Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Sphingosylphosphorylcholine is a ligand for ovarian cancer G-protein-coupled receptor 1

A Retraction to this article was published on 01 March 2006

Abstract

Sphingosylphosphorylcholine (SPC) is a bioactive lipid that acts as an intracellular and extracellular signalling molecule in numerous biological processes. Many of the cellular actions of SPC are believed to be mediated by the activation of unidentified G-protein-coupled receptors. Here we show that SPC is a high-affinity ligand for an orphan receptor, ovarian cancer G-protein-coupled receptor 1 (OGR1). In OGR1-transfected cells, SPC binds to OGR1 with high affinity (Kd = 33.3 nM) and high specificity and transiently increases intracellular calcium. The specific binding of SPC to OGR1 also activates p42/44 mitogen-activated protein kinases (MAP kinases) and inhibits cell proliferation. In addition, SPC causes internalization of OGR1 in a structurally specific manner.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Spiegel, S. & Milstien, S. Sphingolipid metabolites: members of a new class of lipid s messengers. J. Membr. Biol. 146, 225–237 (1995).

    Article  CAS  Google Scholar 

  2. Desai, N. N. & Spiegel, S. Sphingosylphosphorylcholine is a remarkably potent mitogen for a variety of cell lines. Biochem. Biophys. Res. Commun. 181, 361–366 (1991).

    Article  CAS  Google Scholar 

  3. Yamada, T. et al. Growth inhibition of human pancreatic cancer cells by sphingosylphosphorylcholine and influence of culture conditions. Cell Mol. Life Sci. 53, 435–441 (1997).

    Article  CAS  Google Scholar 

  4. Wakita, H. et al. Sphingosylphosphorylcholine stimulates proliferation and upregulates cell surface-associated plasminogen activator activity in cultured human keratinocytes . J. Invest. Dermatol. 110, 253– 258 (1998).

    Article  CAS  Google Scholar 

  5. Xu, Y., Fang, X. J., Casey, G. & Mills, G. B. Lysophospholipids activate ovarian and breast cancer cells. Biochem. J. 309, 933–940 (1995).

    Article  CAS  Google Scholar 

  6. Tokura, Y. et al. Modulation of T-lymphocyte proliferation by exogenous natural ceramides and sphingosylphosphoryl-choline. J. Invest. Dermatol. Symp. Proc. 4, 184–189 (1999).

    Article  CAS  Google Scholar 

  7. Sekiguchi, K., et al. Sphingosylphosphorylcholine induces a hypertrophic growth response through the mitogen-activated protein kinase signalling cascade in rat neonatal cardiac myocytes. Circ. Res. 85, 1000–1008 (1999)

    Article  CAS  Google Scholar 

  8. Bitar, K. N. & Yamada, H. Modulation of smooth muscle contraction by sphingosylphosphorylcholine. Am. J. Physiol. 269 , 370–377 (1995).

    Google Scholar 

  9. Sun, L., et al. A new wound healing agent—sphingosylphosphorylcholine. J. Invest. Dermatol. 106, 232–237 (1996).

    Article  CAS  Google Scholar 

  10. Seufferlein, T. & Rozengurt, E. Sphingosylphosphorylcholine rapidly induces tyrosine phosphorylation of p 125 FAK and paxillin, rearrangement of the actin cytoskeleton and focal contact assembly. Requirement of p 21 rho in the signalling pathway. J. Biol. Chem. 270, 24343–24351 (1995).

    Article  CAS  Google Scholar 

  11. Seufferlein, T. & Rozengurt, E. Sphingosylphosphorylcholine activation of mitogen-activated protein kinase in Swiss 3 T3 cells requires protein kinase C and a pertussis toxin-sensitive G protein. J. Biol. Chem. 270, 24334–24342 (1995).

    Article  CAS  Google Scholar 

  12. Okajima, F. & Kondo, Y. Pertussis toxin inhibits phospholipase C activation and Ca2+ mobilization by sphingosylphosphorylcholine and galactosylsphingosine in HL 60 leukaemia cells. J. Biol. Chem. 270, 26332–26330 (1995).

    Article  CAS  Google Scholar 

  13. Bunemann, M. et al. A novel membrane receptor with high affinity for lysosphingomyelin and sphingosine 1-phosphate in atrial myocytes. EMBO J. 15, 5527–5534 (1996).

    Article  CAS  Google Scholar 

  14. Xu, Y., Casey, G. & Mills, G. B. Effect of lysophospholipids on signalling in the human Jurkat T cell line. J. Cell Physiol. 163, 441–450 (1995).

    Article  CAS  Google Scholar 

  15. Berger, A., Rosenthal, D. & Spiegel, S. Sphingosylphosphocholine, a signalling molecule which accumulates in Niemann-Pick disease type A, stimulates DNA-binding activity of the transcription activator protein AP-1. Proc. Natl Acad. Sci. USA 92, 5885–5889 (1995).

    Article  CAS  Google Scholar 

  16. Imokawa, G. et al. Sphingosylphosphorylcholine is a potent inducer of intercellular adhesion molecule-1 expression in human keratinocytes. J. Invest. Dermatol. 112, 91–96 (1999).

    Article  CAS  Google Scholar 

  17. Spangelo, B. L. & Jarvis, W. D. Lysophosphatidylcholine stimulates interleukin-6 release from rat anterior pituitary cells in vitro . Endocrinology 137, 4419– 4426 (1996).

    Article  CAS  Google Scholar 

  18. Hecht, J. H., Weiner, J. A., Post, S. R. & Chun, J. Ventricular Zone Gene-1 (vzg-1) encodes a lysophosphatidic acid receptor expressed in neurogenic regions of the developing cerebral cortex . J. Cell Biol. 135, 1071– 1083 (1996).

    Article  CAS  Google Scholar 

  19. An, S. et al. Identification of cDNAs encoding two G protein-coupled receptors for lysosphingolipids. FEBS Lett. 417, 279 –282 (1997).

    Article  CAS  Google Scholar 

  20. Lee, M. J. et al. Sphingosine-1-phosphate as a ligand for the G protein-coupled receptor EDG-1. Science 279, 1552– 1555 (1998).

    Article  CAS  Google Scholar 

  21. An, S., Bleu, T., Hallmark, O. G. & Goetzl, E. J. Characterization of a novel subtype of human G protein-coupled receptor for lysophosphatidic acid. J. Biol. Chem. 273, 7906–7910 (1998).

    Article  CAS  Google Scholar 

  22. Graler, M. H., Bernhardt, G. & Lipp, M. EDG 6, a novel G-protein-coupled receptor related to receptors for bioactive lysophospholipids, is specifically expressed in lymphoid tissue. Genomics 53, 164– 169 (1998).

    Article  CAS  Google Scholar 

  23. Ancellin, N. & Hla, T. Differential pharmacological properties and signal transduction of the sphingosine 1-phosphate receptors EDG-1, EDG-3, and EDG-5. J. Biol. Chem. 274, 18997– 19002 (1999).

    Article  CAS  Google Scholar 

  24. Windh, R. T. et al. Differential coupling of the sphingosine 1-phosphate receptors Edg-1, Edg-3, and H 218/Edg-5 to the G(i), G(q), and G(12) families of heterotrimeric G proteins. J. Biol. Chem. 274, 27351– 27358 (1999).

    Article  CAS  Google Scholar 

  25. Okamoto, H. et al. EDG 3 is a functional receptor specific for sphingosine 1-phosphate and sphingosylphosphorylcholine with AGR 16. Biochem. Biophys. Res. Commun. 260, 203–208 (1999).

    Article  CAS  Google Scholar 

  26. Okamoto, H. et al. EDG 1 is a functional sphingosine-1-phosphate receptor that is linked via a Gi/o to multiple signalling pathways, including phospholipase C activation, Ca2+ mobilization, Ras-mitogen-activated protein kinase activation, and adenylate cyclase inhibition. J. Biol. Chem. 273, 27104–27110 (1998).

    Article  CAS  Google Scholar 

  27. Sato, K. et al. Activation of phospholipase C-Ca2+ system by sphingosine 1-phosphate in CHO cells transfected with Edg-3, a putative lipid receptor . FEBS Lett. 443, 25–30 (1999).

    Article  CAS  Google Scholar 

  28. van Brocklyn, J. R. et al. Sphingosine 1-phosphate-induced cell rounding and neurite retraction are mediated by the G protein-coupled receptor H 218. J. Biol. Chem. 274, 4626–4632 (1999).

    Article  CAS  Google Scholar 

  29. Liu, C. H. et al. Ligand-induced trafficking of the sphingosine-1-phosphate receptor EDG-1. Mol. Biol. Cell 10, 1179 –1190 (1999).

    Article  CAS  Google Scholar 

  30. Meyer zu Heringdorf, D. et al. Discrimination between plasma membrane and intracellular target sites of sphingosylphosphorylcholine. Eur. J. Pharmacol. 354, 113–122 (1998).

    Article  CAS  Google Scholar 

  31. van Koppen, C. J. et al. A distinct G(i) protein-coupled receptor for sphingosylphosphorylcholine in human leukaemia HL-60 cells and human neutrophils. Mol. Pharmacol. 49, 956–961 (1996).

    CAS  PubMed  Google Scholar 

  32. Xu, Y. & Casey, G. Identification of human OGR 1, a novel G protein-coupled receptor that maps to chromosome 14. Genomics 35, 397–402 (1996).

    Article  CAS  Google Scholar 

  33. Yatomi, Y. et al. Phosphorylation of the inhibitory guanine-nucleotide-binding protein as a possible mechanism of inhibition by protein kinase C of agonist-induced Ca2+ mobilization in human platelet. Eur. J. Biochem. 205, 1003–1009 (1992).

    Article  CAS  Google Scholar 

  34. Pang, L., Sawada, T., Decker, S. J. & Saltiel, A. R. Inhibition of MAP kinase kinase blocks the differentiation of PC-12 cells induced by nerve growth factor. J. Biol. Chem. 270, 13585–13588 (1995).

    Article  CAS  Google Scholar 

  35. Iismaa, T. P. & Shine, J. G protein-coupled receptors. Curr. Opin. Cell. Biol. 4, 195–202 (1992).

    Article  CAS  Google Scholar 

  36. Hawes, B. E., van Biesen, T., Koch, W. J., Luttrell, L. M. & Lefkowitz, R. J. Distinct pathways of Gi- and Gq-mediated mitogen-activated protein kinase activation. J. Biol. Chem. 270, 17148–17153 (1995).

    Article  CAS  Google Scholar 

  37. Bogoyevitch, M. A., Clerk, A. & Sugden, P. H. Activation of the mitogen-activated protein kinase cascade by pertussis toxin-sensitive and -insensitive pathways in cultured ventricular cardiomyocytes. Biochem. J. 309, 437– 443 (1995).

    Article  CAS  Google Scholar 

  38. Munsch, N., Gavaret, J. M. & Pierre, M. Ca2+ dependent purinergic regulation of p 42 and p 44 MAP kinases in astroglial cultured cells. Biomed. Pharmacother. 52, 180–186 (1998).

    Article  CAS  Google Scholar 

  39. Cobb, M. MAP kinase pathways. Prog. Biophys. Mol. Biol. 71, 479–500 (1999).

    Article  CAS  Google Scholar 

  40. Casillas, A. M., Amaral, K., Chegini-Farahani, S. & Nel, A. E. Okadaic acid activates p 42 mitogen-activated protein kinase (MAP kinase; ERK-2) in B-lymphocytes but inhibits rather than augments cellular proliferation: contrast with phorbol 12-myristate 13-acetate. Biochem. J. 290, 545–550 (1993).

    Article  CAS  Google Scholar 

  41. Zhu, L. et al. Role of mitogen-activated protein kinases in activation-induced apoptosis of T cells. Immunology 97, 26– 35 (1999).

    Article  CAS  Google Scholar 

  42. van den Brink, M. R., Kapeller, R., Pratt, J. C., Chang, J. H., & Burakoff, S. J. The extracellular signal-regulated kinase pathway is required for activation-induced cell death of T cells. J. Biol. Chem. 274, 11178–11185 (1999)

    Article  CAS  Google Scholar 

  43. Strasberg, P. M. & Callahan, J. W. Lysosphingolipids and mitochondrial function. II. Deleterious effects of sphingosylphosphorylcholine . Biochem. Cell. Biol. 66, 1322– 1332 (1988).

    Article  CAS  Google Scholar 

  44. Rodriguez-Lafrasse, C. & Vanier, M. T. Sphingosylphosphorylcholine in Niemann-Pick disease brain: accumulation in type A but not in type B. Neurochem. Res. 24, 199–205 (1999).

    Article  CAS  Google Scholar 

  45. Murata, Y. et al. Abnormal expression of sphingomyelin acylase in atopic dermatitis: an etiologic factor for ceramide deficiency? J. Invest. Dermatol. 106, 1242–1249 (1996).

    Article  CAS  Google Scholar 

  46. Sugiyama, E., Uemura, K., Hara, A. & Taketomi, T. Metabolism and neurite promoting effect of xogenous sphingosylphosphocholine in cultured murine neuroblastoma cells. J. Biochem. (Tokyo) 113 , 467–472 (1993)

    Article  CAS  Google Scholar 

  47. Xu, Y. & Demron, D. Calcium mobilisation in ovarian cancer by lysophospholipids. Meth. Mol. Med.: Ovarian Cancer (in the press).

  48. Hamada, H. et al. Phenylephrine-induced Ca2+ oscillations in canine pulmonary artery smooth muscle cells. Circ. Res. 81, 812–823 (1997).

    Article  CAS  Google Scholar 

  49. Grynkiewicz, G., Poenie, M. & Tsien, R. Y. A new generation of Ca2+ indicators with greatly improved fluorescence properties. J. Biol. Chem. 260, 3440–3450 (1985).

    CAS  Google Scholar 

  50. Keen, M. Protocols in Receptor Signalling Transduction (ed. Challiss, R. A. J.) 1-24 (Humana Press, Totowa, NJ 1997).

Download references

Acknowledgements

We thank Bryan Willams and Dianne Perez for their critical reading of this manuscript. This work is supported in part by American Cancer Society grant RPG-99-062-01-CNE, an American Cancer Society OHIO Division grant, US Army grant DAMD 17-99-1-9563 to Y.X. and by Betsey De Windt endowment funds for the Department of Cancer Biology.

Correspondence and requests for materials should be addressed to Y.X.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yan Xu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Xu, Y., Zhu, K., Hong, G. et al. Sphingosylphosphorylcholine is a ligand for ovarian cancer G-protein-coupled receptor 1. Nat Cell Biol 2, 261–267 (2000). https://doi.org/10.1038/35010529

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/35010529

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing