Sphingosine-l-phosphate and lipid phosphohydrolases

Sphingosine-1-phosphate (SIP) is a bioactive sphingolipid that acts as both an extracellular ligand for the endothelial differentiation gene-1 (EDG-1) G-protein coupled receptor (GPCR) family and as an intracellular messenger. Cellular levels of S1P are low and tightly regulated in a spatial-temporal manner not only by sphingosine kinase (SPHK) but also by degradation catalyzed by SIP lyase, specific SIP phosphohydrolases, and by general lipid phosphate phosphohydrolases (LPPs). LPPs are characterized as magnesium-independent, insensitive to inhibition by N-ethylmaleimide (NEW and possessing broad substrate specificity with a variety of phosphorylated lipids, including SIP, phosphatidic acid (PA), and lysophosphatidic acid (LPA). LPPs contain three highly conserved domains that define a phosphohydrolase superfamily. Recently, several specific SIP phosphohydrolases have been identified in yeast and mammalian cells. Phylogenetic and biochemical analyses indicate that these enzymes constitute a new subset of the LPP family. As further evidence, SIP phosphohydrolases exhibit high specificity for phosphorylated sphingoid bases. Enforced expression of SIP phosphohydrolase alters the cellular levels of sphingolipid metabolites in yeast and mammalian cells, increasing sphingosine and ceramide, bioactive sphingolipids that often have opposing biological actions to SIP. By regulating the cellular ratio between ceramide/sphingosine and SIP, SIP phosphohydrolase is poised to be a critical factor in cell survival/cell death decisions. Indeed, expression of SIP phosphohydrolase in mammalian cells increases apoptosis, whereas deletion of SIP phosphohydrolases in yeast correlates with resistance to heat stress. In this review, we discuss the role of phosphohydrolases in the metabolism of SIP and how turnover of SIP can regulate sphingolipid metabolites signaling. (C) 2002 Elsevier Science B.V All rights reserved.