SphK1 and SphK2, Sphingosine Kinase Isoenzymes with Opposing Functions in Sphingolipid Metabolism*

By Michael Maceyka, Heidi M. Sankala, N. Hait, H. Le Stunff, Hong Liu, R. Toman, Claiborne Collier, M. Zhang, L. Satin, Alfred H. Merrill Jr. and 2 more. Journal of Biological Chemistry, 2005

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The potent sphingolipid metabolite sphingosine 1-phosphate is produced by phosphorylation of sphingosine catalyzed by sphingosine kinase (SphK) types 1 and 2. In contrast to pro-survival SphK1, the putative BH3-only protein SphK2 inhibits cell growth and enhances apoptosis. Here we show that SphK2 catalytic activity also contributes to its ability to induce apoptosis. Overexpressed SphK2 also increased cytosolic free calcium induced by serum starvation. Transfer of calcium to mitochondria was required for SphK2-induced apoptosis, as cell death and cytochrome c release was abrogated by inhibition of the mitochondrial Ca2+ transporter. Serum starvation increased the proportion of SphK2 in the endoplasmic reticulum and targeting SphK1 to the endoplasmic reticulum converted it from anti-apoptotic to pro-apoptotic. Overexpression of SphK2 increased incorporation of [3H]palmitate, a substrate for both serine palmitoyltransferase and ceramide synthase, into C16-ceramide, whereas SphK1 decreased it. Electrospray ionizationmass spectrometry/mass spectrometry also revealed an opposite effect on ceramide mass levels. Importantly, specific down-regulation of SphK2 reduced conversion of sphingosine to ceramide in the recycling pathway and conversely, down-regulation of SphK1 increased it. Our results demonstrate that SphK1 and SphK2 have opposing roles in the regulation of ceramide biosynthesis and suggest that the location of sphingosine 1-phosphate production dictates its functions.

Subfields: Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/184cc9dcc24becb2be7336ea1c9034b69e578bcd

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Citations in the corpus

(Dihydro)ceramide Synthase 1–Regulated Sensitivity to Cisplatin Is Associated with the Activation of p38 Mitogen-Activated Protein Kinase and Is Abrogated by Sphingosine Kinase 1 (2007, background): “For example, various agonists cause SphK1 to translocate from the cytoplasm to the plasma membrane (33), and stress has been shown to cause SphK2 to translocate from the cytoplasm to the ER (13).”
An overview of sphingolipid metabolism: from synthesis to breakdown (2010, background): “Early reports on SK2 function suggest that it enhances apoptotic responses and can induce apoptosis through overexpression [128].”
“Inside-Out” Signaling of Sphingosine-1-Phosphate: Therapeutic Targets (2008, background): “Moreover, SphK1 and SphK2 have opposing roles in regulation of ceramide biosynthesis (Maceyka et al., 2005).”
Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium (2008, background): “Sphingosine-1-phosphate is an essential signaling lipid that regulates many processe”