Sphingosine 1-Phosphate, a Key Cell Signaling Molecule

Abstract

sphingosine 1-phosphate G protein-coupled receptor S1P receptor platelet-derived growth factor PDGF receptor phospholipase C sphingosine kinase The bioactive sphingolipid metabolite sphingosine 1-phosphate (S1P),1 formed by phosphorylation of sphingosine catalyzed by sphingosine kinase (Fig.1), is an important lipid mediator that has been implicated in many biological processes. S1P has been detected in organisms as diverse as plants, yeast, worms, flies, and mammals. More than a decade has elapsed since it was first suggested that S1P can regulate cell growth (1Zhang H. Desai N.N. Olivera A. Seki T. Brooker G. Spiegel S. J. Cell Biol. 1991; 114: 155-167Crossref PubMed Scopus (564) Google Scholar). Because it has multiple actions and regulates many processes, only relatively recently have we begun to make major progress in unraveling its pleiotropic actions following the cloning of the enzymes that regulate its levels and identification of its specific cell surface receptors. Much still remains to be uncovered, and its name, derived from the riddle of the mysterious sphinx, remains appropriate for this enigmatic lipid. It is now well established that S1P is the natural ligand for specific G protein-coupled receptors (GPCRs), hereafter referred to as S1PRs. To date, five members, EDG-1/S1P1, EDG-5/S1P2, EDG-3/S1P3, EDG-6/S1P4, and EDG-8/S1P5 have been identified (2Goetzl E.J. An S. FASEB J. 1998; 12: 1589-1598Crossref PubMed Scopus (490) Google Scholar, 3Spiegel S. Milstien S. Biochim. Biophys. Acta. 2000; 1484: 107-116Crossref PubMed Scopus (186) Google Scholar, 4Pyne S. Pyne N.J. Biochem. J. 2000; 349: 385-402Crossref PubMed Scopus (662) Google Scholar, 5Hla T. Lee M.J. Ancellin N. Paik J.H. Kluk M.J. Science. 2001; 294: 1875-1878Crossref PubMed Scopus (482) Google Scholar). These receptors are highly specific and only bind S1P and dihydro-S1P, which lacks the trans double bond of the sphingoid base. Although earlier studies suggested that S1P1 might also bind the structurally related serum-borne phospholipid, lysophosphatidic acid (6Lee M.J. Thangada S. Liu C.H. Thompson B.D. Hla T. J. Biol. Chem. 1998; 273: 22105-22112Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar), it is now clear that this lipid is not a ligand for any of the S1PRs and has its own closely related family of GPCRs (7Contos J.J. Ishii I. Chun J. Mol. Pharmacol. 2000; 58: 1188-1196Crossref PubMed Scopus (369) Google Scholar). The S1PRs are ubiquitously expressed and are coupled to a variety of G proteins. Whereas S1P1 and S1P5 are coupled mainly to Gi, S1P2 can be coupled to all G proteins, S1P3 is coupled to Gi, Gq, and G12/13, and S1P4 activates Gi and G12 but not Gs or Gq/11 in response to S1P. As a consequence, S1P influences distinct biological processes depending on the relative expression of S1PRs as well as G proteins. Members of the S1PRs also differentially regulate the small GTPases of the Rho family, particularly Rho and Rac (8Lee M.J. Thangada S. Claffey K.P. Ancellin N. Liu C.H. Kluk M. Volpi M. Sha'afi R.I. Hla T. Cell. 1999; 99: 301-312Abstract Full Text Full Text PDF PubMed Scopus (877) Google Scholar), which are downstream of the heterotrimeric G proteins and are important for cytoskeletal rearrangements and cell movement (9Hall A. Science. 1998; 280: 2074-2075Crossref PubMed Scopus (166) Google Scholar). Activation of S1P1 stimulates Rac-coupled cortical actin formation and enhances motility (8Lee M.J. Thangada S. Claffey K.P. Ancellin N. Liu C.H. Kluk M. Volpi M. Sha'afi R.I. Hla T. Cell. 1999; 99: 301-312Abstract Full Text Full Text PDF PubMed Scopus (877) Google Scholar, 10Wang F. Van Brocklyn J.R. Hobson J.P. Movafagh S. Zukowska-Grojec Z. Milstien S. Spiegel S. J. Biol. Chem. 1999; 274: 35343-35350Abstract Full Text Full Text PDF PubMed Scopus (348) Google Scholar, 11Liu Y. Wada R. Yamashita T., Mi, Y. Deng C.X. Hobson J.P. Rosenfeldt H.M. Nava V.E. Chae S.S. Lee M.J. Liu C.H. Hla T. Spiegel S. Proia R.L. J. Clin. Invest. 2000; 106: 951-961Crossref PubMed Scopus (996) Google Scholar, 12Garcia J.G. Liu F. Verin A.D. Birukova A. Dechert M.A. Gerthoffer W.T. Bamberg J.R. English D. J. Clin. Invest. 2001; 108: 689-701Crossref PubMed Scopus (756) Google Scholar, 13Hobson J.P. Rosenfeldt H.M. Barak L.S. Olivera A. Poulton S. Caron M.G. Milstien S. Spiegel S. Science. 2001; 291: 1800-1803Crossref PubMed Scopus (385) Google Scholar) whereas S1P2 elicits Rho-coupled stress fiber assembly and suppresses Rac activation (14Okamoto H. Takuwa N. Yokomizo T. Sugimoto N. Sakurada S. Shigematsu H. Takuwa Y. Mol. Cell. Biol. 2000; 20: 9247-9261Crossref PubMed Scopus (289) Google Scholar), thereby inhibiting cell migration. Interestingly, only higher eukaryotes express S1PRs, whereas lower organisms, including plants and yeast, though responsive to S1P, seem not to have them. Understanding the biological functions of the S1PRs is still in its infancy although some major advances have emerged from recent gene disru