and is essential for platelet activation in arterial thrombosis and ischemic stroke in vivo.

Abstract

Platelets, anucleated megakaryocyte-derived cells, play a major role in hemostasis and arterial thrombosis. While protein kinase Casein Kinase 2 (CK2) is readily detected in megakaryocytes and platelets, the impact of CK2-dependent signaling on megakaryocyte/platelet (patho-) physiology has remained elusive. The present study explored the impact of the CK2 regulatory β-subunit on platelet biogenesis and activation. Megakaryocyte/platelet-specific genetic deletion of CK2β (ck2β-/-) in mice resulted in a significant macrothrombocytopenia and an increased extramedullar megakaryopoiesis with enhanced proportion of premature platelets. While platelet lifespan was only mildly affected, ck2β-/- megakaryocytes 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 IP3 receptor-dependent intracellular Ca2+ release. Presumably due to blunted increase of cytosolic Ca2+-concentration ([Ca2+]i), activation-dependent increases of alpha and dense granule secretion, 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 tMCAO, ck2β-/- mice displayed significantly reduced cerebral infarct volumes, developed significantly less neurological deficits and showed significantly better outcome after ischemic stroke than ck2βfl/fl mice. The present observations reveal CK2β as novel powerful regulator of thrombopoiesis, Ca2+-dependent platelet activation and arterial thrombosis in vivo.

  • Submitted May 12, 2017.
  • Accepted September 12, 2017.