Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Sphingosine Kinase 2 (SPHK2)

  • Heidi Neubauer
  • Stuart PitsonEmail author
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101836


Historical Background

Sphingosine kinases are a group of enzymes, highly conserved in eukaryotes, which catalyze the phosphorylation of the lipid sphingosine, to produce the bioactive signaling molecule sphingosine-1-phosphate (S1P) (Fig. 1). Sphingosine kinase 2 (SK2), transcribed from the SPHK2 gene located on chromosome 19 (19q13.2), was the second of two functional mammalian sphingosine kinase isoforms to be identified (Liu et al. 2000). The first, sphingosine kinase 1 (SK1), shares a high level of sequence similarity with SK2, although, as outlined below, some differences exist.
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  1. Chipuk JE, McStay GP, Bharti A, Kuwana T, Clarke CJ, Siskind LJ, et al. Sphingolipid metabolism cooperates with BAK and BAX to promote the mitochondrial pathway of apoptosis. Cell. 2012;148:988–1000.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Coldewey SM, Benetti E, Collino M, Pfeilschifter J, Sponholz C, Bauer M, et al. Elevation of serum sphingosine-1-phosphate attenuates impaired cardiac function in experimental sepsis. Sci Rep. 2016;6:27594.PubMedPubMedCentralCrossRefGoogle Scholar
  3. Ding G, Sonoda H, Yu H, Kajimoto T, Goparaju SK, Jahangeer S, et al. Protein kinase D-mediated phosphorylation and nuclear export of sphingosine kinase 2. J Biol Chem. 2007;282:27493–502.PubMedPubMedCentralCrossRefGoogle Scholar
  4. Hait NC, Allegood J, Maceyka M, Strub GM, Harikumar KB, Singh SK, et al. Regulation of histone acetylation in the nucleus by sphingosine-1-phosphate. Science. 2009;325:1254–7.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Hait NC, Bellamy A, Milstien S, Kordula T, Spiegel S. Sphingosine kinase type 2 activation by ERK-mediated phosphorylation. J Biol Chem. 2007;282:12058–65.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Hait NC, Wise LE, Allegood JC, O'Brien M, Avni D, Reeves TM, et al. Active, phosphorylated fingolimod inhibits histone deacetylases and facilitates fear extinction memory. Nat Neurosci. 2014;17:971–80.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Jung M, Oren B, Mora J, Mertens C, Dziumbla S, Popp R, et al. Lipocalin 2 from macrophages stimulated by tumor cell-derived sphingosine 1-phosphate promotes lymphangiogenesis and tumor metastasis. Sci Signal. 2016;9:ra64.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Liu H, Sugiura M, Nava VE, Edsall LC, Kono K, Poulton S, et al. Molecular cloning and functional characterization of a novel mammalian sphingosine kinase type 2 isoform. J Biol Chem. 2000;275:19513–20.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Liu H, Toman RE, Goparaju SK, Maceyka M, Nava VE, Sankala H, et al. Sphingosine kinase type 2 is a putative BH3-only protein that induces apoptosis. J Biol Chem. 2003;278:40330–6.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Maceyka M, Sankala H, Hait NC, Le Stunff H, Liu H, Toman R, et al. SphK1 and SphK2, sphingosine kinase isoenzymes with opposing functions in sphingolipid metabolism. J Biol Chem. 2005;280:37118–29.PubMedPubMedCentralCrossRefGoogle Scholar
  11. Nagahashi M, Takabe K, Liu R, Peng K, Wang X, Wang Y, et al. Conjugated bile acid-activated S1P receptor 2 is a key regulator of sphingosine kinase 2 and hepatic gene expression. Hepatology. 2015;61:1216–26.PubMedPubMedCentralCrossRefGoogle Scholar
  12. Neubauer HA, Pham DH, Zebol JR, Moretti PA, Peterson AL, Leclercq TM, et al. An oncogenic role for sphingosine kinase 2. Oncotarget. 2016;7:64886–99.Google Scholar
  13. Neubauer HA, Pitson SM. Roles, regulation and inhibitors of sphingosine kinase 2. FEBS J. 2013;280:5317–36.PubMedPubMedCentralCrossRefGoogle Scholar
  14. Newton J, Lima S, Maceyka M, Spiegel S. Revisiting the sphingolipid rheostat: evolving concepts in cancer therapy. Exp Cell Res. 2015;333:195–200.PubMedPubMedCentralCrossRefGoogle Scholar
  15. Okada T, Ding G, Sonoda H, Kajimoto T, Haga Y, Khosrowbeygi A, 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;280:36318–25.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Panneer Selvam S, De Palma RM, Oaks JJ, Oleinik N, Peterson YK, Stahelin RV, et al. Binding of the sphingolipid S1P to hTERT stabilizes telomerase at the nuclear periphery by allosterically mimicking protein phosphorylation. Sci Signal. 2015;8:ra58.PubMedPubMedCentralCrossRefGoogle Scholar
  17. Pitman MR, Costabile M, Pitson SM. Recent advances in the development of sphingosine kinase inhibitors. Cell Signal. 2016;28:1349–63.PubMedPubMedCentralCrossRefGoogle Scholar
  18. Pitson SM. Regulation of sphingosine kinase and sphingolipid signaling. Trends Biochem Sci. 2011;36:97–107.PubMedPubMedCentralCrossRefGoogle Scholar
  19. Wallington-Beddoe CT, Powell JA, Tong D, Pitson SM, Bradstock KF, Bendall LJ. Sphingosine kinase 2 promotes acute lymphoblastic leukemia by enhancing MYC expression. Cancer Res. 2014;74:2803–15.PubMedPubMedCentralCrossRefGoogle Scholar
  20. Xia P, Gamble JR, Wang L, Pitson SM, Moretti PA, Wattenberg BW, et al. An oncogenic role of sphingosine kinase. Curr Biol. 2000;10:1527–30.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Centre for Cancer BiologyUniversity of South Australia and SA PathologyAdelaideAustralia
  2. 2.School of Biological SciencesUniversity of AdelaideAdelaideAustralia
  3. 3.School of MedicineUniversity of AdelaideAdelaideAustralia