Sphingosine kinase 2 (Sphk2) regulates platelet biogenesis by providing intracellular sphingosine 1-phosphate (S1P)

• Published in: Blood 2013-08, Vol.122 (5), p.791-802
• Main Authors: Zhang, Lin, Urtz, Nicole, Gaertner, Florian, Legate, Kyle R., Petzold, Tobias, Lorenz, Michael, Mazharian, Alexandra, Watson, Steve P., Massberg, Steffen
• Format: Article
• Language: English
• Subjects: Animals; Blood Platelets - metabolism; Blood Platelets - physiology; Cell Differentiation - genetics; Cell Survival - genetics; Homeostasis - genetics; Homeostasis - physiology; Intracellular Space - metabolism; Lysophospholipids - metabolism; Megakaryocytes - metabolism; Megakaryocytes - physiology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Phosphotransferases (Alcohol Group Acceptor) - genetics; Phosphotransferases (Alcohol Group Acceptor) - metabolism; Phosphotransferases (Alcohol Group Acceptor) - physiology; Sphingosine - analogs & derivatives; Sphingosine - metabolism; src-Family Kinases - genetics; src-Family Kinases - metabolism; Thrombopoiesis - genetics; Thrombopoietin - blood
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2012-12-473884

Human megakaryocytes (MKs) release trillions of platelets each day into the circulation to maintain normal homeostatic platelet levels. We have previously shown that extracellular sphingosine 1-phosphate (S1P) plays a key role in thrombopoiesis via its receptor S1pr1. In addition to its role as an extracellular mediator, S1P can also function as a second messenger in the intracellular compartment. Although signaling via intracellular S1P is involved in various cellular processes, a role in thrombopoiesis has not been examined. Sphingosine kinases are the key enzymes that produce intracellular S1P. Here we report that sphingosine kinase 2 (Sphk2) is the major messenger RNA species present in MKs. Sphk2 predominantly localizes to the nucleus and is the major source of intracellular S1P in MKs. Loss of Sphk2 significantly reduced intracellular S1P in MKs and downregulated the expression and activity of Src family kinases (SFKs). Loss of Sphk2 and inhibition of SFK activity resulted in defective intravascular proplatelet shedding, the final stage of thrombopoiesis. Correspondingly, mice lacking Sphk2 in the hematopoietic system display thrombocytopenia. Together, our data suggest that Sphk2 provides the source of intracellular S1P that controls thrombopoiesis, which is associated with SFK expression and activity in MKs. •Sphk2 provides a source of intracellular S1P that tightly controls thrombopoiesis by regulating SFK expression and activity in MKs.•Modulation of intracellular S1P by regulating Sphk2 may provide a new strategy to enhance platelet production in patients with thrombocytopenia.