The Cell Cycle pp 111-119 | Cite as

Sphingolipids Metabolites: A New Class of Second Messengers in the Regulation of Cell Growth

  • Sarah Spiegel
Part of the GWUMC Department of Biochemistry Annual Spring Symposia book series (GWUN)


The interaction of growth factors with specific cell surface receptors triggers multiple intracellular signaling pathways that culminate in DNA synthesis and cell division.1, 2 Growth signaling networks in which glycerophospholipid metabolites, such as diacylglycerol, inositol 1, 4, 5-trisphosphate (InsP3), phosphatidic acid, and arachidonic acid, serve as second messengers have been well characterized.3–5 Much less is known of the second messengers derived from another major class of membrane lipids, the sphingolipids. All sphingolipids, including ceramide, sphingomyelin, cerebrosides, gangliosides, and sulfatides, contain (1) a long-chain sphingoid base as their backbone, of which sphingosine is the most prominent, (2) an amide-linked fatty acid, and (3) a polar head group (hydroxyl for ceramide, phosphorylcholine for sphingomyelin, and carbohydrate residues of varying complexity for glycosphingolipids). These ubiquitous cellular components have long been known to play an important, yet undefined, role in cell growth regulation.6–8


Phosphatidic Acid Sphingoid Base Sphingosine Kinase Specific Cell Surface Receptor Multiple Intracellular Signaling Pathway 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    S.A. Aaronson, Growth factors and cancer, Science 254: 1146 (1991).PubMedCrossRefGoogle Scholar
  2. 2.
    A. Ullrich and J. Schlessinger, Signal transduction by receptors with tyrosine kinase activity, Cell 61: 203 (1990).PubMedCrossRefGoogle Scholar
  3. 3.
    M.J. Berridge, Inositol trisphosphates and calcium signalling, Nature 361: 315 (1993).PubMedCrossRefGoogle Scholar
  4. 4.
    Y. Nishizuka, Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C, Science 258: 607 (1992).PubMedCrossRefGoogle Scholar
  5. 5.
    J.H. Exton, Signaling through phosphatidylcholine breakdown, J. Biol. Chem. 265: 1 (1990).PubMedGoogle Scholar
  6. 6.
    S. Hakomori, Bifunctional role’ of glycosphingolipids. Modulators for transmembrane signaling and mediators for cellular interactions, J. Biol. Chem. 265: 18713 (1990).PubMedGoogle Scholar
  7. 7.
    R.K. Yu, Gangliosides: structure and function, in: “Ganglioside Structure, Function, and Biomedical Potential,” R. Ledgen, R.K. Yu, M.M. Rapport, and K. Suzuki, Eds. Plenum, New York, pp. 39–45 (1984).CrossRefGoogle Scholar
  8. 8.
    A. Olivera and S. Spiegel, Ganglioside GM1 and sphingolipid breakdown products in cellular proliferation and signal transduction pathways, Glycoconjugate J. 9: 109 (1992).CrossRefGoogle Scholar
  9. 9.
    Y.A. Hanrun and R.M. Bell, Lysosphingolipids inhibit protein kinase C: Implcations for the sphingolipidoses, Science 235: 670 (1987).CrossRefGoogle Scholar
  10. 10.
    Y.A. Hanrun and R.M. Bell, Functions of sphingolipids and sphingolipid breakdown products in cellular regulation, Science 243: 500 (1989).CrossRefGoogle Scholar
  11. 11.
    A.H. Merrill, Cell regulation by sphingosine and more complex sphingolipids, J. Bioenerg. Biomembr. 23: 83 (1991).PubMedGoogle Scholar
  12. 12.
    H. Zhang, N.N. Desai, J.M. Murphey and S. Spiegel, Increases in phosphatidic acid levels accompany sphingosine-stimulated proliferation of quiescent Swiss 3T3 cells, J. Biol. Chem. 265: 21309 (1990).PubMedGoogle Scholar
  13. 13.
    H. Zhang, N.E. Buckley, K. Gibson and S. Spiegel, Sphingosine stimulates cellular proliferation via a protein kinase C-independent pathway, J. Biol. Chem. 265: 76 (1990).PubMedGoogle Scholar
  14. 14.
    H. Zhang, N.N. Desai, A. Olivera, T. Seid, G. Brooker and S. Spiegel, Sphingosine-lphosphate, a novel lipid, involved in cellular proliferation, J. Cell Biol. 114: 155 (1991).PubMedCrossRefGoogle Scholar
  15. 15.
    N.N. Desai, H. Zhang, A. Olivera, M.E. Mattie and S. Spiegel, Sphingosine-l-phosphate, a metabolite of sphingosine, increases phosphatidic acid levels by phospholipase D activation, J. Biol. Chem. 267: 23122 (1992).PubMedGoogle Scholar
  16. 16.
    S. Spiegel, A. Olivera and R.O. Carlson, The role of sphingosine in cell growth and transmembrane signaling. in “Advances in Lipid Research: Sphingolipids in Signaling, Part A”, R. M. Bell, Y. A. Hannun and A. H. Merrill. Eds., Academic Press Inc., Orlando. p105 (1993).Google Scholar
  17. 17.
    Z. Kiss and W.B. Anderson, ATP stimulates the hydrolysis of phosphatidylethanolamine in NIH 3T3 cells. Potentiating effects of guanosine triphosphates and sphingosine, J. BM. Chem. 265: 7188 (1990).Google Scholar
  18. 18.
    Y. Lavie and M. Liscovitch, Activation of phospholipase D by sphingoid bases in NG108-15 neural-derived cells, Biochem. Biophys. Res. Commun. 167: 607 (1990).CrossRefGoogle Scholar
  19. 19.
    F. Sakane, K. Yamada and H. Kanoh, Different effects of sphingosine, R59022 and anionic amphiphiles on two diacylglycerol kinase isozymes purified from porcine thymus cytosol, Eur. J. Pediatr. 149: 31 (1989).CrossRefGoogle Scholar
  20. 20.
    Y. Lavie, O. Piterman and M. Liscovitch, Inhibition of phosphatidic acid phosphohydrolase activity by sphingosine: Dual action of sphingosine in diacylglycerol signal termination, FEES Lett. 277: 7 (1990).CrossRefGoogle Scholar
  21. 21.
    T.J. Mullmann, M.I. Siegel, R.W. Egan and M.M. Billah, Sphingosine inhibits phosphatidate phosphohydrolase in human neutrophils by a protein kinase C-independent mechanism, J. Biol. Chem. 266: 2013 (1991).PubMedGoogle Scholar
  22. 22.
    Z. Jamal, A. Martin, A.G. Munoz and D.N. Brindley, Plasma membrane fractions from rat liver contain a phosphatidate phosphohydrolase distinct from that in the endoplasmic reticulum and cytosol, J. Biol. Chem. 266: 2988 (1991).PubMedGoogle Scholar
  23. 23.
    D.K. Perry, W.L. Hand, D.E. Edondson and J.D. Lambeth, Role of phospholipase D-derived diradylglycerol in activation of the human neutrophil respiratory burst oxidase, Inhibition by phosphatidic aid phosphoydrolase inhibitors. J. Immunol. 149: 2749 (1992).PubMedGoogle Scholar
  24. 24.
    J.A. Johnson and R.B. Clark, Multiple non-specific effects of sphingosine on adenylate cyclase and cyclic AMP accumulation in S49 lymphoma cells preclude its use as a specific inhibitor of protein kinase C, J. Biol. Chem 265: 9333 (1990).Google Scholar
  25. 25.
    M. Wahl and G. Carpenter, Regulation of the epidermal growth factor-stimulated formation of inositol phosphates in A-431 cells by calcium and protein kinase C, J. Biol. Chem 263: 7581 (1988).PubMedGoogle Scholar
  26. 26.
    W.H. Moolenaar, W. Krujer, B.C. Tilly, I. Verlaan, A.J. Bierman and S.W. deLaat, Growth factor-like action of phospatidic acid, Nature 323: 171 (1986).PubMedCrossRefGoogle Scholar
  27. 27.
    C. Yu, M. Tsai and D.W. Stacey, Cellular ras activity and phospholipid metabolism, Cell 52: 63 (1988).PubMedCrossRefGoogle Scholar
  28. 28.
    P. Ben-Av and M. Liscovitch. Phospholipase D activation by the mitogens platelet-derived growth factor and 12-0-tetradecanoyl phorbol 13-acetate in NIH-3T3 cells. FEES Lett. 259: 64 66 (1989).Google Scholar
  29. 29.
    M.H. Tsai, C.L. Yu, F.S. Wei and D.W. Stacey, The effect of GTPase activating protein upon ras is inhibited by mitogenically responsive lipids, Science 243: 522 (1989).PubMedCrossRefGoogle Scholar
  30. 30.
    M. Tsai, C. Yu and D.W. Stacey, A cytoplasmic protein Inhibits the GTPase activity of H-Ras in a phospholipid-dependent manner, Science 250: 982 (1990).PubMedCrossRefGoogle Scholar
  31. 31.
    M. Barbacid, Ras genes, Annu. Rev. Biochem, 56: 779 (1987).PubMedCrossRefGoogle Scholar
  32. 32.
    S.L. Pelech and J.S. Sanghera, MAP kinases: charting the regulatory pathways, Science 257: 1355 (1992).PubMedCrossRefGoogle Scholar
  33. 23.
    M. Trahey and F. McCormick, A cytoplasmic protein stimulates normal N-ras p21 GTPase, but does not affect oncogenic mutants, Science 238: 524 (1987).Google Scholar
  34. 34.
    M. Tsai, M. Roudebush, S. Dobrowolski, C. Yu, J. B. Gibbs and D. W. Stacey, Ras GTPaseactivating protein physically associates with mitogenically active phospholipids, Mol. Cell. Biol. 11: 2785 (1991).Google Scholar
  35. 35.
    T.K. Ghosh, J. Sian and D.L. Gill. Intracellular calcium release mediated by sphingosine derivatives generated in cells, Science 248: 1653 (1990).Google Scholar
  36. 36.
    M. E. Mattie, G. Brooker and S. Spiegel Sphingosine-l-phosphate, a putative second messenger, mobilizes calcium from internal stores via an inositol tfisphosphate-independent pathway. J. Biol. Chem., Submitted (1993).Google Scholar
  37. 37.
    E. Wilson, E. Wang, R.E. Mullins, D.J. Uhlinger, D.C. Liotta, J.D. Lambeth and A.H. Merrill, Modulation of free sphingosine levels in human neutrophils by phorbol esters and other factors J. Biol. Chem. 263: 9304 (1988).PubMedGoogle Scholar
  38. 37.
    E. Wilson, E. Wang, R.E. Mullins, D.J. Uhlinger, D.C. Liotta, J.D. Lambeth and A.H. Merrill, Modulation of free sphingosine levels in human neutrophils by phorbol esters and other factors J. Biol. Chem. 263: 9304 (1988).PubMedGoogle Scholar
  39. 39.
    W. Stoffel, B. Hellenbroich and G. Heimann, Properties and specificities of sphingosine kinase from blood platelets, Hoppe-Seyler’s Z. Physiol. Chem. 354: 1311 (1973).PubMedCrossRefGoogle Scholar
  40. 40.
    B.M. Buehier and R.M. Bell, Inhibition of sphingosine kinase in vitro and in platelets. Implications for signal transduction pathways, J. Biol. Chem. 267: 3154 (1992).Google Scholar
  41. 41.
    W. Stoffel and G. Assmann, Metabolism of sphingoid bases, W. Enzymatic degradation of 4tsphingenine 1-phosphate (sphingosine-l-phosphate) to 2t-hexadecan-1-al and ethanolamine phosphate, Hoppe-Seyler’s Z. Physiol. Chem. 351: 1041 (1970).PubMedCrossRefGoogle Scholar
  42. 42.
    P.P. Van Veldhoven and G.P. Mannaerts, Subcellular localization and membrane topology of sphingosine-l-phosphate lyase in rat liver, J. Biol. Chem. 266: 12502 (1991).PubMedGoogle Scholar
  43. 43.
    L.T. Williams, Signal transduction by the platelet-derived growth factor receptor. Science 243: 1564 (1989).PubMedCrossRefGoogle Scholar
  44. 44.
    K.G. Peters, J. Marie, E. Wilson, H.E. Ives, J. Escobedo, M.D. Rosario, D. Mirda and L.T. Williams, Point mutation of an FGF receptor abolishes phosphatidylinositol turnover and Cat+ flux but not mitogenesis, Nature 358: 678 (1992).PubMedCrossRefGoogle Scholar
  45. 45.
    B. Margolis, A. Zilberstein, C. Franks, S. Felder, S. Kremer, A. Ullrich, S.G. Rhee, K. Skorecki and J. Schlessinger, Effect of phospholipase C-γoverexpression on PDGF-induced second messengers and mitogenesis, Science 247: 607 (1990).CrossRefGoogle Scholar
  46. 46.
    K. Fukami and T. Takenawa, Phosphatidic acid that accumulates in platelet-derived growth factor Balb/c 3T3 cells is a potential mitogenic signal, J. Biol. Chem. 267: 10988 (1992).PubMedGoogle Scholar
  47. 47.
    A. Lopez-Rivas, S.A. Mendoza, E. Nanherg, J. Sinnett-Smith and E. Rozengurt, Cat+-mobilizing actions of platelet-derived growth factor differ from those of bombesin and vasopressin in Swiss 3T3 mouse cells, Proc. Natl. Acad. Sci. USA 84: 5768 (1987).CrossRefGoogle Scholar
  48. 48.
    Y. Sadahira, F. Ruan, S. Hakomori and Y. Igarashi, Sphingosine 1-phosphate, a specific endogenous signaling molecule controlling motility and tumor cell invasivenes, Proc. Natl. Acad. Sci. USA 89: 9686 (1992).PubMedCrossRefGoogle Scholar
  49. 49.
    D.D. Louie, A. Kisic and G.J. Schroepfer, Sphingolipid base metabolism. Partial purification and properties of sphingosine kinase of brain, J. Biol. Chem. 251: 4557 (1976).PubMedGoogle Scholar
  50. 50.
    C.B. Hirschberg, A. Kisic and G.J. Schroepfer, Enzymatic formation of dihydrosphingosine 1-phosphate, J. Biol. Chem. 245: 3084 (1970).PubMedGoogle Scholar
  51. 51.
    N.W. Gale, S. Kaplan, E.J. Lowenstein, J. Schlessinger and D. Bar-Sagi, Grb2 mediates the EGF-dependent activation of guanine nucleotide exchange on Ras, Nature 363: 88 (1993).PubMedCrossRefGoogle Scholar
  52. 52.
    S.E. Egan, B.W. Giddings, M.W. Brooks, L. Buday, A.M. Sizeland and R.A. Weinberg, Association of Sos Ras exchange protein with Grb2 is implicated in tyrosine kinase signal transduction and transformation, Nature 363: 45 (1993).PubMedCrossRefGoogle Scholar
  53. 53.
    M. Rozakis-Adcock, R. Fernley, J. Wade, T. Pawson and D. Bowtell, The SH2 and SH3 domains of mammalian Grb2 couple the EGF receptor to the Ras activator mSosl, Nature 363: 83 (1993).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1994

Authors and Affiliations

  • Sarah Spiegel
    • 1
  1. 1.Department of Biochemistry and Molecular BiologyGeorgetown University Medical CenterUSA

Personalised recommendations