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  • Review Article
  • Published:

Sphingosine-1-phosphate: an enigmatic signalling lipid

Nature Reviews Molecular Cell Biology volume 4, pages 397–407 (2003)Cite this article

Key Points

  • Sphingosine-1-phosphate (S1P) levels in cells are regulated by the balance between its synthesis, which is catalysed by sphingosine kinases (SphKs), and degradation, which is catalysed by specific S1P phosphatases (SPPs) and an S1P lyase (Spl). The genes encoding all of these enzymes have now been cloned and their regulation is an important area of investigation.

  • Sphingolipid metabolites have important roles in regulating stress responses. Some clues about this come from studies in yeast.

  • The relative cellular balance between ceramide and sphingosine, which are both associated with growth arrest and apoptosis, versus S1P, which is proliferative and anti-apoptotic, can be considered as a kind of rheostat that determines whether cells live or die.

  • Regulation of cellular calcium levels is crucial to almost all physiological processes. This regulation is an important function of S1P, which seems to be conserved throughout evolution.

  • There are five specific S1P receptors that couple to different G proteins and regulate many downstream signalling pathways. The biological functions of S1P are now known to depend on the relative expression of these receptors.

  • Crosstalk back and forth between G-protein-coupled receptors, such as those that S1P functions as the ligand for, and other types of cell-surface receptors is an important mechanism that allows cells to integrate many external signals to specifically regulate physiological responses.

  • It is not known exactly how external stimuli increase SphK1 activity but some recent studies indicate that it might be phosphorylated or translocated to membranes where its substrate, sphingosine, resides.

  • The list of growth factors, cytokines, agonists, and so on, that are reported to stimulate SphK1 and increase the formation of S1P is lengthy and growing rapidly. New molecular approaches should help sort out those responses that are really crucial for normal and pathophysiology.

Abstract

The evolutionarily conserved actions of the sphingolipid metabolite, sphingosine-1-phosphate (S1P), in yeast, plants and mammals have shown that it has important functions. In higher eukaryotes, S1P is the ligand for a family of five G-protein-coupled receptors. These S1P receptors are differentially expressed, coupled to various G proteins, and regulate angiogenesis, vascular maturation, cardiac development and immunity, and are important for directed cell movement.

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Figure 1: Formation and degradation of S1P.
Figure 2: The sphingolipid rheostat: a conserved stress regulator.
Figure 3: S1P regulates calcium homeostasis in plants, yeast and mammals.
Figure 4: S1P is a ligand for five G-protein-coupled receptors.
Figure 5: S1P, through S1P receptors, regulates important physiological processes.
Figure 6: Crosstalk of VEGF and S1P signalling.
Figure 7: Transactivation of EDG1/S1P1 and PDGF-directed cell movement.

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References

  1. Thudichum, J. L. W. A Treatise on the Chemical Constitution of Brain. 149 (Bailliere, Tindall and Cox, London, 1884).

    Google Scholar 

  2. Stoffel, W. & Assmann, G. Metabolism of sphingoid bases, XV. Enzymatic degradation of 4t-sphingenine 1-phosphate (sphingosine-1-phosphate) to 2t-hexadecen-1-al and ethanolamine phosphate. Hoppe-Seyler's Z. Physiol. Chem. 351, 1041–1049 (1970).

    Article  CAS  Google Scholar 

  3. Zhang, H. et al. Sphingosine-1-phosphate, a novel lipid, involved in cellular proliferation. J. Cell Biol. 114, 155–167 (1991).

    Article  CAS  PubMed  Google Scholar 

  4. Olivera, A. & Spiegel, S. Sphingosine-1-phosphate as a second messenger in cell proliferation induced by PDGF and FCS mitogens. Nature 365, 557–560 (1993). This was a pioneering study that showed that S1P was a signalling molecule.

    Article  CAS  PubMed  Google Scholar 

  5. Cuvillier, O. et al. Suppression of ceramide-mediated programmed cell death by sphingosine-1-phosphate. Nature 381, 800–803 (1996). This was the first evidence that S1P can suppress apoptosis and proposed the concept of the sphingolipid rheostat.

    Article  CAS  PubMed  Google Scholar 

  6. Liu, H., Chakravarty, D., Maceyka, M., Milstien, S. & Spiegel, S. Sphingosine kinases: a novel family of lipid kinases. Prog. Nucleic Acid Res. Mol. Biol. 71, 493–511 (2002).

    Article  CAS  PubMed  Google Scholar 

  7. Hait, N. C., Fujita, K., Lester, R. L. & Dickson, R. C. Lcb4p sphingoid base kinase localizes to the Golgi and late endosomes. FEBS Lett. 532, 97–102 (2002).

    Article  CAS  PubMed  Google Scholar 

  8. Funato, K., Lombardi, R., Vallée, B. & Riezman, H. Lcb4p is a key regulator of ceramide synthesis from exogenous long chain sphingoid base in Saccharomyces cerevisiae. J. Biol. Chem. 278, 7325–7334 (2003).

    Article  CAS  PubMed  Google Scholar 

  9. Pitson, S. M. et al. The nucleotide-binding site of human sphingosine kinase 1. J. Biol. Chem. 277, 49545–49553 (2002).

    Article  CAS  PubMed  Google Scholar 

  10. Saba, J. D., Nara, F., Bielawska, A., Garrett, S. & Hanun, Y. A. The BST1 gene of Saccharomyces cerevisiae is the sphingosine-1-phosphate lyase. J. Biol. Chem. 272, 26087–26090 (1997).

    Article  CAS  PubMed  Google Scholar 

  11. Gottlieb, D., Heideman, W. & Saba, J. D. The DPL1 gene is involved in mediating the response to nutrient deprivation in Saccharomyces cerevisiae. Mol. Cell Biol. Res. Commun. 1, 66–71 (1999).

    Article  CAS  PubMed  Google Scholar 

  12. Li, G., Foote, C., Alexander, S. & Alexander, H. Sphingosine-1-phosphate lyase has a central role in the development of Dictyostelium discoideum. Development 128, 3473–3483 (2001).

    Article  CAS  PubMed  Google Scholar 

  13. Mao, C., Wadleigh, M., Jenkins, G. M., Hannun, Y. A. & Obeid, L. M. Identification and characterization of Saccharomyces cerevisiae dihydrosphingosine-1-phosphate phosphatase. J. Biol. Chem. 272, 28690–28694 (1997).

    Article  CAS  PubMed  Google Scholar 

  14. Mandala, S. M. et al. Sphingoid base 1-phosphate phosphatase: a key regulator of sphingolipid metabolism and stress response. Proc. Natl Acad. Sci. USA 95, 150–155 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Mao, C., Saba, J. D. & Obeid, L. M. The dihydrosphingosine-1-phosphate phosphatases of Saccharomyces cerevisiae are important regulators of cell proliferation and heat stress responses. Biochem. J. 342, 667–675 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Mandala, S. M. et al. Molecular cloning and characterization of a lipid phosphohydrolase that degrades sphingosine-1-phosphate and induces cell death. Proc. Natl Acad. Sci. USA 97, 7859–7864 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Le Stunff, H. et al. Characterization of murine sphingosine-1-phosphate phosphohydrolase. J. Biol. Chem. 277, 8920–8927 (2002).

    Article  CAS  PubMed  Google Scholar 

  18. Ogawa, C., Kihara, A., Gokoh, M. & Igarashi, Y. Identification and characterization of a novel human sphingosine 1-phosphate phosphohydrolase, hSPP2. J. Biol. Chem. 278, 1268–1272 (2003).

    Article  CAS  PubMed  Google Scholar 

  19. Stukey, J. & Carman, G. M. Identification of a novel phosphatase sequence motif. Protein Sci. 6, 469–472 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Jasinska, R. et al. Lipid phosphate phosphohydrolase-1 degrades exogenous glycerolipid and sphingolipid phosphate esters. Biochem. J. 340, 677–686 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Le Stunff, H., Galve-Roperh, I., Peterson, C., Milstien, S. & Spiegel, S. Sphingosine-1-phosphate phosphohydrolase in regulation of sphingolipid metabolism and apoptosis. J. Cell Biol. 158, 1039–1049 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Spiegel, S. & Milstien, S. Sphingosine 1-phosphate, a key cell signaling molecule. J. Biol. Chem. 277, 25851–25854 (2002).

    Article  CAS  PubMed  Google Scholar 

  23. Hannun, Y. A. & Obeid, L. M. The ceramide-centric universe of lipid-mediated cell regulation: stress encounters of the lipid kind. J. Biol. Chem. 277, 25487–25850 (2002).

    Article  CAS  Google Scholar 

  24. Kolesnick, R. The therapeutic potential of modulating the ceramide/sphingomyelin pathway. J. Clin. Invest. 110, 3–8 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Olivera, A. et al. Sphingosine kinase expression increases intracellular sphingosine-1-phosphate and promotes cell growth and survival. J. Cell Biol. 147, 545–558 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Xia, P. et al. An oncogenic role of sphingosine kinase. Curr. Biol. 10, 1527–1530 (2000).

    Article  CAS  PubMed  Google Scholar 

  27. Nava, V. E., Hobson, J. P., Murthy, S., Milstien, S. & Spiegel, S. Sphingosine kinase type 1 promotes estrogen-dependent tumorigenesis of breast cancer MCF-7 cells. Exp. Cell Res. 281, 115–127 (2002).

    Article  CAS  PubMed  Google Scholar 

  28. Shu, X., Wu, W., Mosteller, R. D. & Broek, D. Sphingosine kinase mediates vascular endothelial growth factor-induced activation of ras and mitogen-activated protein kinases. Mol. Cell. Biol. 22, 7758–7768 (2002). This important study highlights a new mechanism by which SphK1 mediates signalling from VEGF and PKC to Ras. The mechanism seems not to use a Ras-GEF but rather modulates Ras-GAP activity to favour Ras activation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Edsall, L. C., Cuvillier, O., Twitty, S., Spiegel, S. & Milstien, S. Sphingosine kinase expression regulates apoptosis and caspase activation in PC12 cells. J. Neurochem. 76, 1573–1584 (2001).

    Article  CAS  PubMed  Google Scholar 

  30. Xia, P. et al. Sphingosine kinase interacts with TRAF2 and dissects tumor necrosis factor-α signaling. J. Biol. Chem. 277, 7996–8003 (2002). This paper indicates that there is a role for SphK in the signal transduction by TRAF2 leading to activation of NF-κB and survival.

    Article  CAS  PubMed  Google Scholar 

  31. Jenkins, G. M. & Hannun, Y. A. Role for de novo sphingoid base biosynthesis in the heat-induced transient cell cycle arrest of Saccharomyces cerevisiae. J. Biol. Chem. 276, 8574–8581 (2001). This study uncovered the role of sphingolipids in yeast heat-stress adaptation.

    Article  CAS  PubMed  Google Scholar 

  32. Kolesnick, R. & Hannun, Y. A. Ceramide and apoptosis. Trends Biochem. Sci. 24, 224–225 (1999).

    Article  CAS  PubMed  Google Scholar 

  33. Kroesen, B. J. et al. Induction of apoptosis through B-cell receptor cross-linking occurs via de novo generated C16-ceramide and involves mitochondria. J. Biol. Chem. 276, 13606–13614 (2001).

    Article  CAS  PubMed  Google Scholar 

  34. Perry, D. K. et al. Serine palmitoyltransferase regulates de novo ceramide generation during etoposide-induced apoptosis. J. Biol. Chem. 275, 9078–9084 (2000).

    Article  CAS  PubMed  Google Scholar 

  35. Bose, R. et al. Ceramide synthase mediates daunorubicin-induced apoptosis: an alternative mechanism for generating death signals. Cell 82, 405–414 (1995).

    Article  CAS  PubMed  Google Scholar 

  36. Marsh, B. J., Mastronarde, D. N., Buttle, K. F., Howell, K. E. & McIntosh, J. R. Organellar relationships in the Golgi region of the pancreatic β-cell line, HIT-T15, visualized by high resolution electron tomography. Proc. Natl Acad. Sci. USA 98, 2399–2406 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. El Bawab, S. et al. Biochemical characterization of the reverse activity of rat brain ceramidase. A CoA-independent and fumonisin B1-insensitive ceramide synthase. J. Biol. Chem. 276, 16758–16766 (2001).

    Article  CAS  PubMed  Google Scholar 

  38. Gillard, B. K., Clement, R. G. & Marcus, D. M. Variations among cell lines in the synthesis of sphingolipids in de novo and recycling pathways. Glycobiology 8, 885–890 (1998).

    Article  CAS  PubMed  Google Scholar 

  39. Zanolari, B. et al. Sphingoid base synthesis requirement for endocytosis in Saccharomyces cerevisiae. EMBO J. 19, 2824–2833 (2000). This is the first evidence of a physiological role for sphingoid base synthesis, other than as a precursor for ceramide or phosphorylated sphingoid base synthesis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. van Echten-Deckert, G. et al. cis-4-Methylsphingosine decreases sphingolipid biosynthesis by specifically interfering with serine palmitoyltransferase activity in primary cultured neurons. J. Biol. Chem. 272, 15825–15833 (1997).

    Article  CAS  PubMed  Google Scholar 

  41. Ghosh, T. K., Bian, J. & Gill, D. L. Intracellular calcium release mediated by sphingosine derivatives generated in cells. Science 248, 1653–1656 (1990).

    Article  CAS  PubMed  Google Scholar 

  42. Ghosh, T. K., Bian, J. & Gill, D. L. Sphingosine 1-phosphate generated in the endoplasmic reticulum membrane activates release of stored calcium. J. Biol. Chem. 269, 22628–22635 (1994).

    Article  CAS  PubMed  Google Scholar 

  43. 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. 269, 3181–3188 (1994).

    Article  CAS  PubMed  Google Scholar 

  44. Choi, O. H., Kim, J. -H. & Kinet, J. -P. Calcium mobilization via sphingosine kinase in signalling by the FcεRI antigen receptor. Nature 380, 634–636 (1996).

    Article  CAS  PubMed  Google Scholar 

  45. Meyer zu Heringdorf, D. et al. Role of sphingosine kinase in Ca2+ signalling by epidermal growth factor receptor. FEBS Lett. 461, 217–222 (1999).

    Article  CAS  PubMed  Google Scholar 

  46. Melendez, A. J. & Khaw, A. K. Dichotomy of Ca2+ signals triggered by different phospholipid pathways in antigen stimulation of human mast cells. J. Biol. Chem. 277, 17255–17262 (2002).

    Article  CAS  PubMed  Google Scholar 

  47. Mathes, C., Fleig, A. & Penner, R. Calcium release-activated calcium current (ICRAC) is a direct target for sphingosine. J. Biol. Chem. 273, 25020–25030 (1998).

    Article  CAS  PubMed  Google Scholar 

  48. Meyer zu Heringdorf, D. et al. Sphingosine kinase-mediated Ca2+ signalling by G-protein-coupled receptors. EMBO J. 17, 2830–2837 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. van Koppen, C. J., Meyer zu Heringdorf, D., Alemany, R. & Jakobs, K. H. Sphingosine kinase-mediated calcium signaling by muscarinic acetylcholine receptors. Life Sci. 68, 2535–2540 (2001).

    Article  CAS  PubMed  Google Scholar 

  50. Birchwood, C. J., Saba, J. D., Dickson, R. C. & Cunningham, K. W. Calcium influx and signaling in yeast stimulated by intracellular sphingosine 1-phosphate accumulation. J. Biol. Chem. 276, 11712–11718 (2001).

    Article  CAS  PubMed  Google Scholar 

  51. Ng, C. K., Carr, K., McAinsh, M. R., Powell, B. & Hetherington, A. M. Drought-induced guard cell signal transduction involves sphingosine-1-phosphate. Nature 410, 596–599 (2001). This provides the first evidence that S1P is involved in the signal-transduction pathway in plants. It links the perception of the amount of drought hormone abscisic acid to reductions in guard-cell turgor.

    Article  CAS  PubMed  Google Scholar 

  52. Coursol, S. et al. Sphingosine-1-phosphate signalling in Arabidopsis guard cells involves heterotrimeric G proteins. Nature (in the press). This study shows that the heterotrimeric G protein in plants is required for S1P signals that mediate ABA regulation of stomatal function.

  53. Lee, M. J. et al. Sphingosine-1-phosphate as a ligand for the G protein-coupled receptor EDG-1. Science 279, 1552–1555 (1998). This study showed conclusively that S1P is a bona fide ligand for an orphan GPCR, now known as EDG1/S1P 1.

    Article  CAS  PubMed  Google Scholar 

  54. Chun, J. et al. International Union of Pharmacology. XXXIV. Lysophospholipid receptor nomenclature. Pharmacol. Rev. 54, 265–269 (2002).

    Article  CAS  PubMed  Google Scholar 

  55. Wang, F. et al. Sphingosine 1-phosphate stimulates cell migration through a Gi-coupled cell surface receptor. Potential involvement in angiogenesis. J. Biol. Chem. 274, 35343–35350 (1999).

    Article  CAS  PubMed  Google Scholar 

  56. Lee, M. J. et al. Vascular endothelial cell adherens junction assembly and morphogenesis induced by sphingosine-1-phosphate. Cell 99, 301–312 (1999).

    Article  CAS  PubMed  Google Scholar 

  57. Liu, Y. et al. Edg-1, the G protein-coupled receptor for sphingosine-1-phosphate, is essential for vascular maturation. J. Clin. Invest. 106, 951–961 (2000). An important finding that EDG1/S1P 1 is required for vascular maturation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Garcia, J. G. et al. Sphingosine 1-phosphate promotes endothelial cell barrier integrity by Edg-dependent cytoskeletal rearrangement. J. Clin. Invest. 108, 689–701 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Kupperman, E., An, S., Osborne, N., Waldron, S. & Stainier, D. Y. A sphingosine-1-phosphate receptor regulates cell migration during vertebrate heart development. Nature 406, 192–195 (2000). This work provided a link between EDG5/S1P 2 and heart development in zebrafish.

    Article  CAS  PubMed  Google Scholar 

  60. Brinkmann, V. et al. The immune modulator, FTY720, targets sphingosine 1-phosphate receptors. J. Biol. Chem. 277, 21453–21457 (2002).

    Article  CAS  PubMed  Google Scholar 

  61. Mandala, S. et al. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 296, 346–349 (2002). References 60 and 61 provide a provocative link between the immunomodulating drug FTY720, S1P receptors and lymphocyte homing.

    Article  CAS  PubMed  Google Scholar 

  62. Graeler, M., Shankar, G. & Goetzl, E. J. Cutting edge: suppression of T cell chemotaxis by sphingosine 1-phosphate. J. Immunol. 169, 4084–4087 (2002).

    Article  CAS  PubMed  Google Scholar 

  63. Hall, A. G proteins and small GTPases: distant relatives keep in touch. Science 280, 2074–2075 (1998).

    Article  CAS  PubMed  Google Scholar 

  64. Hobson, J. P. et al. Role of the sphingosine-1-phosphate receptor EDG-1 in PDGF-induced cell motility. Science 291, 1800–1803 (2001). This paper proposed a new model for cross-communication between tyrosine kinase receptors and the S1P receptors.

    Article  CAS  PubMed  Google Scholar 

  65. Okamoto, H. et al. Inhibitory regulation of Rac activation, membrane ruffling, and cell migration by the G protein-coupled sphingosine-1-phosphate receptor EDG5 but not EDG1 or EDG3. Mol. Cell. Biol. 20, 9247–9261 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Hla, T., Lee, M. J., Ancellin, N., Paik, J. H. & Kluk, M. J. Lysophospholipids — receptor revelations. Science 294, 1875–1878 (2001).

    Article  CAS  PubMed  Google Scholar 

  67. English, D., Brindley, D. N., Spiegel, S. & Garcia, J. G. Lipid mediators of angiogenesis and the signalling pathways they initiate. Biochim. Biophys. Acta 1582, 228–239 (2002).

    Article  CAS  PubMed  Google Scholar 

  68. Ishii, I. 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. 277, 25152–25159 (2002).

    Article  CAS  PubMed  Google Scholar 

  69. Paik, J. H., Chae, S., Lee, M. J., Thangada, S. & Hla, T. Sphingosine 1-phosphate-induced endothelial cell migration requires the expression of EDG-1 and EDG-3 receptors and Rho-dependent activation of αvβ3- and β1-containing integrins. J. Biol. Chem. 276, 11830–11827 (2001).

    Article  CAS  PubMed  Google Scholar 

  70. Tanimoto, T., Jin, Z. G. & Berk, B. C. Transactivation of vascular endothelial growth factor (VEGF) receptor Flk-1/KDR is involved in sphingosine 1-phosphate-stimulated phosphorylation of Akt and endothelial nitric-oxide synthase (eNOS). J. Biol. Chem. 277, 42997–43001 (2002).

    Article  CAS  PubMed  Google Scholar 

  71. Benaud, C. et al. Sphingosine 1-phosphate, present in serum-derived lipoproteins, activates matriptase. J. Biol. Chem. 277, 10539–10546 (2002).

    Article  CAS  PubMed  Google Scholar 

  72. Endo, A. et al. Sphingosine 1-phosphate induces membrane ruffling and increases motility of human umbilical vein endothelial cells via vascular endothelial growth factor receptor and CrkII. J. Biol. Chem. 277, 23747–23754 (2002).

    Article  CAS  PubMed  Google Scholar 

  73. Igarashi, J. & Michel, T. Sphingosine 1-phosphate and isoform-specific activation of phosphoinositide 3-kinase-β. Evidence for divergence and convergence of receptor-regulated endothelial nitric-oxide synthase signaling pathways. J. Biol. Chem. 276, 36281–36288 (2001).

    Article  CAS  PubMed  Google Scholar 

  74. Lee, M. et al. Akt-mediated phosphorylation of the G protein-coupled receptor EDG-1 is required for endothelial cell chemotaxis. Mol. Cell 8, 693–704 (2001).

    Article  CAS  PubMed  Google Scholar 

  75. Rosenfeldt, H. M. et al. EDG-1 links the PDGF receptor to Src and focal adhesion kinase activation leading to lamellipodia formation and cell migration. FASEB J. 15, 2649–2659 (2001).

    Article  CAS  PubMed  Google Scholar 

  76. Rosenfeldt, H. M., Hobson, J. P., Milstien, S. & Spiegel, S. The sphingosine-1-phosphate receptor EDG-1 is essential for platelet-derived growth factor-induced cell motility. Biochem. Soc. Trans. 29, 836–839 (2001).

    Article  CAS  PubMed  Google Scholar 

  77. Johnson, K. R., Becker, K. P., Facchinetti, M. M., Hannun, Y. A. & Obeid, L. M. PKC-dependent activation of sphingosine kinase 1 and translocation to the plasma membrane. Extracellular release of sphingosine-1-phosphate induced by phorbol 12-myristate 13-acetate (PMA). J. Biol. Chem. 277, 35257–35262 (2002). This study provided a clue to mechanisms of activation of SphK1 by translocation to plasma membranes.

    Article  CAS  PubMed  Google Scholar 

  78. Lacana, E., Maceyka, M., Milstien, S. & Spiegel, S. Cloning and characterization of a protein kinase A anchoring protein (AKAP)-related protein that interacts with and regulates sphingosine kinase 1 activity. J. Biol. Chem. 277, 32947–32953 (2002).

    Article  CAS  PubMed  Google Scholar 

  79. Hayashi, S. et al. Identification and characterization of RPK118, a novel sphingosine kinase-1-binding protein. J. Biol. Chem. 277, 33319–33324 (2002).

    Article  CAS  PubMed  Google Scholar 

  80. Nagiec, M. M., Skrzypek, M., Nagiec, E. E., Lester, R. L. & Dickson, R. C. The LCB4 (YOR171c) and LCB5 (YLR260w) genes of Saccharomyces encode long chain base kinases. J. Biol. Chem. 273, 19437–19442 (1998).

    Article  CAS  PubMed  Google Scholar 

  81. Kohama, T. et al. Molecular cloning and functional characterization of murine sphingosine kinase. J. Biol. Chem. 273, 23722–23728 (1998).

    Article  CAS  PubMed  Google Scholar 

  82. Zhou, J. & Saba, J. D. Identification of the first mammalian sphingosine phosphate lyase gene and its functional expression in yeast. Biochem. Biophys. Res. Commun. 242, 502–507 (1998).

    Article  CAS  PubMed  Google Scholar 

  83. Van Veldhoven, P. P., Gijsbers, S., Mannaerts, G. P., Vermeesch, J. R. & Brys, V. Human sphingosine-1-phosphate lyase: cDNA cloning, functional expression studies and mapping to chromosome 10q22(1). Biochim. Biophys. Acta 1487, 128–134 (2000).

    Article  CAS  PubMed  Google Scholar 

  84. Qie, L., Nagiec, M. M., Baltisberger, J. A., Lester, R. L. & Dickson, R. C. Identification of a Saccharomyces gene, LCB3, necessary for incorporation of exogenous long chain bases into sphingolipids. J. Biol. Chem. 272, 16110–16117 (1997).

    Article  CAS  PubMed  Google Scholar 

  85. Futerman, A. H., Stieger, B., Hubbard, A. L. & Pagano, R. E. Sphingomyelin synthesis in rat liver occurs predominantly at the cis and medial cisternae of the Golgi apparatus. J. Biol. Chem. 265, 8650–8657 (1990).

    Article  CAS  PubMed  Google Scholar 

  86. Merrill, A. H. Jr. De novo sphingolipid biosynthesis: a necessary, but dangerous, pathway. J. Biol. Chem. 277, 25843–25846 (2002).

    Article  CAS  PubMed  Google Scholar 

  87. Michel, C. & van Echten-Deckert, G. Conversion of dihydroceramide to ceramide occurs at the cytosolic face of the endoplasmic reticulum. FEBS Lett. 416, 153–155 (1997).

    Article  CAS  PubMed  Google Scholar 

  88. van Meer, G. & Holthuis, J. C. Sphingolipid transport in eukaryotic cells. Biochim. Biophys. Acta 1486, 145–170 (2000).

    Article  CAS  PubMed  Google Scholar 

  89. Hannun, Y. Functions of ceramide in coordinating cellular responses to stress. Science 274, 1855–1859 (1996).

    Article  CAS  PubMed  Google Scholar 

  90. Driever, W. Bringing two hearts together. Nature 406, 141–142 (2000).

    Article  CAS  PubMed  Google Scholar 

  91. Brinkmann, V & Lynch, K. R. FTY720: targeting G-protein-coupled receptors for sphingosine 1-phosphate in transplantation and autoimmunity. Curr. Opin. Immunol. 14, 569–575 (2002).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We apologize that out of more than 650 citations in PubMed to S1P, we cited only 91. The authors also gratefully acknowledge the generous support of the National Institutes of Health and the Department of the Army.

Author information

Authors and Affiliations

  1. Department of Biochemistry, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, 23298-0614, Virginia, USA

    Sarah Spiegel

  2. Laboratory of Cellular and Molecular Regulation, National Institute of Mental Health, Bethesda, 20892, Maryland, USA

    Sheldon Milstien

Authors
  1. Sarah Spiegel
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  2. Sheldon Milstien
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Corresponding author

Correspondence to Sarah Spiegel.

Related links

Related links

DATABASES

<i>Saccharomyces</i> Genome Database

BST1

Dpl1

Lbp1

Lcb3

Lcb4

Lcb5

SwissProt

EDG1

EDG3

EDG5

EDG6

EDG8

RPK118

Slp

SphK1

SphK2

SPP1

SPP2

TRAF-2

VEGFR-2

FURTHER INFORMATION

Sarah Spiegel's laboratory

Glossary

MITOCHONDRIAL OR INTRINSIC DEATH PATHWAY

The pathway that leads to death through the release, by stress-induced signals, of cytochrome c and other apoptogenic factors from the mitochondrial intermembrane space.

SPHINGOMYELINASE

An enzyme that catalyses the hydrolysis of sphingomyelin to ceramide (N-acylsphingosine) and choline phosphate.

CASPASES

A family of intracellular cysteine endopeptidases that have a crucial role in inflammation and mammalian apoptosis. They cleave proteins at specific aspartic acid residues.

PHOSPHOLIPASE C

A phosphoric diester hydrolase that splits the bond between the phosphorus atom and the oxygen atom at C1 of the glycerol moiety of a glycerophospholipid.

STOMATA

The pores in the epidermis of plants, in particular in the leaves, through which gaseous exchange occurs.

GUARD CELLS

Cells that are found on the underside of plant leaves, which pair up to form stomata, or leaf pores. Guard cells control the size of the stomata, and so, in turn, regulate gas exchange in the leaf.

G-PROTEIN-COUPLED RECEPTOR

A seven-helix transmembrane-spanning cell-surface receptor that signals through heterotrimeric GTP-binding and -hydrolysing G-proteins to stimulate or inhibit the activity of a downstream enzyme.

HETEROTRIMERIC G PROTEIN

A component of receptor-mediated activation or inhibition of adenylyl cyclase and other second messenger systems.

PARAXIAL CELLS

Cells of a region of the mesoderm, which is known as the paraxial mesoderm, that is adjacent to the notochord. The paraxial mesoderm becomes segmented rostrocaudally to give rise to the somites early in development.

PERICYTE

A support cell of the capillaries. Pericytes are known as smooth muscle cells in larger vessels.

IMMUNOMODULATOR

Any agent that alters the extent of the immune response to an antigen.

LYMPHOPENIA

A decrease in the number of lymphocytes in the blood, which might occur in various diseases.

DOMINANT-NEGATIVE

A defective protein that retains interaction abilities and so distorts or competes with normal proteins.

SMALL INTERFERING RNA

(siRNA). Short (21–23mers) sequences of double-stranded RNA that are used in RNA interference, a process by which the expression of homologous genes is silenced through degradation of their cognate mRNA.

PERTUSSIS TOXIN

A mixture of proteins that is produced by Bordetella pertussis. It causes the persistent activation of Gi proteins by catalysing the ADP-ribosylation of the α-subunit.

PHORBOL ESTERS

Polycyclic esters that are isolated from croton oil. The most common is phorbol myristoyl acetate (PMA, also known as 12,13-tetradecanoyl phorbol acetate or TPA). They are potent co-carcinogens or tumour promoters because they mimic diacylglycerol, thereby irreversibly activating protein kinase C.

PHOX HOMOLOGY DOMAIN

A domain that is similar in function to pleckstrin homology domains. It has an affinity for certain phosphorylated phospholipids.

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Spiegel, S., Milstien, S. Sphingosine-1-phosphate: an enigmatic signalling lipid. Nat Rev Mol Cell Biol 4, 397–407 (2003). https://doi.org/10.1038/nrm1103

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