Sphingosine-1-phosphate phosphatases.
Sphingosine-1-phosphate is a potent proliferative, survival, and morphogenetic factor, acting as an extracellular ligand for the EDG family of G-protein-coupled receptors and possibly intracellularly through as yet, unidentified targets. It is produced within most, if not all cells by phosphorylation of sphingosine, and is an abundant serum lipid that is released from activated platelets. Sphingosine and sphingosine-1-phosphate are in dynamic equilibrium with each other due to the activities of sphingosine kinase and sphingosine-1-phosphate phosphatase (SPPase). Several SPPase genes have now been cloned, first from yeast and more recently from mammalian cells. By sequence homology, these enzymes can be classified as a subset of membrane bound, Type 2 lipid phosphohydrolases that contain conserved residues within three domains predicted to be at the active site of the enzyme. Outside of the consensus motif, there is very little homology between SPPases and the other type 2 lipid phosphohydrolases in the LPP/PAP family. Type 2 phosphatase activity is Mg+-independent and insensitive to N-ethylmaleimide, and substrate specificity is broad for LPP enzymes, whereas SPPases are highly selective for sphingolipid substrates. SPPase activity in yeast and mammalian cells regulates intracellular sphingosine-1-phosphate levels, and also alters the levels of sphingosine and ceramide, two other signaling molecules that often oppose the actions of sphingosine-1-phosphate. Thus, loss of SPPase in yeast results in high sphingosine-1-phosphate levels and cells are more resistant to stress, and in mammalian cells, overexpression of SPPase elevates ceramide levels and provokes apoptosis.
Mandala
S M
SM
Department of Infectious Diseases, Merck Research Laboratories, Rahway, NJ 07065, USA. suzanne_mandala@merck.com
D000595:Amino Acid Sequence; D000818:Animals; D008246:Lysophospholipids; D008565:Membrane Proteins; D008954:Models, Biological; D008969:Molecular Sequence Data; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism*
D008246:Lysophospholipids; D008565:Membrane Proteins; C060506:sphingosine 1-phosphate; C076020:lysophosphatidic acid phosphatase; C401298:sphingosine-1-phosphate phosphatase; D010744:Phosphoric Monoester Hydrolases; D013110:Sphingosine