Molecular and Chemical Neuropathology

, Volume 21, Issue 2–3, pp 287–297 | Cite as

Signal transduction through the sphingomyelin pathway

  • Richard Kolesnick
Article

Abstract

The sphingomyelin pathway is a new signal transduction system initiated by hydrolysis of palsma membrane sphingomyelin to ceramide by the actin of a neutral sphingomyelinase. Ceramide serine/threonine protein kinase termed ceramide-activated protein kinase. This kinase belongs to a family of proline-directed protein kinases that recognize substrates containing the minimal motif, X-Thr/Ser-Pro-X, where the phosphoacceptor site is followed on the carboxyl terminus by a proline residue and X may be any amino acid. Three lines of evidence, rapid kinetics of activation of the sphingomyelin pathway by tumor necrosis factor (TNF)α, the ability of cell-permeable ceramide analogs to bypass receptor activation and mimic the effect of TNFα, and reconstitution of this cascade in a cell-free system, support the concept that the sphingomyelin pathway serves to signal TNFα-induced monocytic differentiation. Hence, the sphingomyelin pathway may represent a signaling system analogous to more well-defined systems such as the cyclic adenosine monophosphate and phosphoinositide pathways.

Index Entries

Signal transduction sphingomyelin phorbol esters diacylglycerols ceramide kinase phospholipase C sphingosine epidermal growth factor receptor protein kinases 

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References

  1. Aitken A., Holmes C. F. B., Campbell D. G., Resink T. J., Cohen P., Leung C. T. W., and Williams D. (1984) Amino acid sequence on protein phosphatase inhibitor-2 phosphorylated by glycogen synthetase kinase-3.Biochim. Biophys. Acta 790, 288–291.PubMedGoogle Scholar
  2. Alvarez E., Northwood I. C., Gonzalez F. A., Latour D. A., Seth A., Abate C., Curran T., and Davis R. J. (1991) Pro-Leu-Ser/Thr-Pro is a consensus primary sequence for substrate protein phosphorylation: characterization of the phosphorylation of c-myc and c-jun proteins by an epidermal growth factor receptor threonine 669 protein kinase.J. Biol. Chem. 266, 15277–15285.PubMedGoogle Scholar
  3. Bajjalieh S. M., Martin T. F. J., and Floor E. (1989) Synaptic vesicle ceramide kinase: a calcium-stimulated lipid kinase that co-purifies with brain synaptic vesicles.J. Biol. Chem. 264, 14354–14360.PubMedGoogle Scholar
  4. Berenholz Y. and Gatt S. (1982) Sphingomyelin: metabolism, chemical synthesis, chemical and physical properties. inPhospholipids (Hawthorne J. N. and Ansell G. B., eds.), pp. 129–177, Elsevier, NY.Google Scholar
  5. Berridge M. J. (1989) Inositol trisphosphate, calcium, lithium and cell signaling.J. Am. Med. Assoc. 262, 1834–1841.CrossRefGoogle Scholar
  6. Boulton T. G., Nye S. H., Robbins D. J., Ip N. Y., Radziejewska E., Morgenbesser S. D., DePinho R. A., Panayotatos N., Cobb M. H., and Yancopoulos G. D. (1990) ERKs: a family of protein serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF.Cell 65, 663–675.CrossRefGoogle Scholar
  7. Dobrowsky R. T. and Hannun Y. A. (1992) Ceramide 1-phosphate, a novel phospholipid in human leukemia (HL-60) cells: Synthesis via ceramide from sphingomyelin.J. Biol. Chem. 265, 14917–14921.Google Scholar
  8. Dressler K. A., Mathias S., and Kolesnick R. N. (1992) Tumor necrosis factor-α activates the sphingomyelin signal transduction pathway in a cell-free system.Science 255, 1715–1718.PubMedCrossRefGoogle Scholar
  9. Faucher M., Girones N., Hannun Y. U., Bell R. M., and David R. J. (1988) Regulation of the epidermal growth factor receptor phosphorylation state by sphingosine in A431 human epidermoid carcinoma cells.J. Biol. Chem. 263, 5319–5327.PubMedGoogle Scholar
  10. Ghosh T. K., Bian J., and Gill D. L. (1990) Intracellular calcium release mediated by sphingosine derivatives generated in cells.Science 48, 1653–1656.CrossRefGoogle Scholar
  11. Goldkorn T., Dressler K. A., Muindi J., Radin N. S., Mendelsohn J., Menaldino D., Liotta D., and Kolesnick R. N. (1991) Ceramide stimulates epidermal growth factor receptor phosphorylation in A431 human epidermoid carcinoma cells: evidence that ceramide may mediate sphingosine action.J. Biol. Chem. 266, 16092–16097.PubMedGoogle Scholar
  12. Hall F. L., Braun R. K., Mihara K., Fung Y.-K. T., Berndt N., Carbonaro-Hall D. A., and Vulliet P. R. (1991) Characterization of the cytoplasmic proline-directed protein kinase in proliferative cells and tissues as a heterodimer comprised of p34cdc2 and p58cyclinA.J. Biol. Chem. 266, 17430–17440.PubMedGoogle Scholar
  13. Hannun Y. A., Loomis C., Merrill A. H., Jr., and Bell R. M. (1986) Sphingosine inhibition of protein kinase C activity and of phorbol ester binding in vitro and in human platelets.J. Biol. Chem. 261, 12604–12609.PubMedGoogle Scholar
  14. Heiserman G. J. and Gill G. N. (1988) Epidermal growth factor receptor threonine and serine residues phosphorylated in vivo.J. Biol. Chem. 263, 13152–13158.Google Scholar
  15. Kim M-Y., Linardic C., Obeid L., and Hannun Y. (1991) Identification of sphingomyelin turnover as an effector mechanism for the action of tumor necrosis factor α and γ-interferon: specific role in cell differentiation.J. Biol. Chem. 266, 484–489.PubMedGoogle Scholar
  16. Kolesnick R. N. (1987) 1,2-Diacylglycerols but not phorbol esters stimulate sphingomyelin hydrolysis in GH3 pituitary cells.J. Biol. Chem. 262, 16759–16762.PubMedGoogle Scholar
  17. Kolesnick R. N. (1991) Sphingomyelin and derivatives as cellular signals.Prog. Lipid Res. 1, 1–38.CrossRefGoogle Scholar
  18. Kolesnick R. N. (1992) Ceramide: a novel second messenger.Trends Cell Biol. 2, 232–236.PubMedCrossRefGoogle Scholar
  19. Kolesnick R. N. and Clegg S. (1988) 1,2-Diacylglycerols, but not phorbol esters, activate a potential inhibitory pathway for protein kinase C in GH3 pituitary cells: Evidence for involvement of a sphingomyelinase.J. Biol. Chem. 263, 6534–6537.PubMedGoogle Scholar
  20. Kolesnick R. N. and Hemer M. (1990) Characterization of a ceramide kinase activity from human leukemia (HL-60) cells: separation from diacylglycerol kinase.J. Biol. Chem. 265, 18803–18808.PubMedGoogle Scholar
  21. Lipsky N. G. and Pagano R. E. (1985) Intracellular translocation of fluorescent sphingolipids in cultured fibroblasts: endogenously synthesized sphingomyelin and glucocerebroside analogues pass through the Golgi apparatus en route to the plasma membrane.J. Cell Biol. 100, 27–34.PubMedCrossRefGoogle Scholar
  22. Mathias S., Dressler K. A., and Kolesnick R. N. (1991) Characterization of a ceramide-activated protein kinase: stimulation by tumor necrosis factor α.Proc. Natl. Acad. Sci. USA 88, 10009–10013.PubMedCrossRefGoogle Scholar
  23. Merrill A. H., Jr., Nimkar S., Menaldino D., Hannun Y. A., Loomis C., Bell R. M., Tyagi S. R., Lambeth D., Stevens V. L., Hunter R., and Liotta D. C. (1989) Structural requirements for long-chain base inhibition of protein kinase C in vitro and for the cellular effects of these compounds.Biochemistry 28, 3138–3145.PubMedCrossRefGoogle Scholar
  24. Merrill A. H., Jr., Sereni A. M., Stevens V. L., Hannun Y. A., and Bell, R. M. (1986) Inhibition of phorbol ester-dependent differentiation of human promyelocytic leukemic (HL-60) cells by sphinganine and other long-chain bases.J. Biol. Chem. 261, 12610–12615.PubMedGoogle Scholar
  25. Merrill A. H., Jr. and Stevens V. L. (1989) Modulation of protein kinase C and diverse cell functions by sphingosine—a pharmacologically interesting compound linking sphingolipids and signal transduction.Biochim. Biophys. Acta 1010, 131–139.PubMedCrossRefGoogle Scholar
  26. Northwood I. C., Gonzalez F. A., Wartmann M., Raden D. L., and Davis R. J. (1991) Isolation and characterization of two growth factor-stimulated protein kinases that phosphorylate the epidermal growth factor receptor at threonine 669.J. Biol. Chem. 266, 15266–15276.PubMedGoogle Scholar
  27. Okazaki T., Bell R. M., and Hannun Y. A. (1989) Sphingomyelin turnover induced by vitamin D3 in HL-60 cells: role in cell differentiation.J. Biol. Chem. 264, 19076–19080.PubMedGoogle Scholar
  28. Okazaki T., Bielawaska A., Bell R. M., and Hannun Y. A. (1990) Role of ceramide as a lipid mediator of 1α, 25-dihydroxyvitamin D3-induced H1-60 cell differentiation.J. Biol. Chem. 265, 15823–15831.PubMedGoogle Scholar
  29. Pushkavera M. Y., Khan W. A., Alessenko A. V., Sahyoun N., and Hannun Y. A. (1992) Sphingosine activation of protein kinases in jurkat T cells: in vitro phosphorylation of endogenous protein substrates and specificity of action.J. Biol. Chem. 267, 15426–15251.Google Scholar
  30. Schneider E. G. and Kennedy E. P. (1973) Phosphorylation of ceramide by diglyceride kinase preparations fromEscherichia coli.J. Biol. Chem. 248, 3739–3741.PubMedGoogle Scholar
  31. Seger R., Ahn N. G., Boulton T. G., Yancopoulos G. D., Panayotatos N., Radziejewska E., Ericsson L., Bratlein R. L., Cobb M. H., and Krebs E. G. (1991) Microtubule-associated protein 2 kinases, ERK1 and ERK2, undergo autophosphorylation on both tyrosine and threonine residues: implications for their mechanism of action.Proc. Natl. Acad. Sci. USA 88, 6142–6146.PubMedCrossRefGoogle Scholar
  32. Slife C. W., Wang E., Hunter R., Wang S., Burgess C., Liotta D. C., and Merrill A. H., Jr. (1989) Free sphingosine formation from endogenous substrates by a liver plasma membrane system with a divalent cation dependence and a neutral pH optimum.J. Biol. Chem. 264, 10371–10377.PubMedGoogle Scholar
  33. Vilcek J. and Lee T. H. (1991) Tumor necrosis factor: new insights into the molecular mechanisms of its multiple actions.J. Biol. Chem. 266, 7313–7316.PubMedGoogle Scholar
  34. Wilson E., Olcott M. C., Bell R. M., Merrill A. H., Jr., and Lambeth J. D. (1986) Inhibition of the oxidative burst in human neutrophils by sphingoid longchain bases.J. Biol. Chem. 261, 12616–12623.PubMedGoogle Scholar
  35. Younes A., Kahn D. W., Besterman J. M., Bittman R., Byun H.-S., and Kolesnick R. N. (1992) Ceramide is a competitive inhibitor of diacylglycerol kinase in vitro and in intact human leukemia (HL-60) cells.J. Biol. Chem. 267, 842–847.PubMedGoogle Scholar
  36. Zhang H., Desai N. N., Olivera A., Seki T., Brooker G., and Spiegel S. (1991) Sphingosine 1-phosphate, a novel lipid, involved in cellular proliferation.J. Cell Biol. 114, 155–167.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 1994

Authors and Affiliations

  • Richard Kolesnick
    • 1
  1. 1.The Laboratory of Signal TransductionMemorial Sloan-Kettering Cancer CenterNew York

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