Sphingosine kinase type 1 inhibition reveals rapid turnover of circulating sphingosine 1-phosphate

Yugesh Kharel, Thomas P. Mathews, Amanda M. Gellett, Jose L. Tomsig, Perry C. Kennedy, Morgan L. Moyer, Timothy L. Macdonald, Kevin R. Lynch

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

S1P (sphingosine 1-phosphate) is a signalling molecule involved in a host of cellular and physiological functions, most notably cell survival and migration. S1P, which signals via a set of five G-protein-coupled receptors (S1P1-S1P5), is formed by the action of two SphKs (sphingosine kinases) from Sph (sphingosine). Interfering RNA strategies and SphK1 (sphingosine kinase type 1)-null (Sphk1 -/-) mouse studies implicate SphK1 in multiple signalling cascades, yet there is a paucity of potent and selective SphK1 inhibitors necessary to evaluate the effects of rapid onset inhibition of this enzyme. We have identified a set of submicromolar amidine-based SphK1 inhibitors and report using a pair of these compounds to probe the cellular and physiological functions of SphK1. In so doing, we demonstrate that our inhibitors effectively lower S1P levels in cell-based assays, but we have been unable to correlate SphK1 inhibition with changes in cell survival. However, SphK1 inhibition did diminish EGF (epidermal growth factor)-driven increases in S1P levels and Akt (also known as protein kinase B)/ERK (extracellular-signal- regulated kinase) phosphorylation. Finally, administration of the SphK1 inhibitor to wild-type, but not Sphk1 -/-, mice resulted in a rapid decrease in blood S1P levels indicating that circulating S1P is rapidly turned over.

Original languageEnglish (US)
Pages (from-to)345-353
Number of pages9
JournalBiochemical Journal
Volume440
Issue number3
DOIs
StatePublished - Dec 15 2011
Externally publishedYes

Keywords

  • Sphingosine 1-phosphate (S1P)
  • Sphingosine kinase (SphK)
  • Sphingosine kinase inhibitor

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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