Extracellular export of sphingosine kinase-1a contributes to the vascular S1P gradient
| Autor: | Krishnan Venkataraman, Faraz Idris Khan, Ming-Tao Wu, Myat Lin Oo, Youxi Ai, Jason Michaud, Nehal S. Parikh, Yong-Moon Lee, Richard L. Proia, Shobha Thangada, Timothy Hla |
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| Rok vydání: | 2006 |
| Předmět: |
media_common.quotation_subject
Intracellular Space Sphingosine kinase Biology Biochemistry Mice chemistry.chemical_compound Sphingosine Extracellular Animals Humans Sphingosine-1-phosphate Internalization Molecular Biology Cells Cultured media_common Mice Knockout Kinase Cell Biology Lipid signaling Cell biology Isoenzymes Mice Inbred C57BL Phosphotransferases (Alcohol Group Acceptor) Protein Transport Receptors Lysosphingolipid SPHK2 chemistry Culture Media Conditioned Endothelium Vascular Lysophospholipids Extracellular Space Research Article |
| Zdroj: | Biochemical Journal. 397:461-471 |
| ISSN: | 1470-8728 0264-6021 |
| DOI: | 10.1042/bj20060251 |
| Popis: | Sphingosine 1-phosphate (S1P), produced by Sphks (sphingosine kinases), is a multifunctional lipid mediator that regulates immune cell trafficking and vascular development. Mammals maintain a large concentration gradient of S1P between vascular and extravascular compartments. Mechanisms by which S1P is released from cells and concentrated in the plasma are poorly understood. We recently demonstrated [Ancellin, Colmont, Su, Li, Mittereder, Chae, Stefansson, Liau and Hla (2002) J. Biol. Chem. 277, 6667–6675] that Sphk1 activity is constitutively secreted by vascular endothelial cells. In the present study, we show that among the five Sphk isoforms expressed in endothelial cells, the Sphk-1a isoform is selectively secreted in HEK-293 cells (human embryonic kidney cells) and human umbilical-vein endothelial cells. In sharp contrast, Sphk2 is not secreted. The exported Sphk-1a isoform is enzymatically active and produced sufficient S1P to induce S1P receptor internalization. Wild-type mouse plasma contains significant Sphk activity (179 pmol·min−1·g−1). In contrast, Sphk1−/− mouse plasma has undetectable Sphk activity and approx. 65% reduction in S1P levels. Moreover, human plasma contains enzymatically active Sphk1 (46 pmol·min−1·g−1). These results suggest that export of Sphk-1a occurs under physiological conditions and may contribute to the establishment of the vascular S1P gradient. |
| Databáze: | OpenAIRE |
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