Key points are not available for this paper at this time.
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 disruption studies. The phenotype of s1p1 null mice revealed the important function of S1P1 in vascular maturation (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). The embryos died in utero between E12.5 and E14.5 because of incomplete vascular maturation (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) resulting from a failure of vascular smooth muscle cells and pericytes to migrate around arteries and capillaries and properly reinforce them. Disruption of the PDGF-BB or PDGFR-β genes in mice also resulted in defective ensheathment of nascent blood vessels (15Lindahl P. Johansson B.R. Leveen P. Betsholtz C. Science. 1997; 277: 242-245Crossref PubMed Scopus (1759) Google Scholar, 16Hellstrom M. Kaln M. Lindahl P. Abramsson A. Betsholtz C. Development. 1999; 126: 3047-3055PubMed Google Scholar). Dysfunctional migration of S1P1 null embryonic fibroblasts toward a gradient of PDGF (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) links these two phenotypes at the final steps of vascular development, underscoring the importance of S1P1 and endothelial cell-pericyte communication in vascular maturation and angiogenesis. This study also revealed novel cross-talk between a receptor tyrosine kinase, PDGFR, and a GPCR, S1P1. Hence, binding of PDGF to its receptor activates and recruits sphingosine kinase to the leading edge of the cell (17Rosenfeldt H.M. Hobson J.P. Maceyka M. Olivera A. Nava V.E. Milstien S. Spiegel S. FASEB J. 2001; 15: 2649-2659Crossref PubMed Scopus (143) Google Scholar). This localized formation of S1P spatially and temporally stimulates S1P1 (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), resulting in activation and integration of downstream signals essential for cell locomotion, such as FAK and Src, necessary for turnover of focal complexes, and the small guanosine triphosphatase Rac, important for protrusion of lamellipodia and forward movement (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, 17Rosenfeldt H.M. Hobson J.P. Maceyka M. 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Cell. 2001; 8: 693-704Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar). Thus, in this scheme, insulin-like growth factor-1-activated Akt binds S1P1 and phosphorylates its third intracellular loop at Thr-236, which is required for Rac activation and chemotaxis (21Lee M. Thangada S. Paik J. Sapkota G.P. Ancellin N. Chae S., Wu, M. Morales-Ruiz M. Sessa W.C. Alessi D.R. Hla T. Mol. Cell. 2001; 8: 693-704Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar). Further studies are necessary to validate the generality of this concept of S1P-independent activation of S1PRs. The importance of S1P2 in cardiac development was revealed in the zebrafish mutant miles apart (mil), the S1P2 orthologue, by the formation of a bilateral heart on the either side of the midline (22Kupperman E., An, S. Osborne N. Waldron S. Stainier D.Y. Nature. 2000; 406: 192-195Crossref PubMed Scopus (347) Google Scholar). Remarkably, the S1P2gene is not expressed in the migrating heart precursors; rather, it is expressed in the midline region of zebrafish embryos (22Kupperman E., An, S. Osborne N. Waldron S. Stainier D.Y. Nature. 2000; 406: 192-195Crossref PubMed Scopus (347) Google Scholar). In contrast to what might be expected, S1P2 deletion in mice did not produce a similar cardiovascular or any other physiological defect (23MacLennan A.J. Carney P.R. Zhu W.J. Chaves A.H. Garcia J. Grimes J.R. Anderson K.J. Roper S.N. Lee N. Eur. J. Neurosci. 2001; 14: 203-209Crossref PubMed Google Scholar). S1P3-deleted mice also developed normally suggesting that it is likewise nonessential for development (24Ishii I. Friedman B., Ye, X. Kawamura S. McGiffert C. Contos J.J. Kingsbury M.A. Zhang G. Heller Brown J. Chun J. J. Biol. Chem. 2001; 276: 33697-33704Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar). However, S1P-dependent activation of PLC and not Rho was defective in fibroblasts from these mice (24Ishii I. Friedman B., Ye, X. Kawamura S. McGiffert C. Contos J.J. Kingsbury M.A. Zhang G. Heller Brown J. Chun J. J. Biol. Chem. 2001; 276: 33697-33704Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar). These results suggest that S1P3 is the predominant receptor coupling Gi to PLC activation and inositol 1,4,5-trisphosphate formation. Even less is known of S1P4, which is mainly expressed in lymphoid and hematopoietic tissues and activates ERK1/2 (25Van Brocklyn J.R. Graler M.H. Bernhardt G. Hobson J.P. Lipp M. Spiegel S. Blood. 2000; 95: 2624-2629Crossref PubMed Google Scholar) and PLC via pertussis toxin-sensitive G proteins (26Yamazaki Y. Kon J. Sato K. Tomura H. Sato M. Yoneya T. Okazaki H. Okajima F. Ohta H. Biochem. Biophys. Res. Commun. 2000; 268: 583-589Crossref PubMed Scopus (138) Google Scholar). 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The acid in stress is to the it by activation of calcium plants in the levels of S1P S1P, but not dihydro-S1P, calcium and as the of acid was by with a these suggest that S1P might as a second messenger in plants and that S1P regulates cell The results of the many studies only the that are in this support for the that S1P functions as a first messenger and a second In of its most well established functions to date, S1P by binding to of the family of GPCRs, thereby cell and it to regulate survival and of the specific physiological of the S1PRs, identification of the intracellular targets of S1P, the of S1P, and of its and of The of genes known to be in S1P has the yet it is that other be identified and to be of these gene as well as of and of activation of the functions of S1P. The development of or of S1PRs and of or of enzymes that the intracellular of S1P may the for the development of novel to those not be because of and we the for to the studies that in this and especially Liu and Rosenfeldt for with the
Spiegel et al. (Mon,) studied this question.