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Gene Review

Sphk1  -  sphingosine kinase 1

Mus musculus

Synonyms: 1110006G24Rik, SK 1, SK1, SPK 1, Sk1, ...
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Disease relevance of Sphk1

  • The immunosuppressant FTY720 was phosphorylated and elicited lymphopenia in the Sphk1 null mice showing that SPHK1 is not required for the functional activation of this sphingosine analogue prodrug [1].
  • Concomitantly, epithelial cell proliferation in the polyps was significantly attenuated, suggesting that Sphk1 regulates adenoma progression [2].
  • Our findings suggest that Sphk1 plays a critical role in intestinal tumor cell proliferation and that inhibitors of Sphk1 may be useful in the control of intestinal cancer [2].
  • CONCLUSIONS: Overall, these studies demonstrate that inhibitors of SK attenuate the effects of proliferative and inflammatory stimuli on RECs both in vitro and in vivo, and so could be significant therapeutics in the treatment of diabetic retinopathy [3].
  • All three structurally diverse SK inhibitors tested showed antitumor activity in mice without exhibiting toxicity [4].

High impact information on Sphk1


Chemical compound and disease context of Sphk1


Biological context of Sphk1


Anatomical context of Sphk1

  • The results with these Sphk1 null mice reveal that some key physiologic processes that require S1P receptor signaling, such as vascular development and proper lymphocyte distribution, can occur in the absence of SPHK1 [1].
  • 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 [16].
  • Extracellular nucleotides induce migration of renal mesangial cells by upregulating sphingosine kinase-1 expression and activity [11].
  • After FcepsilonRI triggering, enhanced sphingosine kinase activity was associated with FcepsilonRI in sphingolipid-enriched rafts of mast cells [17].
  • Using fibroblasts from embryonic mice devoid of functional S1PRs, we also demonstrated that, in contrast to exogenous S1P, intracellular S1P formed by overexpression of sphingosine kinase type 1 promoted growth and survival independent of its GPCRs [18].

Associations of Sphk1 with chemical compounds


Regulatory relationships of Sphk1


Other interactions of Sphk1


Analytical, diagnostic and therapeutic context of Sphk1


  1. Mice deficient in sphingosine kinase 1 are rendered lymphopenic by FTY720. Allende, M.L., Sasaki, T., Kawai, H., Olivera, A., Mi, Y., van Echten-Deckert, G., Hajdu, R., Rosenbach, M., Keohane, C.A., Mandala, S., Spiegel, S., Proia, R.L. J. Biol. Chem. (2004) [Pubmed]
  2. Intracellular role for sphingosine kinase 1 in intestinal adenoma cell proliferation. Kohno, M., Momoi, M., Oo, M.L., Paik, J.H., Lee, Y.M., Venkataraman, K., Ai, Y., Ristimaki, A.P., Fyrst, H., Sano, H., Rosenberg, D., Saba, J.D., Proia, R.L., Hla, T. Mol. Cell. Biol. (2006) [Pubmed]
  3. Pharmacologic manipulation of sphingosine kinase in retinal endothelial cells: implications for angiogenic ocular diseases. Maines, L.W., French, K.J., Wolpert, E.B., Antonetti, D.A., Smith, C.D. Invest. Ophthalmol. Vis. Sci. (2006) [Pubmed]
  4. Antitumor activity of sphingosine kinase inhibitors. French, K.J., Upson, J.J., Keller, S.N., Zhuang, Y., Yun, J.K., Smith, C.D. J. Pharmacol. Exp. Ther. (2006) [Pubmed]
  5. Transactivation of sphingosine-1-phosphate receptors by FcepsilonRI triggering is required for normal mast cell degranulation and chemotaxis. Jolly, P.S., Bektas, M., Olivera, A., Gonzalez-Espinosa, C., Proia, R.L., Rivera, J., Milstien, S., Spiegel, S. J. Exp. Med. (2004) [Pubmed]
  6. Sphingosine kinase type 2 is essential for lymphopenia induced by the immunomodulatory drug FTY720. Zemann, B., Kinzel, B., Müller, M., Reuschel, R., Mechtcheriakova, D., Urtz, N., Bornancin, F., Baumruker, T., Billich, A. Blood (2006) [Pubmed]
  7. Overexpression of sphingosine kinase 1 is an oncogenic event in erythroleukemic progression. Le Scolan, E., Pchejetski, D., Banno, Y., Denis, N., Mayeux, P., Vainchenker, W., Levade, T., Moreau-Gachelin, F. Blood (2005) [Pubmed]
  8. Involvement of sphingosine kinase in TNF-alpha-stimulated tetrahydrobiopterin biosynthesis in C6 glioma cells. Vann, L.R., Payne, S.G., Edsall, L.C., Twitty, S., Spiegel, S., Milstien, S. J. Biol. Chem. (2002) [Pubmed]
  9. Normal acute and chronic inflammatory responses in sphingosine kinase 1 knockout mice. Michaud, J., Kohno, M., Proia, R.L., Hla, T. FEBS Lett. (2006) [Pubmed]
  10. Downregulation of the angiogenesis inhibitor thrombospondin 1 in fibroblasts exposed to platelets and their related phospholipids. Kalas, W., Klement, P., Rak, J. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  11. Extracellular nucleotides induce migration of renal mesangial cells by upregulating sphingosine kinase-1 expression and activity. Klawitter, S., Hofmann, L.P., Pfeilschifter, J., Huwiler, A. Br. J. Pharmacol. (2007) [Pubmed]
  12. Aminoacylase 1 is a sphingosine kinase 1-interacting protein. Maceyka, M., Nava, V.E., Milstien, S., Spiegel, S. FEBS Lett. (2004) [Pubmed]
  13. Non-coding RNA directed DNA demethylation of Sphk1 CpG island. Imamura, T., Yamamoto, S., Ohgane, J., Hattori, N., Tanaka, S., Shiota, K. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  14. Phosphorylation and action of the immunomodulator FTY720 inhibits vascular endothelial cell growth factor-induced vascular permeability. Sanchez, T., Estrada-Hernandez, T., Paik, J.H., Wu, M.T., Venkataraman, K., Brinkmann, V., Claffey, K., Hla, T. J. Biol. Chem. (2003) [Pubmed]
  15. Sphingosine-1-phosphate inhibits cell migration and endothelial to mesenchymal cell transformation during cardiac development. Wendler, C.C., Rivkees, S.A. Dev. Biol. (2006) [Pubmed]
  16. Extracellular export of sphingosine kinase-1a contributes to the vascular S1P gradient. Venkataraman, K., Thangada, S., Michaud, J., Oo, M.L., Ai, Y., Lee, Y.M., Wu, M., Parikh, N.S., Khan, F., Proia, R.L., Hla, T. Biochem. J. (2006) [Pubmed]
  17. Early activation of sphingosine kinase in mast cells and recruitment to FcepsilonRI are mediated by its interaction with Lyn kinase. Urtz, N., Olivera, A., Bofill-Cardona, E., Csonga, R., Billich, A., Mechtcheriakova, D., Bornancin, F., Woisetschläger, M., Rivera, J., Baumruker, T. Mol. Cell. Biol. (2004) [Pubmed]
  18. Sphingosine kinase type 1 induces G12/13-mediated stress fiber formation, yet promotes growth and survival independent of G protein-coupled receptors. Olivera, A., Rosenfeldt, H.M., Bektas, M., Wang, F., Ishii, I., Chun, J., Milstien, S., Spiegel, S. J. Biol. Chem. (2003) [Pubmed]
  19. Mouse sphingosine kinase isoforms SPHK1a and SPHK1b differ in enzymatic traits including stability, localization, modification, and oligomerization. Kihara, A., Anada, Y., Igarashi, Y. J. Biol. Chem. (2006) [Pubmed]
  20. Asp177 in C4 domain of mouse sphingosine kinase 1a is important for the sphingosine recognition. Yokota, S., Taniguchi, Y., Kihara, A., Mitsutake, S., Igarashi, Y. FEBS Lett. (2004) [Pubmed]
  21. Sphingosine kinase expression regulates apoptosis and caspase activation in PC12 cells. Edsall, L.C., Cuvillier, O., Twitty, S., Spiegel, S., Milstien, S. J. Neurochem. (2001) [Pubmed]
  22. Inducible nitric oxide has protective effect on fumonisin B(1) hepatotoxicity in mice via modulation of sphingosine kinase. Suzuki, H., Riley, R.T., Sharma, R.P. Toxicology (2007) [Pubmed]
  23. Sphingosine kinase 1 is a negative regulator of CD4+ Th1 cells. Yang, J., Castle, B.E., Hanidu, A., Stevens, L., Yu, Y., Li, X., Stearns, C., Papov, V., Rajotte, D., Li, J. J. Immunol. (2005) [Pubmed]
  24. Sphingosine kinase activation mediates ischemic preconditioning in murine heart. Jin, Z.Q., Goetzl, E.J., Karliner, J.S. Circulation (2004) [Pubmed]
  25. Roles of AKT and sphingosine kinase in the antiapoptotic effects of bile duct ligation in mouse liver. Osawa, Y., Hannun, Y.A., Proia, R.L., Brenner, D.A. Hepatology (2005) [Pubmed]
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