title: Sphingosine 1-phosphate and sphingosine kinases in health and disease: Recent advances.
abstract: Sphingosine kinases (isoforms SK1 and SK2) catalyse the formation of a bioactive lipid, sphingosine 1-phosphate (S1P). S1P is a well-established ligand of a family of five S1P-specific G protein coupled receptors but also has intracellular signalling roles. There is substantial evidence to support a role for sphingosine kinases and S1P in health and disease. This review summarises recent advances in the area in relation to receptor-mediated signalling by S1P and novel intracellular targets of this lipid. New evidence for a role of each sphingosine kinase isoform in cancer, the cardiovascular system, central nervous system, inflammation and diabetes is discussed. There is continued research to develop isoform selective SK inhibitors, summarised here. Analysis of the crystal structure of SK1 with the SK1-selective inhibitor, PF-543, is used to identify residues that could be exploited to improve selectivity in SK inhibitor development for future therapeutic application.
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral St, Glasgow, G4 0RE, Scotland, UK. Electronic address: susan.pyne@strath.ac.uk.
authors.forename: Susan
authors.initials: S
authors.lastname: Pyne
authors.affiliation: School of Engineering & Physical Sciences, Heriot-Watt University, Edinburgh EH14 4AS, Scotland, UK. Electronic address: d.r.adams@hw.ac.uk.
authors.forename: David R
authors.initials: DR
authors.lastname: Adams
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral St, Glasgow, G4 0RE, Scotland, UK. Electronic address: n.j.pyne@strath.ac.uk.
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Pyne
mesh_terms: D000818:Animals; D002318:Cardiovascular Diseases / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008246:Lysophospholipids / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D009369:Neoplasms / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000096:biosynthesis*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D000099157:Sphingosine Kinase
chemical_list: D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D047428:Protein Kinase Inhibitors; D043562:Receptors, G-Protein-Coupled; D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate
keywords: Intracellular signalling; S1P receptors; Sphingosine 1-phosphate; Sphingosine kinase; Sphingosine kinase inhibitors