title: Emerging biology of sphingosine-1-phosphate: its role in pathogenesis and therapy.
abstract: Membrane sphingolipids are metabolized to sphingosine-1-phosphate (S1P), a bioactive lipid mediator that regulates many processes in vertebrate development, physiology, and pathology. Once exported out of cells by cell-specific transporters, chaperone-bound S1P is spatially compartmentalized in the circulatory system. Extracellular S1P interacts with five GPCRs that are widely expressed and transduce intracellular signals to regulate cellular behavior, such as migration, adhesion, survival, and proliferation. While many organ systems are affected, S1P signaling is essential for vascular development, neurogenesis, and lymphocyte trafficking. Recently, a pharmacological S1P receptor antagonist has won approval to control autoimmune neuroinflammation in multiple sclerosis. The availability of pharmacological tools as well as mouse genetic models has revealed several physiological actions of S1P and begun to shed light on its pathological roles. The unique mode of signaling of this lysophospholipid mediator is providing novel opportunities for therapeutic intervention, with possibilities to target not only GPCRs but also transporters, metabolic enzymes, and chaperones.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Proia
authors.forename: Timothy
authors.initials: T
authors.lastname: Hla
mesh_terms: D055371:Acute Lung Injury / Q000188:drug therapy; D000755:Anemia, Sickle Cell / Q000097:blood; D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000378:metabolism; D002468:Cell Physiological Phenomena / Q000502:physiology; D004195:Disease Models, Animal; D000068876:Fingolimod Hydrochloride; D019650:Hematopoietic Stem Cell Mobilization; D006801:Humans; D007251:Influenza, Human / Q000378:metabolism; D008246:Lysophospholipids / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D008563:Membrane Lipids / Q000378:metabolism; D051379:Mice; D009103:Multiple Sclerosis / Q000188:drug therapy; D009369:Neoplasms / Q000097:blood; D018919:Neovascularization, Physiologic / Q000502:physiology; D055495:Neurogenesis / Q000502:physiology; D011409:Propylene Glycols / Q000627:therapeutic use; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors / Q000502:physiology; D013107:Sphingolipids / Q000378:metabolism; D013110:Sphingosine / Q000819:agonists / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000502:physiology / Q000627:therapeutic use
chemical_list: D008246:Lysophospholipids; D008563:Membrane Lipids; D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; D013107:Sphingolipids; C060506:sphingosine 1-phosphate; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine
references.citation: J Clin Invest. 2014 May;124(5):2076-86
references.pmid: 24667638
references.citation: J Biol Chem. 2007 Apr 6;282(14):10690-6
references.pmid: 17284444
references.citation: Nat Rev Drug Discov. 2010 Nov;9(11):883-97
references.pmid: 21031003
references.citation: Cell. 2007 Nov 30;131(5):994-1008
references.pmid: 18045540
references.citation: Hear Res. 2006 Oct;220(1-2):38-48
references.pmid: 16945494
references.citation: Annu Rev Immunol. 2012;30:69-94
references.pmid: 22149932
references.citation: Mol Immunol. 2007 Jul;44(13):3305-16
references.pmid: 17475330
references.citation: FASEB J. 2013 Mar;27(3):1001-11
references.pmid: 23180825
references.citation: Nat Cell Biol. 2014 Jul;16(7):652-62
references.pmid: 24929359
references.citation: Biochem J. 2011 Dec 15;440(3):345-53
references.pmid: 21848514
references.citation: Science. 2007 Apr 13;316(5822):295-8
references.pmid: 17363629
references.citation: Nature. 2013 Jan 31;493(7434):684-8
references.pmid: 23263181
references.citation: Arterioscler Thromb Vasc Biol. 2007 Mar;27(3):607-13
references.pmid: 17158351
references.citation: Mol Pharmacol. 2010 Apr;77(4):704-13
references.pmid: 20097776
references.citation: Biochim Biophys Acta. 2014 Nov;1841(11):1581-9
references.pmid: 25158625
references.citation: PLoS One. 2013;8(7):e68328
references.pmid: 23861887
references.citation: FEBS Lett. 2006 Oct 9;580(23):5456-66
references.pmid: 16962101
references.citation: Circ Res. 2008 Mar 28;102(6):669-76
references.pmid: 18258856
references.citation: Cardiovasc Res. 2006 Apr 1;70(1):88-96
references.pmid: 16545787
references.citation: J Clin Invest. 2011 Jun;121(6):2290-300
references.pmid: 21555855
references.citation: Cardiovasc Res. 2009 May 1;82(2):193-200
references.pmid: 19282351
references.citation: Biochem Biophys Res Commun. 1998 Jan 26;242(3):502-7
references.pmid: 9464245
references.citation: Mol Cell Biol. 2005 Dec;25(24):11113-21
references.pmid: 16314531
references.citation: Biochem Pharmacol. 2012 Dec 15;84(12):1551-62
references.pmid: 22971335
references.citation: J Neurosci. 2013 Feb 6;33(6):2582-92
references.pmid: 23392686
references.citation: PLoS One. 2009;4(1):e4112
references.pmid: 19119317
references.citation: Hum Mol Genet. 2008 Aug 1;17(15):2257-64
references.pmid: 18424450
references.citation: J Biol Chem. 2004 Dec 10;279(50):52487-92
references.pmid: 15459201
references.citation: J Exp Med. 2010 Jan 18;207(1):17-27
references.pmid: 20026661
references.citation: J Neurosci. 2007 Feb 7;27(6):1474-8
references.pmid: 17287522
references.citation: Am J Respir Crit Care Med. 2004 Nov 1;170(9):987-93
references.pmid: 15282202
references.citation: Clin Neuropharmacol. 2010 Mar-Apr;33(2):91-101
references.pmid: 20061941
references.citation: Proc Natl Acad Sci U S A. 2011 Jun 7;108(23):9613-8
references.pmid: 21606363
references.citation: Prostaglandins Other Lipid Mediat. 2001 Apr;64(1-4):107-22
references.pmid: 11324700
references.citation: Cancer Res. 2009 Nov 15;69(22):8686-92
references.pmid: 19903857
references.citation: Cancer Cell. 2013 Jan 14;23(1):107-20
references.pmid: 23273921
references.citation: J Exp Med. 2010 Jul 5;207(7):1475-83
references.pmid: 20584883
references.citation: Nat Med. 2010 Dec;16(12):1421-8
references.pmid: 21102457
references.citation: Virology. 2014 Mar;452-453:152-7
references.pmid: 24606692
references.citation: J Biol Chem. 2011 Mar 4;286(9):7348-58
references.pmid: 21173151
references.citation: Cardiovasc Res. 2007 Oct 1;76(1):41-50
references.pmid: 17610857
references.citation: PLoS One. 2013;8(3):e59630
references.pmid: 23544080
references.citation: Nature. 2014 Dec 11;516(7530):254-8
references.pmid: 25274307
references.citation: Nat Immunol. 2011 Jul;12(7):672-80
references.pmid: 21642988
references.citation: J Exp Med. 2009 Oct 26;206(11):2469-81
references.pmid: 19808259
references.citation: Nature. 2014 Jun 5;510(7503):68-75
references.pmid: 24899306
references.citation: J Immunol. 2005 Mar 15;174(6):3551-61
references.pmid: 15749892
references.citation: Proc Natl Acad Sci U S A. 2005 Feb 22;102(8):2725-30
references.pmid: 15710896
references.citation: Br J Pharmacol. 2000 Aug;130(8):1871-7
references.pmid: 10952677
references.citation: Cell. 2011 Mar 4;144(5):646-74
references.pmid: 21376230
references.citation: Mol Cell. 2012 May 25;46(4):461-71
references.pmid: 22633490
references.citation: Nat Immunol. 2013 Nov;14(11):1166-72
references.pmid: 24076635
references.citation: J Exp Med. 2012 Nov 19;209(12):2165-81
references.pmid: 23148237
references.citation: FASEB J. 2009 Jan;23(1):143-52
references.pmid: 18815359
references.citation: J Clin Invest. 2014 Jun;124(6):2750-61
references.pmid: 24837436
references.citation: PLoS One. 2012;7(6):e38941
references.pmid: 22723910
references.citation: Biochem J. 2012 May 15;444(1):79-88
references.pmid: 22397330
references.citation: J Biol Chem. 2013 Jan 25;288(4):2143-56
references.pmid: 23229546
references.citation: J Clin Invest. 2009 Jul;119(7):1871-9
references.pmid: 19603543
references.citation: J Immunol. 2013 Apr 1;190(7):3533-40
references.pmid: 23436932
references.citation: Prostaglandins Other Lipid Mediat. 2004 Jan;73(1-2):141-50
references.pmid: 15165038
references.citation: Proc Natl Acad Sci U S A. 2012 Mar 6;109(10):3879-84
references.pmid: 22343534
references.citation: Proc Natl Acad Sci U S A. 2014 Mar 11;111(10):3799-804
references.pmid: 24572573
references.citation: J Clin Invest. 2014 Nov;124(11):4823-8
references.pmid: 25250575
references.citation: J Biol Chem. 2004 Jul 9;279(28):29367-73
references.pmid: 15138255
references.citation: N Engl J Med. 2012 Jan 26;366(4):339-47
references.pmid: 22276823
references.citation: Cell. 2008 Oct 31;135(3):561-71
references.pmid: 18984166
references.citation: Arterioscler Thromb Vasc Biol. 2007 Jun;27(6):1312-8
references.pmid: 17431187
references.citation: J Clin Invest. 2012 Apr;122(4):1416-26
references.pmid: 22406534
references.citation: Nat Rev Cancer. 2010 Jul;10(7):489-503
references.pmid: 20555359
references.citation: Am J Physiol Regul Integr Comp Physiol. 2007 Jan;292(1):R440-6
references.pmid: 16990495
references.citation: Cardiovasc Res. 2003 Apr 1;58(1):170-7
references.pmid: 12667959
references.citation: Nat Rev Mol Cell Biol. 2003 May;4(5):397-407
references.pmid: 12728273
references.citation: J Clin Invest. 2014 Jun;124(6):2571-84
references.pmid: 24812668
references.citation: Nature. 2013 Oct 3;502(7469):105-9
references.pmid: 23995678
references.citation: Cell. 2011 Sep 16;146(6):980-91
references.pmid: 21925319
references.citation: Cell Rep. 2012 Nov 29;2(5):1104-10
references.pmid: 23103166
references.citation: J Biol Chem. 2007 Nov 23;282(47):34372-80
references.pmid: 17895250
references.citation: Stroke. 2001 Dec 1;32(12):2913-9
references.pmid: 11739995
references.citation: Pharmacol Rev. 2010 Dec;62(4):579-87
references.pmid: 21079037
references.citation: J Clin Invest. 2000 Aug;106(3):337-8
references.pmid: 10930436
references.citation: Biochim Biophys Acta. 2014 May;1841(5):799-810
references.pmid: 24184515
references.citation: Chem Rev. 2011 Oct 12;111(10):6387-422
references.pmid: 21942574
references.citation: J Biol Chem. 1990 Jun 5;265(16):9308-13
references.pmid: 2160972
references.citation: EMBO J. 2003 Oct 15;22(20):5491-500
references.pmid: 14532121
references.citation: Blood. 2013 Aug 15;122(7):1256-65
references.pmid: 23699601
references.citation: Mol Cell Biol. 2007 May;27(9):3429-40
references.pmid: 17325039
references.citation: J Lipid Res. 2007 Nov;48(11):2325-33
references.pmid: 17698855
references.citation: Biochim Biophys Acta. 2013 Jan;1831(1):239-50
references.pmid: 22889995
references.citation: J Biol Chem. 2008 Nov 21;283(47):32442-51
references.pmid: 18805787
references.citation: EMBO Mol Med. 2012 Aug;4(8):761-75
references.pmid: 22707406
references.citation: Blood. 2012 Jan 19;119(3):707-16
references.pmid: 22049516
references.citation: J Lipid Res. 2009 Mar;50(3):556-64
references.pmid: 18955732
references.citation: Proc Natl Acad Sci U S A. 2011 Jan 11;108(2):751-6
references.pmid: 21177428
references.citation: J Exp Med. 2011 Jun 6;208(6):1267-78
references.pmid: 21576386
references.citation: J Biol Chem. 2003 Nov 21;278(47):46832-9
references.pmid: 12954646
references.citation: J Clin Invest. 2012 Aug;122(8):2731-40
references.pmid: 22850883
references.citation: Am J Respir Crit Care Med. 2004 Jun 1;169(11):1245-51
references.pmid: 15020292
references.citation: J Lipid Res. 2014 Aug;55(8):1596-608
references.pmid: 24459205
references.citation: Neuroscience. 2010 Dec 29;171(4):973-80
references.pmid: 20950672
references.citation: J Lipid Res. 2013 Mar;54(3):843-51
references.pmid: 23296878
references.citation: Biochim Biophys Acta. 2013 Jan;1831(1):193-202
references.pmid: 22735358
references.citation: Am J Respir Cell Mol Biol. 2010 Dec;43(6):662-73
references.pmid: 20081052
references.citation: J Clin Invest. 2004 Oct;114(8):1082-9
references.pmid: 15489955
references.citation: Prostaglandins Other Lipid Mediat. 2005 Sep;77(1-4):197-209
references.pmid: 16099404
references.citation: J Immunol. 2007 Feb 15;178(4):2458-68
references.pmid: 17277153
references.citation: Arterioscler Thromb Vasc Biol. 2011 Jan;31(1):81-5
references.pmid: 20947824
references.citation: Curr Biol. 2000 Nov 30;10(23):1527-30
references.pmid: 11114522
references.citation: Science. 2012 Feb 17;335(6070):851-5
references.pmid: 22344443
references.citation: Science. 2005 Sep 9;309(5741):1735-9
references.pmid: 16151014
references.citation: Circulation. 2004 Oct 5;110(14):1980-9
references.pmid: 15451787
references.citation: Arterioscler Thromb Vasc Biol. 2013 Jul;33(7):1505-12
references.pmid: 23640484
references.citation: Science. 2011 Sep 30;333(6051):1898-903
references.pmid: 21960637
references.citation: J Biol Chem. 2013 Nov 8;288(45):32563-73
references.pmid: 24081141
references.citation: Science. 2002 May 3;296(5569):879-83
references.pmid: 11988566
references.citation: Cancer Cell. 2006 Mar;9(3):225-38
references.pmid: 16530706
references.citation: J Biol Chem. 2010 Apr 2;285(14):10880-9
references.pmid: 20097939
references.citation: Circ Res. 2011 Feb 4;108(3):314-23
references.pmid: 21164103
references.citation: J Immunol. 2012 Jul 1;189(1):102-11
references.pmid: 22664872
references.citation: Genes Dev. 2012 May 15;26(10):1070-85
references.pmid: 22588719
references.citation: J Biol Chem. 2003 Jan 10;278(2):1268-72
references.pmid: 12411432
references.citation: J Immunol. 2010 Feb 1;184(3):1475-83
references.pmid: 20042570