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• W2072835764 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." @default.
• W2072835764 created "2016-06-24" @default.
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• W2072835764 date "2011-11-28" @default.
• W2072835764 modified "2023-09-28" @default.
• W2072835764 title "Sphingosine kinase type 1 inhibition reveals rapid turnover of circulating sphingosine 1-phosphate" @default.
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• W2072835764 doi "https://doi.org/10.1042/bj20110817" @default.
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