Extracellular and Intracellular Actions of Sphingosine-1-Phosphate

  • Graham M. Strub
  • Michael Maceyka
  • Nitai C. Hait
  • Sheldon Milstien
  • Sarah SpiegelEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 688)


Sphingosine-1-phosphate (S1P) is a bioactive lipid mediator with crucial roles in a wide variety of cellular functions across a broad range of organisms. Though a simple molecule in structure, S1P functions are complex. The formation of S1P is catalyzed by one of two sphingosine kinases that have differential cellular distributions as well as both overlapping and opposing functions and which are activated by many different stimuli. S1P can act on a family of G protein-coupled receptors (S1PRs) that are also differentially expressed in different cell types, which influences the cellular responses to S1P. In addition to acting on receptors located on the plasma membrane, S1P can also function inside the cell, independently of S1PRs. It also appears that both the intracellular location and the isotype of sphingosine kinase involved are major determinants of inside-out signaling of S1P in response to many extracellular stimuli. This chapter is focused on the current literature on extracellular and intracellular actions of S1P.


Mast Cell Sphingosine Kinase SphK2 Expression Bioactive Lipid Mediator Ulatory Molecule 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Spiegel S, Milstien S. Sphingosine-1-phosphate: an enigmatic signalling lipid. Nat Rev Mol Cell Biol 2003; 4:397–407.PubMedGoogle Scholar
  2. 2.
    Takabe K, Paugh SW, Milstien S et al. “Inside-out” signaling of sphingosine-1-phosphate: therapeutic targets. Pharmacol Rev 2008; 60:181–195.PubMedGoogle Scholar
  3. 3.
    Ogretmen B, Hannun YA. Biologically active sphingolipids in cancer pathogenesis and treatment. Nature Rev Cancer 2004; 4:604–616.Google Scholar
  4. 4.
    Reynolds CP, Maurer BJ, Kolesnick RN. Ceramide synthesis and metabolism as a target for cancer therapy. Cancer Lett 2004; 206:169–180.PubMedGoogle Scholar
  5. 5.
    Maceyka M, Milstien S, Spiegel S. Measurement of mammalian sphingosine-1-phosphate phosphohydrolase activity in vitro and in vivo. Methods Enzymol 2007; 434:243–256.PubMedGoogle Scholar
  6. 6.
    Bandhuvula P, Saba JD. Sphingosine-1-phosphate lyase in immunity and cancer: silencing the siren. Trends Mol Med 2007; 13:210–217.PubMedGoogle Scholar
  7. 7.
    Maceyka M, Payne SG, Milstien S et al. Sphingosine kinase, sphingosine-1-phosphate and apoptosis. Biochim Biophys Acta 2002; 1585:193–201.PubMedGoogle Scholar
  8. 8.
    Saba JD, Hla T. Point-counterpoint of sphingosine 1-phosphate metabolism. Circ Res 2004; 94:724–734.PubMedGoogle Scholar
  9. 9.
    Cyster JG. Chemokines, sphingosine-1-phosphate and cell migration in secondary lymphoid organs. Annu Rev Immunol 2005; 23:127–159.PubMedGoogle Scholar
  10. 10.
    Cuvillier O, Pirianov G, Kleuser B et al. Suppression of ceramide-mediated programmed cell death by sphingosine-1-phosphate. Nature 1996; 381:800–803.PubMedGoogle Scholar
  11. 11.
    Kohama T, Olivera A, Edsall L et al. Molecular cloning and functional characterization of murine sphingosine kinase. J Biol Chem 1998; 273:23722–23728.PubMedGoogle Scholar
  12. 12.
    Liu H, Sugiura M, Nava VE et al. Molecular cloning and functional characterization of a novel mammalian sphingosine kinase type 2 isoform. J Biol Chem 2000; 275:19513–19520.PubMedGoogle Scholar
  13. 13.
    Liu H, Chakravarty D, Maceyka M et al. Sphingosine kinases: a novel family of lipid kinases. Prog Nucl Acid Res 2002; 71:493–511.Google Scholar
  14. 14.
    Nagiec MM, Skrzypek M, Nagiec EE et al. The LCB4 (YOR171c) and LCB5 (YLR260w) genes of Saccharomyces encode long chain base kinases. J Biol Chem 1998; 273:19437–19442.PubMedGoogle Scholar
  15. 15.
    Allende ML, Sasaki T, Kawai H et al. Mice deficient in sphingosine kinase 1 are rendered lymphopenic by FTY720. J Biol Chem 2004; 279:52487–52492.PubMedGoogle Scholar
  16. 16.
    Mizugishi K, Yamashita T, Olivera A et al. Essential role for sphingosine kinases in neural and vascular development. Mol Cell Biol 2005; 25:11113–11121.PubMedGoogle Scholar
  17. 17.
    Herr DR, Fyrst H, Creason MB et al. Characterization of the Drosophila sphingosine kinases and requirement for Sk2 in normal reproductive function. J Biol Chem 2004; 279:12685–12694.PubMedGoogle Scholar
  18. 18.
    Billich A, Bornancin F, Devay P et al. Phosphorylation of the immunomodulatory drug FTY720 by sphingosine kinases. J Biol Chem 2003; 278:47408–47415.PubMedGoogle Scholar
  19. 19.
    Venkataraman K, Thangada S, Michaud J et al. Extracellular export of sphingosine kinase-1a contributes to the vascular S1P gradient. Biochem J 2006; 397:461–471.PubMedGoogle Scholar
  20. 20.
    Olivera A, Kohama T, Tu Z et al. Purification and characterization of rat kidney sphingosine kinase. J Biol Chem 1998; 273:12576–12583.PubMedGoogle Scholar
  21. 21.
    Sutherland CM, Moretti PA, Hewitt NM et al. The calmodulin-binding site of sphingosine kinase and its role in agonist-dependent translocation of sphingosine kinase 1 to the plasma membrane. J Biol Chem 2006; 281:11693–11701.PubMedGoogle Scholar
  22. 22.
    Pitson SM, Moretti PA, Zebol JR et al. Activation of sphingosine kinase 1 by ERK1/2-mediated phosphorylation. EMBO J 2003; 22:5491–5500.PubMedGoogle Scholar
  23. 23.
    Pitson SM, Xia P, Leclercq TM et al. Phosphorylation-dependent translocation of sphingosine kinase to the plasma membrane drives its oncogenic signalling. J Exp Med 2005; 201:49–54.PubMedGoogle Scholar
  24. 24.
    Hayashi S, Okada T, Igarashi N et al. Identification and characterization of RPK118, a novel sphingosine kinase-1-binding protein. J Biol Chem 2002; 277:33319–33324.PubMedGoogle Scholar
  25. 25.
    Fukuda Y, Aoyama Y, Wada A et al. Identification of PECAM-1 association with sphingosine kinase 1 and its regulation by agonist-induced phosphorylation. Biochim Biophys Acta 2004; 1636:12–21.PubMedGoogle Scholar
  26. 26.
    Maceyka M, Nava VE, Milstien S et al. Aminoacylase 1 is a sphingosine kinase 1-interacting protein. FEBS Lett 2004; 568:30–34.PubMedGoogle Scholar
  27. 27.
    Fujita T, Okada T, Hayashi S et al. Delta-catenin/NPRAP (neural plakophilin-related armadillo repeat protein) interacts with and activates sphingosine kinase 1. Biochem J 2004; 382:717–723.PubMedGoogle Scholar
  28. 28.
    Hait NC, Oskeritzian CA, Paugh SW et al. Sphingosine kinases, sphingosine 1-phosphate, apoptosis and diseases. Biochim Biophys Acta 2006; 1758:2016–2026.PubMedGoogle Scholar
  29. 29.
    Hannun YA, Obeid LM. Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Biol 2008; 9:139–150.PubMedGoogle Scholar
  30. 30.
    Okada T, Ding G, Sonoda H et al. Involvement of N-terminal-extended form of sphingosine kinase 2 in serum-dependent regulation of cell proliferation and apoptosis. J Biol Chem 2005; 280:36318–36325.PubMedGoogle Scholar
  31. 31.
    Paugh SW, Payne SG, Barbour SE et al. The immunosuppressant FTY720 is phosphorylated by sphingosine kinase type 2. FEBS Lett 2003; 554:189–193.PubMedGoogle Scholar
  32. 32.
    Sanchez T, Estrada-Hernandez T, Paik JH et al. Phosphorylation and action of the immunomodulator FTY720 inhibits VEGF-induced vascular permeability. J Biol Chem 2003; 278:47281–47290.PubMedGoogle Scholar
  33. 33.
    Yoshimoto T, Furuhata M, Kamiya S et al. Positive modulation of IL-12 signaling by sphingosine kinase 2 associating with the IL-12 receptor beta1 cytoplasmic region. J Immunol 2003; 171:1352–1359.PubMedGoogle Scholar
  34. 34.
    Liu H, Toman RE, Goparaju S et al. Sphingosine kinase type 2 is a putative BH3-only protein that induces apoptosis. J Biol Chem 2003; 278:40330–40336.PubMedGoogle Scholar
  35. 35.
    Hait NC, Sarkar S, Le Stunff H et al. Role of sphingosine kinase 2 in cell migration towards epidermal growth factor. J Biol Chem 2005; 280:29462–29469.PubMedGoogle Scholar
  36. 36.
    Olivera A, Urtz N, Mizugishi K et al. IgE-dependent activation of sphingosine kinases 1 and 2 and secretion of sphingosine 1-phosphate requires Fyn kinase and contributes to mast cell responses. J Biol Chem 2006; 281:2515–2525.PubMedGoogle Scholar
  37. 37.
    Mastrandrea LD, Sessanna SM, Laychock SG. Sphingosine kinase activity and sphingosine-1 phosphate production in rat pancreatic islets and INS-1 cells: response to cytokines. Diabetes 2005; 54:1429–1436.PubMedGoogle Scholar
  38. 38.
    Hait NC, Bellamy A, Milstien S et al. Sphingosine kinase type 2 activation by ERK-mediated phosphorylation. J Biol Chem 2007; 282:12058–12065.PubMedGoogle Scholar
  39. 39.
    Igarashi N, Okada T, Hayashi S et al. Sphingosine kinase 2 is a nuclear protein and inhibits DNA synthesis. J Biol Chem 2003; 278:46832–46839.PubMedGoogle Scholar
  40. 40.
    Min J, Mesika A, Sivaguru M et al. (Dihydro)ceramide synthase 1 regulated sensitivity to cisplatin is associated with the activation of p38 mitogen-activated protein kinase and is abrogated by sphingosine kinase 1. Mol Cancer Res 2007; 5:801–812.PubMedGoogle Scholar
  41. 41.
    Sankala HM, Hait NC, Paugh SW et al. Involvement of sphingosine kinase 2 in p53-independent induction of p21 by the chemotherapeutic drug doxorubicin. Cancer Res 2007; 67:10466–10474.PubMedGoogle Scholar
  42. 42.
    Funato K, Lombardi R, Vallée B et al. Lcb4p is a key regulator of ceramide synthesis from exogenous long chain sphingoid base in Saccharomyces cerevisiae. J Biol Chem 2003; 278:7325–7334.PubMedGoogle Scholar
  43. 43.
    Van Brocklyn JR, Jackson CA, Pearl DK et al. Sphingosine kinase-1 expression correlates with poor survival of patients with glioblastoma multiforme: roles of sphingosine kinase isoforms in growth of glioblastoma cell lines. J Neuropathol Exp Neurol 2005; 64:695–705.PubMedGoogle Scholar
  44. 44.
    French KJ, Schrecengost RS, Lee BD et al. Discovery and evaluation of inhibitors of human sphingosine kinase. Cancer Res 2003; 63:5962–5969.PubMedGoogle Scholar
  45. 45.
    Weigert A, Johann AM, von Knethen A et al. Apoptotic cells promote macrophage survival by releasing the antiapoptotic mediator sphingosine-1-phosphate. Blood 2006; 108:1635–1642.PubMedGoogle Scholar
  46. 46.
    Gude DR, Alvarez SE, Paugh SW et al. Apoptosis induces expression of sphingosine kinase 1 to release sphingosine-1-phosphate as a “come-and-get-me” signal. FASEB J 2008; 22:2629–2638.PubMedGoogle Scholar
  47. 47.
    Maceyka M, Sankala H, Hait NC et al. Sphk1 and Sphk2: Sphingosine kinase isoenzymes with opposing functions in sphingolipid metabolism. J Biol Chem 2005; 280:37118–37129.PubMedGoogle Scholar
  48. 48.
    Laviad EL, Albee L, Pankova-Kholmyansky I et al. Characterization of ceramide synthase 2: tissue distribution, substrate specificity and inhibition by sphingosine 1-phosphate. J Biol Chem 2008; 283:5677–5684.PubMedGoogle Scholar
  49. 49.
    Le Stunff H, Galve-Roperh I, Peterson C et al. Sphingosine-1-phosphate phosphohydrolase in regulation of sphingolipid metabolism and apoptosis. J Cell Biol 2002; 158:1039–1049.PubMedGoogle Scholar
  50. 50.
    Le Stunff H, Giussani P, Maceyka M et al. Recycling of sphingosine is regulated by the concerted actions of sphingosine-1-phosphate phosphohydrolase 1 and sphingosine kinase 2. J Biol Chem 2007; 282:3472–3480.Google Scholar
  51. 51.
    Zhao Y, Kalari SK, Usatyuk PV et al. Intracellular generation of sphingosine 1-phosphate in human lung endothelial cells: Role of lipid phosphate phosphatase-1 and sphingosine kinase 1. J Biol Chem 2007; 282:14165–14177.PubMedGoogle Scholar
  52. 52.
    Sukocheva O, Wadham C, Holmes A et al. Estrogen transactivates EGFR via the sphingosine 1-phosphate receptor Edg-3: the role of sphingosine kinase-1. J Cell Biol 2006; 173:301–310.PubMedGoogle Scholar
  53. 53.
    Shu X, Wu W, Mosteller RD et al. Sphingosine kinase mediates vascular endothelial growth factor-induced activation of ras and mitogen-activated protein kinases. Mol Cell Biol 2002; 22:7758–7768.PubMedGoogle Scholar
  54. 54.
    Pettus BJ, Bielawski J, Porcelli AM et al. The sphingosine kinase 1/sphingosine-1-phosphate pathway mediates COX-2 induction and PGE2 production in response to TNF-alpha. FASEB J 2003; 17:1411–1421.PubMedGoogle Scholar
  55. 55.
    Donati C, Bruni P. Sphingosine 1-phosphate regulates cytoskeleton dynamics: Implications in its biological response. Biochim Biophys Acta 2006; 1758:2037–2048.PubMedGoogle Scholar
  56. 56.
    Sarkar S, Maceyka M, Hait NC et al. Sphingosine kinase 1 is required for migration, proliferation and survival of MCF-7 human breast cancer cells. FEBS Lett 2005; 579:5313–5317.PubMedGoogle Scholar
  57. 57.
    Jolly PS, Bektas M, Olivera A et al. Transactivation of sphingosine-1-phosphate receptors by FcepsilonRI triggering is required for normal mast cell degranulation and chemotaxis. J Exp Med 2004; 199:959–970.PubMedGoogle Scholar
  58. 58.
    Olivera A, Mizugishi K, Tikhonova A et al. The sphingosine kinase-sphingosine-1-phosphate axis is a determinant of mast cell function and anaphylaxis. Immunity 2007; 26:287–297.PubMedGoogle Scholar
  59. 59.
    Oskeritzian CA, Alvarez SE, Hait NC et al. Distinct roles of sphingosine kinases 1 and 2 in human mast-cell functions. Blood 2008; 111:4193–4200.PubMedGoogle Scholar
  60. 60.
    Zemann B, Urtz N, Reuschel R et al. Normal neutrophil functions in sphingosine kinase type 1 and 2 knockout mice. Immunol Lett 2007; 109:56–63.PubMedGoogle Scholar
  61. 61.
    Brinkmann V. Sphingosine 1-phosphate receptors in health and disease: mechanistic insights from gene deletion studies and reverse pharmacology. Pharmacol Ther 2007; 115:84–105.PubMedGoogle Scholar
  62. 62.
    Alvarez SE, Milstien S, Spiegel S. Autocrine and paracrine roles of sphingosine-1-phosphate. Trends Endocrinol Metab 2007; 18:300–307.PubMedGoogle Scholar
  63. 63.
    Mitra P, Oskeritzian CA, Payne SG et al. Role of ABCC1 in export of sphingosine-1-phosphate from mast cells. Proc Natl Acad Sci USA 2006; 103:16394–16399.PubMedGoogle Scholar
  64. 64.
    Le Stunff H, Mikami A, Giussani P et al. Role of sphingosine-1-phosphate phosphatase 1 in epidermal growth factor-induced chemotaxis. J Biol Chem 2004; 279:34290–34297.PubMedGoogle Scholar
  65. 65.
    Schwab SR, Pereira JP, Matloubian M et al. Lymphocyte sequestration through S1P lyase inhibition and disruption of S1P gradients. Science 2005; 309:1735–1739.PubMedGoogle Scholar
  66. 66.
    Chen Y, Corriden R, Inoue Y et al. ATP release guides neutrophil chemotaxis via P2Y2 and A3 receptors. Science 2006; 314:1792–1795.PubMedGoogle Scholar
  67. 67.
    Hla T, Maciag T. An abundant transcript induced in differentiating human endothelial cells encodes a polypeptide with structural similarities to G-protein coupled receptors. J Biol Chem 1990; 265:9308–9313.PubMedGoogle Scholar
  68. 68.
    Liu Y, Wada R, Yamashita T et al. Edg-1, the G protein-coupled receptor for sphingosine-1-phosphate, is essential for vascular maturation. J Clin Invest 2000; 106:951–961.PubMedGoogle Scholar
  69. 69.
    Allende ML, Yamashita T, Proia RL. G-protein coupled receptor S1P1 acts within endothelial cells to regulate vascular maturation. Blood 2003; 102:3665–3667.PubMedGoogle Scholar
  70. 70.
    McVerry BJ, Garcia JG. Endothelial cell barrier regulation by sphingosine 1-phosphate. J Cell Biochem 2004; 92:1075–1085.PubMedGoogle Scholar
  71. 71.
    Singleton PA, Dudek SM, Ma SF et al. Transactivation of sphingosine 1-phosphate receptors is essential for vascular barrier regulation. Novel role for hyaluronan and CD44 receptor family. J Biol Chem 2006; 281:34381–34393.PubMedGoogle Scholar
  72. 72.
    Sanchez T, Skoura A, Wu MT et al. Induction of vascular permeability by the sphingosine-1-phosphate receptor-2 (S1P2R) and its downstream effectors ROCK and PTEN. Arterioscler Thromb Vasc Biol 2007; 27:1312–1318.PubMedGoogle Scholar
  73. 73.
    Singleton PA, Dudek SM, Chiang ET et al. Regulation of sphingosine 1-phosphate-induced endothelial cytoskeletal rearrangement and barrier enhancement by S1P1 receptor, PI3 kinase, Tiam1/Rac1 and alpha-actinin. FASEB J 2005; 19:1646–1656.PubMedGoogle Scholar
  74. 74.
    Finigan JH, Dudek SM, Singleton PA et al. Activated protein C mediates novel lung endothelial barrier enhancement: Role of sphingosine 1-phosphate receptor transactivation. J Biol Chem 2005; 280:17286–17293.PubMedGoogle Scholar
  75. 75.
    McVerry BJ, Garcia JG. In vitro and in vivo modulation of vascular barrier integrity by sphingosine 1-phosphate: mechanistic insights. Cell Signal 2005; 17:131–139.PubMedGoogle Scholar
  76. 76.
    Lee JF, Zeng Q, Ozaki H et al. Dual roles of tight junction associated protein, zonula occludens-1, in sphingosine-1-phosphate mediated endothelial chemotaxis and barrier integrity. J Biol Chem 2006; 281:29190–29200.PubMedGoogle Scholar
  77. 77.
    Sanna MG, Wang SK, Gonzalez-Cabrera PJ et al. Enhancement of capillary leakage and restoration of lymphocyte egress by a chiral S1P(1) antagonist in vivo. Nat Chem Biol 2006; 2:434–441.PubMedGoogle Scholar
  78. 78.
    Pappu R, Schwab SR, Cornelissen I et al. Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate. Science 2007; 316:295–298.PubMedGoogle Scholar
  79. 79.
    Matloubian M, Lo CG, Cinamon G et al. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 2004; 427:355–360.PubMedGoogle Scholar
  80. 80.
    Chi H, Flavell RA. Cutting edge: regulation of T-cell trafficking and primary immune responses by sphingosine 1-phosphate receptor 1. J Immunol 2005; 174:2485–2488.PubMedGoogle Scholar
  81. 81.
    MacLennan AJ, Carney PR, Zhu WJ et al. An essential role for the H218/AGR16/Edg-5/LP(B2) sphingosine 1-phosphate receptor in neuronal excitability. Eur J Neurosci 2001; 14:203–209.PubMedGoogle Scholar
  82. 82.
    Kono M, Belyantseva IA, Skoura A et al. Deafness and stria vascularis defects in S1P2 receptor null mice. J Biol Chem 2007; 282:10690–10696.PubMedGoogle Scholar
  83. 83.
    Herr DR, Chun J. Effects of LPA and S1P on the nervous system and implications for their involvement in disease. Curr Drug Targets 2007; 8:155–167.PubMedGoogle Scholar
  84. 84.
    Lepley D, Paik JH, Hla T et al. The G protein-coupled receptor S1P2 regulates Rho/Rho kinase pathway to inhibit tumor cell migration. Cancer Res 2005; 65:3788–3795.PubMedGoogle Scholar
  85. 85.
    Serriere-Lanneau V, Teixeira-Clerc F, Li L et al. The sphingosine 1-phosphate receptor S1P2 triggers hepatic wound healing. FASEB J 2007; 21:2005–2013.PubMedGoogle Scholar
  86. 86.
    Ishii I, Friedman B, Ye X et al. Selective loss of sphingosine 1-phosphate signaling with no obvious phenotypic abnormality in mice lacking its G protein-coupled receptor, LP(B3)/EDG-3. J Biol Chem 2001; 276:33697–33704.PubMedGoogle Scholar
  87. 87.
    Ishii I, Ye X, Friedman B et al. Marked perinatal lethality and cellular signaling deficits in mice Null for the two sphingosine 1-phosphate receptors, S1P2/LPB2/EDG-5 and S1P3/LPB3/EDG-3. J Biol Chem 2002; 277:25152–25159.PubMedGoogle Scholar
  88. 88.
    Kono M, Mi Y, Liu Y et al. The sphingosine-1-phosphate receptors S1P1, S1P2 and S1P3 function coordinately during embryonic angiogenesis. J Biol Chem 2004; 279:29367–29373.PubMedGoogle Scholar
  89. 89.
    Forrest M, Sun SY, Hajdu R et al. Immune cell regulation and cardiovascular efects of sphingosine 1-phosphate receptoragonists in rodents are mediated via distinct receptor sub-types. J Pharmacol Exp Ther 2004; 309:758–768.PubMedGoogle Scholar
  90. 90.
    Gräler MH, Bernhardt G, Lipp M. EDG6, a novel G-protein-coupled receptor related to receptors for bioactive lysophospholipids, is specifically expressed in lymphoid tissue. Genomics 1998; 53:164–169.PubMedGoogle Scholar
  91. 91.
    Im DS, Heise CE, Ancellin N et al. Characterization of a novel sphingosine 1-phosphate receptor, Edg-8. J Biol Chem 2000; 275:14281–14286.PubMedGoogle Scholar
  92. 92.
    Terai K, Soga T, Takahashi M et al. Edg-8 receptors are preferentially expressed in oligodendrocyte lineage cells of the rat CNS. Neuroscience 2003; 116:1053–1062.PubMedGoogle Scholar
  93. 93.
    Walzer T, Chiossone L, Chaix J et al. Natural killer cell trafficking in vivo requires a dedicated sphingosine 1-phosphate receptor. Nat Immunol 2007; 8:1337–1344.PubMedGoogle Scholar
  94. 94.
    Kluk MJ, Hla T. Signaling of sphingosine-1-phosphate via the S1P/EDG-family of G-protein-coupled receptors. Biochim Biophys Acta 2002; 1582:72–80.PubMedGoogle Scholar
  95. 95.
    Graler MH, Grosse R, Kusch A et al. The sphingosine 1-phosphate receptor S1P4 regulates cell shape and motility via coupling to Gi and G12/13. J Cell Biochem 2003; 89:507–519.PubMedGoogle Scholar
  96. 96.
    Van Brocklyn JR, Graler MH, Bernhardt G et al. Sphingosine-1-phosphate is a ligand for the G protein-coupled receptor EDG-6. Blood 2000; 95:2624–2629.PubMedGoogle Scholar
  97. 97.
    Yamazaki Y, Kon J, Sato K et al. Edg-6 as a putative sphingosine 1-phosphate receptor coupling to Ca(2+) signaling pathway. Biochem Biophys Res Commun 2000; 268:583–589.PubMedGoogle Scholar
  98. 98.
    Wang W, Graeler MH, Goetzl EJ. Type 4 sphingosine 1-phosphate G protein-coupled receptor (S1P4) transduces S1P effects on T-cell proliferation and cytokine secretion without signaling migration. FASEB J 2005; 19:1731–1733.PubMedGoogle Scholar
  99. 99.
    Jaillard C, Harrison S, Stankoff B et al. Edg8/S1P5: an oligodendroglial receptor with dual function on process retraction and cell survival. J Neurosci 2005; 25:1459–1469.PubMedGoogle Scholar
  100. 100.
    Gonda K, Okamoto H, Takuwa N et al. The novel sphingosine 1-phosphate receptor AGR16 is coupled via pertussis toxin-sensitive and-insensitive G-proteins to multiple signalling pathways. Biochem J 1999; 337:67–75.PubMedGoogle Scholar
  101. 101.
    Malek RL, Toman RE, Edsall LC et al. Nrg-1 belongs to the endothelial differentiation gene family of G protein-coupled sphingosine-1-phosphate receptors. J Biol Chem 2001; 276:5692–5699.PubMedGoogle Scholar
  102. 102.
    Jung CG, Kim HJ, Miron VE et al. Functional consequences of S1P receptor modulation in rat oligodendroglial lineage cells. Glia 2007; 55:1656–1667.PubMedGoogle Scholar
  103. 103.
    Lanterman MM, Saba JD. Characterization of sphingosine kinase (SK) activity in Saccharomyces cerevisiae and isolation of SK-deficient mutants. Biochem J 1998; 332:525–531.PubMedGoogle Scholar
  104. 104.
    Kim S, Fyrst H, Saba J. Accumulation of phosphorylated sphingoid long chain bases results in cell growth inhibition in Saccharomyces cerevisiae. Genetics 2000; 156:1519–1529.PubMedGoogle Scholar
  105. 105.
    Zhang X, Skrzypek MS, Lester RL et al. Elevation of endogenous sphingolipid long-chain base phosphates kills Saccharomyces cerevisiae cells. Curr Genet 2001; 40:221–233.PubMedGoogle Scholar
  106. 106.
    Birchwood CJ, Saba JD, Dickson RC et al. Calcium influx and signaling in yeast stimulated by intracellular sphingosine 1-phosphate accumulation. J Biol Chem 2001; 276:11712–11718.PubMedGoogle Scholar
  107. 107.
    Jenkins GM, Hannun YA. Role for de novo sphingoid base biosynthesis in the heat-induced transient cell cycle arrest of Saccharomyces cerevisiae. J Biol Chem 2001; 276:8574–8581.PubMedGoogle Scholar
  108. 108.
    Skrzypek MS, Nagiec MM, Lester RL et al. Analysis of phosphorylated sphingolipid long-chain bases reveals potential roles in heat stress and growth control in Saccharomyces. J Bacteriol 1999; 181:1134–1140.PubMedGoogle Scholar
  109. 109.
    Mao C, Saba JD, Obeid LM. The dihydrosphingosine-1-phosphate phosphatases of Saccharomyces cerevisiae are important regulators of cell proliferation and heat stress responses. Biochem J 1999; 342:667–675.PubMedGoogle Scholar
  110. 110.
    Mandala SM, Thornton R, Galve-Roperh I et al. Molecular cloning and characterization of a lipid phosphohydrolase that degrades sphingosine-1-phosphate and induces cell death. Proc Natl Acad Sci USA 2000; 97:7859–7864.PubMedGoogle Scholar
  111. 111.
    Ng CK, Carr K, McAinsh MR et al. Drought-induced guard cell signal transduction involves sphingosine-1-phosphate. Nature 2001; 410:596–599.PubMedGoogle Scholar
  112. 112.
    Coursol S, Fan LM, Le Stunff H et al. Sphingolipid signalling in Arabidopsis guard cells involves heterotrimeric G proteins. Nature 2003; 423:651–654.PubMedGoogle Scholar
  113. 113.
    Pandey S, Assmann SM. The Arabidopsis putative G protein-coupled receptor GCR1 interacts with the G protein alpha subunit GPA1 and regulates abscisic acid signaling. Plant Cell 2004; 16:1616–1632.PubMedGoogle Scholar
  114. 114.
    Thompson CR, Iyer SS, Melrose N et al. Sphingosine kinase 1 (SK1) is recruited to nascent phagosomes in human macrophages: inhibition of SK1 translocation by Mycobacterium tuberculosis. J Immunol 2005; 174:3551–3561.PubMedGoogle Scholar
  115. 115.
    Kleuser B, Maceyka M, Milstien S et al. Stimulation of nuclear sphingosine kinase activity by platelet-derived growth factor. FEBS Lett 2001; 503:85–90.PubMedGoogle Scholar
  116. 116.
    Olivera A, Kohama T, Edsall LC et al. Sphingosine kinase expression increases intracellular sphingosine-1-phosphate and promotes cell growth and survival. J Cell Biol 1999; 147:545–558.PubMedGoogle Scholar
  117. 117.
    Ding G, Sonoda H, Yu H et al. Protein kinase D-mediated phosphorylation and nuclear export of sphingosine kinase 2. J Biol Chem 2007; 282:27493–27502.PubMedGoogle Scholar
  118. 118.
    Mattie M, Brooker G, Spiegel S. Sphingosine-1-phosphate, a putative second messenger, mobilizes calcium from internal stores via an inositol trisphosphate-independent pathway. J Biol Chem 1994; 269:3181–3188.PubMedGoogle Scholar
  119. 119.
    Ghosh TK, Bian J, Gill DL. Sphingosine 1-phosphate generated in the endoplasmic reticulum membrane activates release of stored calcium. J Biol Chem 1994; 269:22628–22635.PubMedGoogle Scholar
  120. 120.
    Meyer zu Heringdorf D, Lass H, Alemany R et al. Sphingosine kinase-mediated Ca2+ signalling by G-protein-coupled receptors. EMBO J 1998; 17:2830–2837.PubMedGoogle Scholar
  121. 121.
    Meyer zu Heringdorf D, Liliom K, Schaefer M et al. Photolysis of intracellular caged sphingosine-1-phosphate causes Ca2+ mobilization independently of G-protein-coupled receptors. FEBS Lett 2003; 554:443–449.PubMedGoogle Scholar
  122. 122.
    Alemany R, Sichelschmidt B, zu Heringdorf DM et al. Stimulation of sphingosine-1-phosphate formation by the P2Y(2) receptor in HL-60 cells: Ca(2+) requirement and implication in receptor-mediated Ca(2+) mobilization, but not MAP kinase activation. Mol Pharmacol 2000; 58:491–497.PubMedGoogle Scholar
  123. 123.
    Blom T, Slotte JP, Pitson SM et al. Enhancement of intracellular sphingosine-1-phosphate production by inositol 1,4,5-trisphosphate-evoked calcium mobilisation in HEK-293 cells: endogenous sphingosine-1-phosphate as a modulator of the calcium response. Cell Signal 2005; 17:827–836.PubMedGoogle Scholar
  124. 124.
    Limaye VS, Li X, Hahn C et al. Sphingosine kinase-1 enhances endothelial cell survival through a PECAM-1-dependent activation of PI-3K/Akt and regulation of Bcl-2 family members. Blood 2005; 105:3169–3177.PubMedGoogle Scholar
  125. 125.
    Van Brocklyn JR, Lee MJ, Menzeleev R et al. Dual actions of sphingosine-1-phosphate: extracellular through the Gi-coupled orphan receptor edg-1 and intracellular to regulate proliferation and survival. J Cell Biol 1998; 142:229–240.PubMedGoogle Scholar
  126. 126.
    Xia P, Gamble JR, Rye KA et al. Tumor necrosis factor-a induces adhesion molecule expression through the sphingosine kinase pathway. Proc Natl Acad Sci USA 1998; 95:14196–14201.PubMedGoogle Scholar
  127. 127.
    Morita Y, Perez GI, Paris F et al. Oocyte apoptosis is suppressed by disruption of the acid sphingomyelinase gene or by sphingosine-1-phosphate therapy. Nature Med 2000; 6:1109–1114.PubMedGoogle Scholar
  128. 128.
    Suomalainen L, Pentikainen V, Dunkel L. Sphingosine-1-phosphate inhibits nuclear factor kappaB activation and germ cell apoptosis in the human testis independently of its receptors. Am J Pathol 2005; 166:773–781.PubMedGoogle Scholar
  129. 129.
    Olivera A, Rosenfeldt HM, Bektas M et al. Sphingosine kinase type 1 Induces G12/13-mediated stress fiber formation yet promotes growth and survival independent of G protein coupled receptors. J Biol Chem 2003; 278:46452–46460.PubMedGoogle Scholar
  130. 130.
    Kohno M, Momoi M, Oo ML et al. Intracellular role for sphingosine kinase 1 in intestinal adenoma cell proliferation. Mol Cell Biol 2006; 26:7211–7223.PubMedGoogle Scholar
  131. 131.
    Don AS, Martinez-Lamenca C, Webb WR et al. Essential requirement for sphingosine kinase 2 in a sphingolipid apoptosis pathway activated by FTY720 analogs. J Biol Chem 2007; 282:15833–15842.PubMedGoogle Scholar
  132. 132.
    Samy ET, Meyer CA, Caplazi P et al. Cutting Edge: Modulation of Intestinal Autoimmunity and IL-2 Signaling by Sphingosine Kinase 2 Independent of Sphingosine 1-Phosphate. J Immunol 2007; 179:5644–5648.PubMedGoogle Scholar
  133. 133.
    Yang J, Castle BE, Hanidu A et al. Sphingosine kinase 1 Is a negative regulator of CD4+ Th1 cells. J Immunol 2005; 175:6580–6588.PubMedGoogle Scholar
  134. 134.
    Mechtcheriakova D, Wlachos A, Sobanov J et al. Sphingosine 1-phosphate phosphatase 2 is induced during inflammatory responses. Cell Signal 2007; 19:748–760.PubMedGoogle Scholar
  135. 135.
    Wang F, Van Brocklyn JR, Edsall L et al. Sphingosine-1-phosphate inhibits motility of human breast cancer cells independently of cell surface receptors. Cancer Res 1999; 59:6185–6191.PubMedGoogle Scholar
  136. 136.
    Hammad SM, Crellin HG, Wu BX et al. Dual and distinct roles for sphingosine kinase 1 and sphingosine 1 phosphate in the response to inflammatory stimuli in RAW macrophages. Prostaglandins Other Lipid Mediat 2007; 85:107–114.PubMedGoogle Scholar
  137. 137.
    Itagaki K, Yun JK, Hengst JA et al. Sphingosine 1-phosphate has dual functions in the regulation of endothelial cell permeability and Ca2+ metabolism. J Pharmacol Exp Ther 2007; 323:186–191.PubMedGoogle Scholar
  138. 138.
    Li X, Stankovic M, Bonder CS et al. Basal and angiopoietin-1-mediated endothelial permeability is regulated by sphingosine kinase-1. Blood 2008; 111:3489–3497.PubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2010

Authors and Affiliations

  • Graham M. Strub
    • 1
  • Michael Maceyka
    • 1
  • Nitai C. Hait
    • 1
  • Sheldon Milstien
    • 2
  • Sarah Spiegel
    • 1
    Email author
  1. 1.Department of Biochemistry and Molecular BiologyVCU School of MedicineRichmondUSA
  2. 2.National Institute of Mental HealthBethesdaUSA

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