lysosphingolipid receptors


Summary: A subfamily of lysophospholipid receptors with specificity for LYSOSPHINGOLIPIDS such as sphingosine-1-phosphate and sphingosine phosphorylcholine.

Top Publications

  1. Kim M, Lee H, Kwak J, Park J, Yun J, Bae Y. Sphingosine-1-phosphate stimulates rat primary chondrocyte proliferation. Biochem Biophys Res Commun. 2006;345:67-73 pubmed
    ..This study demonstrates the physiological role of two important phospholipids (S1P and PhS1P) on the modulation of rat primary chondrocyte proliferation, and the crucial role played by ERK in the process. ..
  2. Mizugishi K, Yamashita T, Olivera A, Miller G, Spiegel S, Proia R. Essential role for sphingosine kinases in neural and vascular development. Mol Cell Biol. 2005;25:11113-21 pubmed
    ..Our findings also suggest that exploitation of this potent neuronal survival pathway could lead to the development of novel therapeutic approaches for neurological diseases. ..
  3. Singer I, Tian M, Wickham L, Lin J, Matheravidathu S, Forrest M, et al. Sphingosine-1-phosphate agonists increase macrophage homing, lymphocyte contacts, and endothelial junctional complex formation in murine lymph nodes. J Immunol. 2005;175:7151-61 pubmed
    ..This subcellular pattern of intranodal receptor distribution was unchanged by treatment with FTY-P. We conclude that S1P1 agonists have profound effects on macrophages and endothelial cells, in addition to inducing lymphopenia. ..
  4. Jo S, Bajwa A, Awad A, Lynch K, Okusa M. Sphingosine-1-phosphate receptors: biology and therapeutic potential in kidney disease. Kidney Int. 2008;73:1220-30 pubmed publisher
    ..This review summarizes current knowledge on the biology of S1P and S1PRs that forms the basis for future drug development and the treatment of kidney disease. ..
  5. Schwab S, Cyster J. Finding a way out: lymphocyte egress from lymphoid organs. Nat Immunol. 2007;8:1295-301 pubmed
    ..In this review we discuss the body of evidence supporting a model in which lymphocyte egress is promoted by encounter with S1P at exit sites. We relate this model to work examining the effects of S1P receptor agonists on endothelium. ..
  6. Gonzalez Cabrera P, Hla T, Rosen H. Mapping pathways downstream of sphingosine 1-phosphate subtype 1 by differential chemical perturbation and proteomics. J Biol Chem. 2007;282:7254-64 pubmed
    ..These data suggest that the hierarchy of ubiquitin recruitment to S1P(1) (AFD-R > S1P > SEW2871) correlates with the efficiency of lysosomal receptor degradation and reflects intrinsic differences between agonists. ..
  7. Rivera J, Proia R, Olivera A. The alliance of sphingosine-1-phosphate and its receptors in immunity. Nat Rev Immunol. 2008;8:753-63 pubmed publisher
  8. Shiow L, Rosen D, Brdicková N, Xu Y, An J, Lanier L, et al. CD69 acts downstream of interferon-alpha/beta to inhibit S1P1 and lymphocyte egress from lymphoid organs. Nature. 2006;440:540-4 pubmed
    ..These observations indicate that CD69 forms a complex with and negatively regulates S1P1 and that it functions downstream of IFN-alpha/beta, and possibly other activating stimuli, to promote lymphocyte retention in lymphoid organs. ..
  9. Pham T, Okada T, Matloubian M, Lo C, Cyster J. S1P1 receptor signaling overrides retention mediated by G alpha i-coupled receptors to promote T cell egress. Immunity. 2008;28:122-33 pubmed publisher
    ..Furthermore, by simultaneously upregulating S1P1 and downregulating CCR7, T cells that have divided multiple times switch to a state favoring egress over retention. ..

More Information


  1. Kono Y, Nishiuma T, Nishimura Y, Kotani Y, Okada T, Nakamura S, et al. Sphingosine kinase 1 regulates differentiation of human and mouse lung fibroblasts mediated by TGF-beta1. Am J Respir Cell Mol Biol. 2007;37:395-404 pubmed
    ..These data suggested that SPHK1 activation by TGF-beta1 leads to Rho-associated myofibroblasts differentiation mediated by transactivated S1P receptors in the lung fibrogenic process. ..
  2. Payne S, Oskeritzian C, Griffiths R, Subramanian P, Barbour S, Chalfant C, et al. The immunosuppressant drug FTY720 inhibits cytosolic phospholipase A2 independently of sphingosine-1-phosphate receptors. Blood. 2007;109:1077-85 pubmed
    ..Our results have important implications for the potential therapeutic mechanism of action of FTY720 in eicosanoid-driven inflammatory disorders such as asthma and multiple sclerosis. ..
  3. Rosen H, Sanna M, Cahalan S, Gonzalez Cabrera P. Tipping the gatekeeper: S1P regulation of endothelial barrier function. Trends Immunol. 2007;28:102-7 pubmed
  4. Sanna M, Wang S, Gonzalez Cabrera P, Don A, Marsolais D, Matheu M, et al. Enhancement of capillary leakage and restoration of lymphocyte egress by a chiral S1P1 antagonist in vivo. Nat Chem Biol. 2006;2:434-41 pubmed
    ..Thus, chemical modulation reveals differences in S1P-S1P1 'set points' among tissues and highlights both mechanistic advantages (lymphocyte sequestration) and risks (pulmonary edema) of therapeutic intervention. ..
  5. Inoki I, Takuwa N, Sugimoto N, Yoshioka K, Takata S, Kaneko S, et al. Negative regulation of endothelial morphogenesis and angiogenesis by S1P2 receptor. Biochem Biophys Res Commun. 2006;346:293-300 pubmed
    ..These observations indicate that in contrast to S1P(1) and S1P(3), S1P(2) negatively regulates endothelial morphogenesis and angiogenesis most likely through down-regulating Rac. ..
  6. Pan S, Mi Y, Pally C, Beerli C, Chen A, Guerini D, et al. A monoselective sphingosine-1-phosphate receptor-1 agonist prevents allograft rejection in a stringent rat heart transplantation model. Chem Biol. 2006;13:1227-34 pubmed
    ..This demonstrates that a selective agonist of the S1P(1) receptor is sufficient to achieve efficacy in an animal model of transplantation. ..
  7. Sinha R, Park C, Hwang I, Davis M, Kehrl J. B lymphocytes exit lymph nodes through cortical lymphatic sinusoids by a mechanism independent of sphingosine-1-phosphate-mediated chemotaxis. Immunity. 2009;30:434-46 pubmed publisher
    ..This study identifies a major site of B lymphocyte lymph node egress, shows that FTY720 treatment blocks passage through the cortical lymphatic endothelium, and argues against a functional role for S1P chemotaxis in B lymphocyte egress. ..
  8. Donati C, Cencetti F, Nincheri P, Bernacchioni C, Brunelli S, Clementi E, et al. Sphingosine 1-phosphate mediates proliferation and survival of mesoangioblasts. Stem Cells. 2007;25:1713-9 pubmed
    ..Disclosure of potential conflicts of interest is found at the end of this article. ..
  9. Massberg S, Schaerli P, Knezevic Maramica I, Köllnberger M, Tubo N, Moseman E, et al. Immunosurveillance by hematopoietic progenitor cells trafficking through blood, lymph, and peripheral tissues. Cell. 2007;131:994-1008 pubmed
    ..Thus, HSPCs can survey peripheral organs and can foster the local production of tissue-resident innate immune cells under both steady-state conditions and in response to inflammatory signals. ..
  10. Ledgerwood L, Lal G, Zhang N, Garin A, Esses S, Ginhoux F, et al. The sphingosine 1-phosphate receptor 1 causes tissue retention by inhibiting the entry of peripheral tissue T lymphocytes into afferent lymphatics. Nat Immunol. 2008;9:42-53 pubmed
    ..Thus, the increased sphingosine 1-phosphate present in inflamed peripheral tissues may induce T cell retention and suppress T cell egress. ..
  11. Matsuyuki H, Maeda Y, Yano K, Sugahara K, Chiba K, Kohno T, et al. Involvement of sphingosine 1-phosphate (S1P) receptor type 1 and type 4 in migratory response of mouse T cells toward S1P. Cell Mol Immunol. 2006;3:429-37 pubmed
    ..These results suggest that the association of S1P4 and S1P1 plays an important role in migratory response of mouse T cells toward S1P. ..
  12. Rubtsov A, Swanson C, Troy S, Strauch P, Pelanda R, Torres R. TLR agonists promote marginal zone B cell activation and facilitate T-dependent IgM responses. J Immunol. 2008;180:3882-8 pubmed
    ..Together, these data demonstrate that in vivo TLR agonist treatment enhances the early production of Ag-specific IgM and activates MZ B cells to promote their relocation. ..
  13. Watterson K, Lanning D, Diegelmann R, Spiegel S. Regulation of fibroblast functions by lysophospholipid mediators: potential roles in wound healing. Wound Repair Regen. 2007;15:607-16 pubmed
    ..Moreover, specific agonists and antagonists of the lysophospholipid receptors may be useful for the treatment of wounds and abnormal wound healing. ..
  14. Pappu R, Schwab S, Cornelissen I, Pereira J, Regard J, Xu Y, et al. Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate. Science. 2007;316:295-8 pubmed
    ..Disruption of compartmentalized S1P signaling is a plausible mechanism by which S1P-receptor-1 agonists function as immunosuppressives. ..
  15. Swaney J, Moreno K, Gentile A, Sabbadini R, Stoller G. Sphingosine-1-phosphate (S1P) is a novel fibrotic mediator in the eye. Exp Eye Res. 2008;87:367-75 pubmed publisher
    ..These data suggest that S1P is a previously unrecognized mediator of profibrotic cellular function and signaling in the eye. ..
  16. Ryser M, Ugarte F, Lehmann R, Bornhauser M, Brenner S. S1P(1) overexpression stimulates S1P-dependent chemotaxis of human CD34+ hematopoietic progenitor cells but strongly inhibits SDF-1/CXCR4-dependent migration and in vivo homing. Mol Immunol. 2008;46:166-71 pubmed publisher
    ..Our data suggest that S1P(1) acts as an inhibitor of CXCR4-dependent migration of hematopoietic cells to sites of SDF-1 production. ..
  17. Osinde M, Mullershausen F, Dev K. Phosphorylated FTY720 stimulates ERK phosphorylation in astrocytes via S1P receptors. Neuropharmacology. 2007;52:1210-8 pubmed
    ..Collectively, these results demonstrate that FTY720P mediates ERK phosphorylation in astrocytes via the activation of S1P1 receptors. ..
  18. Walzer T, Chiossone L, Chaix J, Calver A, Carozzo C, Garrigue Antar L, et al. Natural killer cell trafficking in vivo requires a dedicated sphingosine 1-phosphate receptor. Nat Immunol. 2007;8:1337-44 pubmed
    ..Our data emphasize distinct mechanisms regulating the circulation of various lymphocyte subsets and raise the possibility that NK cell trafficking may be manipulated by therapies specifically targeting S1P5. ..
  19. Olivera A. Unraveling the complexities of sphingosine-1-phosphate function: the mast cell model. Prostaglandins Other Lipid Mediat. 2008;86:1-11 pubmed publisher
    ..In addition, how S1P receptors are activated and their involvement in mast cell functions will also be covered, including new insights on the role of S1P in the mast cell-mediated allergic response of systemic anaphylaxis. ..
  20. Rubtsov A, Strauch P, Digiacomo A, Hu J, Pelanda R, Torres R. Lsc regulates marginal-zone B cell migration and adhesion and is required for the IgM T-dependent antibody response. Immunity. 2005;23:527-38 pubmed
    ..These data demonstrate that Lsc regulates the migration and adhesion of MZB cells, and this regulation appears to be required for these cells to contribute to the antibody response to TD antigens. ..
  21. Gonzalez Diez M, Rodriguez C, Badimon L, Martinez Gonzalez J. Prostacyclin induction by high-density lipoprotein (HDL) in vascular smooth muscle cells depends on sphingosine 1-phosphate receptors: effect of simvastatin. Thromb Haemost. 2008;100:119-26 pubmed publisher
    ..Strategies aimed to therapeutically modulate S1P or S1P receptors could be useful to improve cardiovascular protection. ..
  22. Rosen H, Gonzalez Cabrera P, Marsolais D, Cahalan S, Don A, Sanna M. Modulating tone: the overture of S1P receptor immunotherapeutics. Immunol Rev. 2008;223:221-35 pubmed publisher
  23. Grigorova I, Schwab S, Phan T, Pham T, Okada T, Cyster J. Cortical sinus probing, S1P1-dependent entry and flow-based capture of egressing T cells. Nat Immunol. 2009;10:58-65 pubmed publisher
  24. Ishii M, Egen J, Klauschen F, Meier Schellersheim M, Saeki Y, Vacher J, et al. Sphingosine-1-phosphate mobilizes osteoclast precursors and regulates bone homeostasis. Nature. 2009;458:524-8 pubmed publisher
  25. Igarashi J, Michel T. Sphingosine-1-phosphate and modulation of vascular tone. Cardiovasc Res. 2009;82:212-20 pubmed publisher
  26. Camerer E, Regard J, Cornelissen I, Srinivasan Y, Duong D, Palmer D, et al. Sphingosine-1-phosphate in the plasma compartment regulates basal and inflammation-induced vascular leak in mice. J Clin Invest. 2009;119:1871-9 pubmed
    ..Our results suggest that the blood communicates with blood vessels via plasma S1P to maintain vascular integrity and regulate vascular leak. This pathway prevents lethal responses to leak-inducing mediators in mouse models. ..
  27. Wei S, Rosen H, Matheu M, Sanna M, Wang S, Jo E, et al. Sphingosine 1-phosphate type 1 receptor agonism inhibits transendothelial migration of medullary T cells to lymphatic sinuses. Nat Immunol. 2005;6:1228-35 pubmed
    ..Our results provide visualization of transendothelial migration of T cells into lymphatic sinuses and suggest that S1P(1) agonists act mainly on endothelial cell S1P(1) receptors to inhibit lymphocyte migration. ..
  28. Waters C, Long J, Gorshkova I, Fujiwara Y, Connell M, Belmonte K, et al. Cell migration activated by platelet-derived growth factor receptor is blocked by an inverse agonist of the sphingosine 1-phosphate receptor-1. FASEB J. 2006;20:509-11 pubmed
    ..The data obtained with SB649146 also suggest that the constitutively active endogenous S1P1 receptor enhances PDGF-induced cell migration. ..
  29. Sawicka E, Dubois G, Jarai G, Edwards M, Thomas M, Nicholls A, et al. The sphingosine 1-phosphate receptor agonist FTY720 differentially affects the sequestration of CD4+/CD25+ T-regulatory cells and enhances their functional activity. J Immunol. 2005;175:7973-80 pubmed
    ..Thus, FTY720 differentially affects the sequestration of T-regulatory cells and importantly, increases the functional activity of T-regulatory cells, suggesting that it may have disease-modifying potential in inflammatory disorders. ..
  30. LaMontagne K, Littlewood Evans A, Schnell C, O Reilly T, Wyder L, Sanchez T, et al. Antagonism of sphingosine-1-phosphate receptors by FTY720 inhibits angiogenesis and tumor vascularization. Cancer Res. 2006;66:221-31 pubmed
    ..These data show that functional antagonism of vascular S1P receptors by FTY720 potently inhibits angiogenesis; therefore, this may provide a novel therapeutic approach for pathologic conditions with dysregulated angiogenesis. ..
  31. Balthasar S, Samulin J, Ahlgren H, Bergelin N, Lundqvist M, Toescu E, et al. Sphingosine 1-phosphate receptor expression profile and regulation of migration in human thyroid cancer cells. Biochem J. 2006;398:547-56 pubmed
    ..The results suggest that aberrant S1P receptor expression may enhance thyroid cancer cell migration and thus contribute to the metastatic behaviour of some thyroid tumours. ..
  32. Allende M, Zhou D, Kalkofen D, BenHamed S, Tuymetova G, Borowski C, et al. S1P1 receptor expression regulates emergence of NKT cells in peripheral tissues. FASEB J. 2008;22:307-15 pubmed
    ..Our results indicate that the S1P1 receptor expression on NKT cells is dispensable for development within thymus but is essential for the establishment of their tissue residency in the periphery. ..
  33. Jenne C, Enders A, Rivera R, Watson S, Bankovich A, Pereira J, et al. T-bet-dependent S1P5 expression in NK cells promotes egress from lymph nodes and bone marrow. J Exp Med. 2009;206:2469-81 pubmed publisher
    ..In summary, these findings identify S1P5 as a T-bet-induced gene that is required for NK cell egress from LNs and BM...
  34. Mullershausen F, Zécri F, Cetin C, Billich A, Guerini D, Seuwen K. Persistent signaling induced by FTY720-phosphate is mediated by internalized S1P1 receptors. Nat Chem Biol. 2009;5:428-34 pubmed publisher
    ..We show that persistent signaling translates into an increased chemokinetic migration of primary human umbilical vein endothelial cells, which suggests persistent agonism as a crucial parameter in the mechanism of action of FTY720...
  35. Tauseef M, Kini V, Knezevic N, Brannan M, Ramchandaran R, Fyrst H, et al. Activation of sphingosine kinase-1 reverses the increase in lung vascular permeability through sphingosine-1-phosphate receptor signaling in endothelial cells. Circ Res. 2008;103:1164-72 pubmed publisher
    ..Our results suggest the crucial role of activation of the SPHK1-->S1P-->S1P1 signaling pathway in response to inflammatory mediators in endothelial cells in regulating endothelial barrier homeostasis...
  36. Venkataraman K, Thangada S, Michaud J, Oo M, Ai Y, Lee Y, et al. Extracellular export of sphingosine kinase-1a contributes to the vascular S1P gradient. Biochem J. 2006;397:461-71 pubmed
    ..These results suggest that export of Sphk-1a occurs under physiological conditions and may contribute to the establishment of the vascular S1P gradient. ..
  37. Takabe K, Paugh S, Milstien S, Spiegel S. "Inside-out" signaling of sphingosine-1-phosphate: therapeutic targets. Pharmacol Rev. 2008;60:181-95 pubmed publisher
  38. Carlson C, Endrizzi B, Wu J, Ding X, Weinreich M, Walsh E, et al. Kruppel-like factor 2 regulates thymocyte and T-cell migration. Nature. 2006;442:299-302 pubmed
    ..Our findings suggest that KLF2 serves to license mature T cells for trafficking from the thymus and recirculation through secondary lymphoid tissues. ..
  39. Cinamon G, Zachariah M, Lam O, Foss F, Cyster J. Follicular shuttling of marginal zone B cells facilitates antigen transport. Nat Immunol. 2008;9:54-62 pubmed
    ..Marginal zone-follicle shuttling of marginal zone B cells provides an efficient mechanism for systemic antigen capture and delivery to follicular dendritic cells. ..
  40. Oo M, Thangada S, Wu M, Liu C, Macdonald T, Lynch K, et al. Immunosuppressive and anti-angiogenic sphingosine 1-phosphate receptor-1 agonists induce ubiquitinylation and proteasomal degradation of the receptor. J Biol Chem. 2007;282:9082-9 pubmed
    ..We propose that the ability of FTY720-P to target the S1P1 receptor to the ubiquitinylation and proteasomal degradation pathway may at least in part underlie its immunosuppressive and anti-angiogenic properties. ..
  41. Jongsma M, Hendriks Balk M, Michel M, Peters S, Alewijnse A. BML-241 fails to display selective antagonism at the sphingosine-1-phosphate receptor, S1P(3). Br J Pharmacol. 2006;149:277-82 pubmed
    ..We conclude that BML-241 is a low potency, non-selective inhibitor of increases in [Ca2+]i, rather than a specific antagonist at the S1P3 receptor. ..
  42. Kimura A, Ohmori T, Ohkawa R, Madoiwa S, Mimuro J, Murakami T, et al. Essential roles of sphingosine 1-phosphate/S1P1 receptor axis in the migration of neural stem cells toward a site of spinal cord injury. Stem Cells. 2007;25:115-24 pubmed
  43. Kabashima K, Haynes N, Xu Y, Nutt S, Allende M, Proia R, et al. Plasma cell S1P1 expression determines secondary lymphoid organ retention versus bone marrow tropism. J Exp Med. 2006;203:2683-90 pubmed
  44. Lien Y, Yong K, Cho C, Igarashi S, Lai L. S1P(1)-selective agonist, SEW2871, ameliorates ischemic acute renal failure. Kidney Int. 2006;69:1601-8 pubmed
    ..This new class of renoprotective agent shows promise as a novel approach in preventing/treating ischemic acute renal failure. ..
  45. Kitano M, Hla T, Sekiguchi M, Kawahito Y, Yoshimura R, Miyazawa K, et al. Sphingosine 1-phosphate/sphingosine 1-phosphate receptor 1 signaling in rheumatoid synovium: regulation of synovial proliferation and inflammatory gene expression. Arthritis Rheum. 2006;54:742-53 pubmed
    ..Thus, regulation of S1P/S1P1 signaling may represent a novel therapeutic target in RA. ..
  46. Meacci E, Nuti F, Donati C, Cencetti F, Farnararo M, Bruni P. Sphingosine kinase activity is required for myogenic differentiation of C2C12 myoblasts. J Cell Physiol. 2008;214:210-20 pubmed
    ..This is the first report of the role of endogenous SphK1 in myoblast growth arrest and stimulation of myogenesis through the formation of S1P that acts as morphogenic factor via the engagement of S1P(2). ..
  47. Donovan E, Pelanda R, Torres R. S1P3 confers differential S1P-induced migration by autoreactive and non-autoreactive immature B cells and is required for normal B-cell development. Eur J Immunol. 2010;40:688-98 pubmed publisher
    ..These data indicate that S1P3 signaling directs immature B cells to a bone marrow microenvironment important for both tolerance induction and maturation. ..
  48. Chiba K, Matsuyuki H, Maeda Y, Sugahara K. Role of sphingosine 1-phosphate receptor type 1 in lymphocyte egress from secondary lymphoid tissues and thymus. Cell Mol Immunol. 2006;3:11-9 pubmed
    ..Throughout the analysis of the mechanism of action of FTY720, it is clarified that S1P/S1P1 interaction plays an important role for lymphocyte egress from secondary lymphoid tissues and thymus. ..
  49. Walter D, Rochwalsky U, Reinhold J, Seeger F, Aicher A, Urbich C, et al. Sphingosine-1-phosphate stimulates the functional capacity of progenitor cells by activation of the CXCR4-dependent signaling pathway via the S1P3 receptor. Arterioscler Thromb Vasc Biol. 2007;27:275-82 pubmed
    ..S1P agonists might serve as sensitizers of CXCR4-mediated signaling and may be applied in clinical progenitor cell therapy to improve EPC or BMC function in patients with coronary artery disease. ..
  50. Awad A, Ye H, Huang L, Li L, Foss F, Macdonald T, et al. Selective sphingosine 1-phosphate 1 receptor activation reduces ischemia-reperfusion injury in mouse kidney. Am J Physiol Renal Physiol. 2006;290:F1516-24 pubmed
    ..The mechanism of protection is not known but may be related to peripheral lymphocyte depletion or direct effects on kidney cells expressing S1P1 receptor. ..
  51. Keller C, Rivera Gil P, Tölle M, van der Giet M, Chun J, Radeke H, et al. Immunomodulator FTY720 induces myofibroblast differentiation via the lysophospholipid receptor S1P3 and Smad3 signaling. Am J Pathol. 2007;170:281-92 pubmed
    ..Finally, we determined that downstream of S1P3 signaling Smad3 activation is essential for myofibroblast differentiation in response to FTY720. Thus, FTY720 may have adverse fibrotic effects related to its activity on S1P3 signaling. ..
  52. Serrière Lanneau V, Teixeira Clerc F, Li L, Schippers M, de Wries W, Julien B, et al. The sphingosine 1-phosphate receptor S1P2 triggers hepatic wound healing. FASEB J. 2007;21:2005-13 pubmed
    ..These results unravel a novel major role of S1P2 in the wound healing response to acute liver injury by a mechanism involving enhanced proliferation of hMF...
  53. Sanchez T, Skoura A, Wu M, Casserly B, Harrington E, Hla T. Induction of vascular permeability by the sphingosine-1-phosphate receptor-2 (S1P2R) and its downstream effectors ROCK and PTEN. Arterioscler Thromb Vasc Biol. 2007;27:1312-8 pubmed
    ..S1P2R activation in endothelial cells increases vascular permeability. The balance of S1P1 and S1P2 receptors in the endothelium may determine the regulation of vascular permeability by S1P. ..