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The effects of markedly raised intracellular sphingosine kinase-1 activity in endothelial cells


The enzyme sphingosine kinase-1 (SK1) promotes the formation of sphingosine-1-phosphate (S1P), which is an important survival factor for endothelial cells (EC). Modest increases in intracellular SK1 activity in the EC are known to confer a survival advantage upon the cells. Here, we investigated the effects of more dramatic increases in intracellular SK1 in the EC. We found that these cells show reduced cell survival under conditions of stress, enhanced caspase-3 activity, cell cycle inhibition, and cell-cell junction disruption. We propose that alterations in the phosphorylation state of the enzyme may explain the differential effects on the phenotype with modest versus high levels of enforced expression of SK1. Our results suggest that SK1 activity is subject to control in the EC, and that this control may be lost in conditions involving vascular regression.



endothelial cell


empty vector


human umbilical vein endothelial cell


platelet-endothelial cell adhesion molecule-1


plaque-forming unit


sphingosine kinase-1 (SK1)


sphingosine 1-phosphate


tumour necrosis factor


  1. Kwon, Y.G., Min, J.K., Kim, K.M., Lee, D.J., Billiar, T.R. and Kim, Y.M. Sphingosine 1-phosphate protects human umbilical vein endothelial cells from serum-deprived apoptosis by nitric oxide production. J. Biol. Chem. 276 (2001) 10627–10633.

    PubMed  Article  CAS  Google Scholar 

  2. Wang, F., Van Brocklyn, J.R., Hobson, J.P., Movafagh, S., Zukowska-Grojec, Z., Milstien, S. and Spiegel, S. Sphingosine 1-phosphate stimulates cell migration through a G(i)- coupled cell surface receptor. Potential involvement in angiogenesis. J. Biol. Chem. 274 (1999) 35343–35350.

    PubMed  Article  CAS  Google Scholar 

  3. Lee, M.J., Van Brocklyn, J.R., Thangada, S., Liu, C.H., Hand, A.R., Menzeleev, R., Spiegel, S. and Hla, T. Sphingosine-1-phosphate as a ligand for the G protein-coupled receptor EDG-1. Science 279 (1998) 1552–1555.

    PubMed  Article  CAS  Google Scholar 

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

    PubMed  Article  CAS  Google Scholar 

  5. Desai, N.N., Zhang, H., Olivera, A., Mattie, M.E. and Spiegel, S. Sphingosine-1-phosphate, a metabolite of sphingosine, increases phosphatidic acid levels by phospholipase D activation. J. Biol. Chem. 267 (1992) 23122–23128.

    PubMed  CAS  Google Scholar 

  6. Limaye, V., Li, X., Hahn, C., Xia, P., Berndt, M.C., Vadas, M.A. and Gamble, J.R. 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. 105 (2005) 3169–3177.

    PubMed  Article  CAS  Google Scholar 

  7. Evans, P.C., Taylor, E.R. and Kilshaw, P.J. Signaling through CD31 protects endothelial cells from apoptosis. Transplantation 71 (2001) 457–460.

    PubMed  Article  CAS  Google Scholar 

  8. Xia, P., Gamble, J.R., Wang, L., Pitson, S.M., Moretti, P.A., Wattenberg, B.W., D’Andrea, R.J. and Vadas, M.A. An oncogenic role of sphingosine kinase. Curr. Biol. 10 (2000) 1527–1530.

    PubMed  Article  CAS  Google Scholar 

  9. Cramer, E.M., Berger, G. and Berndt, M.C. Platelet-granule and plasma membrane share two components: CD9 and PECAM-1. Blood 84 (1994) 1722–1730.

    PubMed  CAS  Google Scholar 

  10. Litwin, M., Clark, K., Noack, L., Furze, J., Berndt, M., Albelda, S., Vadas, M., and Gamble, J.R. Novel cytokine-independent induction of endothelial adhesion molecules regulated by platelet/endothelial cell adhesion molecule (CD31). J. Cell. Biol. 139 (1997) 219–228.

    PubMed  Article  CAS  Google Scholar 

  11. Pitson, S.M., Moretti, P.A.B., Zebol, J.R., Lynn, H.E., Xia, P., Vadas, M.A., Wattenberg, B.W. Activation of sphingosine kinase 1 by ERK1/2-mediated phosphorylation. EMBO J. 22 (2003) 5491–5500.

    PubMed  Article  CAS  Google Scholar 

  12. Xia, P., Gamble, J.R., Rye, K.A., Wang, L., Hii, C.S., Cockerill, P., Khew-Goodall, Y., Bert, A.G., Barter, P.J., and Vadas, M.A. Tumor necrosis factor-alpha induces adhesion molecule expression through the sphingosine kinase pathway. Proc. Natl. Acad. Sci. USA 95 (1998) 14196–14201.

    PubMed  Article  CAS  Google Scholar 

  13. Spiegel, S., Olivera, A., Zhang, H., Thompson, E.W., Su, Y. and Berger, A. Sphingosine-1-phosphate, a novel second messenger involved in cell growth regulation and signal transduction, affects growth and invasiveness of human breast cancer cells. Breast Cancer Res. Treat. 31 (1994) 337–348.

    PubMed  Article  CAS  Google Scholar 

  14. Pitson, S.M., Moretti, P.A., Zebol, J.R., Xia, P., Gamble, J.R., Vadas, M.A., D’Andrea, R.J. and Wattenberg, B.W. Expression of a catalytically inactive sphingosine kinase mutant blocks agonist-induced sphingosine kinase activation. A dominant-negative sphingosine kinase. J. Biol. Chem. 275 (2000) 33945–33950.

    PubMed  Article  CAS  Google Scholar 

  15. Limaye, V., Xia, P., Hahn, C., Smith, M., Vadas, M.A, Pitson, S.M. and Gamble, J.R. Chronic increases in sphingosine kinase-1 activity induce a pro-inflammatory, pro-angiogenic phenotype in endothelial cells. Cell. Mol. Biol. Lett. 14 (2009) in press, DOI: 10.2478/s11658-009-0009-1.

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Correspondence to Vidya Limaye.

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Limaye, V., Vadas, M.A., Pitson, S.M. et al. The effects of markedly raised intracellular sphingosine kinase-1 activity in endothelial cells. Cell Mol Biol Lett 14, 411–423 (2009).

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Key words

  • Sphingosine kinase-1
  • Endothelial cells
  • Cell survival