Role of Gangliosides in Transmembrane Signaling and Cell Recognition

  • Sen-itiroh Hakomori


Sialic acid-containing glycosphingolipids (GSLs), collectively called “gan-gliosides,” were discovered in the mid-1930s by Ernst Klenk (Cologne, Germany) (Klenk, 1942) and Gunnar Blix (Uppsala, Sweden), (Blix, 1936) (see Chapter 1). Since then, steadily increasing numbers of scientists have worked on isolation and characterization of gangliosides, determination of different molecular species, and their distribution in animal cells and tissues. Development of new separation technology (e.g., thin-layer and gas chromatography) and instrumental analysis (e.g., mass spectrometry, NMR spectroscopy), together with introduction of the monoclonal antibody (mAb) approach in immunochemistry, allowed identification of many previously unknown ganglioside species (especially those having complex lacto- or globo-series backbone structure) in the 1970s and 1980s.


Epidermal Growth Factor Receptor A431 Cell Integrin Receptor PDGF Receptor Transmembrane Signaling 
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. Berg, E. L., Robinson, M. K., Mansson, O., Butcher, E. C., and Magnani, J. L., 1991, A carbohydrate domain common to both sialyl Lea and sialyl Lea is recognized by the endothelial cell leukocyte adhesion molecule ELAM-1, J. Biol. Chem. 266: 14869–14872.PubMedGoogle Scholar
  2. Blix, G., 1936, Über die Kohlenhydratgruppen des Submaxillarismucins, Hoppe-Seyler’s Z. Physiol. Chem. 240: 43–54.CrossRefGoogle Scholar
  3. Bradshaw, R. A., and Prentis, S., 1987, Oncogenes and Growth Factors, Elsevier, Amsterdam. Bremer, E. G., and Hakomori, S., 1982, GM3 ganglioside induces hamster fibroblast growth inhibition in chemically-defined medium: Ganglioside may regulate growth factor receptor function, Biochem. Biophys. Res. Commun. 106: 711–718.Google Scholar
  4. Bremer, E. G., and Hakomori, S., 1984, Gangliosides as receptor modulators, Adv. Exp. Med. Biol. 174: 381–394.PubMedCrossRefGoogle Scholar
  5. Bremer, E. G., Hakomori, S., Bowen-Pope, D. F., Raines, E., and Ross, R., 1984, Gangliosidemediated modulation of cell growth, growth factor binding, and receptor phosphorylation, J. Biol. Chem. 259: 6818–6825.PubMedGoogle Scholar
  6. Bremer, E. G., Schlessinger, J., and Hakomori, S., 1986, Ganglioside-mediated modulation of cell growth: Specific effects of GM3 on tyrosine phosphorylation of the epidermal growth factor receptor, J. Biol. Chem. 261: 2434–2440.PubMedGoogle Scholar
  7. Brugge, J. S., 1993, New intracellular targets for therapeutic drug design, Science 260: 918–919.PubMedCrossRefGoogle Scholar
  8. Cheresh, D. A., Pytela, R., Pierschbacher, M. D., Klier, F. G., Ruoslahti, E., and Reisfeld, R. A., 1987, An Arg-Gly-Asp-directed receptor on the surface of human melanoma cells exists in a divalent cation-dependent functional complex with the disialoganglioside GD2, J. Cell Biol. 105: 1163–1173.PubMedCrossRefGoogle Scholar
  9. Cohen, S., Carpenter, G., and King, L., 1980, Epidermal growth factor receptor—protein kinase interactions: Co-purification of receptor and epidermal growth factor-enhanced phosphorylation activity, J. Biol. Chem. 255: 4834–4842.PubMedGoogle Scholar
  10. Czech, M. P., 1985, The nature and regulation of the insulin receptor: Structure and function, Annu. Rev. Physiol. 47: 357–381.PubMedCrossRefGoogle Scholar
  11. Hakomori, S., 1984, Glycosphingolipids as differentiation-dependent, tumor-associated markers and as regulators of cell proliferation, Trends Biochem. Sci. 9: 453–455.CrossRefGoogle Scholar
  12. Hakomori, S., 1987, Ganglioside-mediated modulation of growth factor receptor function and cell adhesion, in: Gangliosides and Modulation of Neuronal Functions, ( H. Rahmann, eds.), Springer-Verlag, Berlin, pp. 465–479.CrossRefGoogle Scholar
  13. Hakomori, S., 1990, Bifunctional role of glycosphingolipids: Modulators for transmembrane signaling and mediators for cellular interactions, J. Biol. Chem. 265: 18713–18716.PubMedGoogle Scholar
  14. Hakomori, S., 1993, Structure and function of sphingoglycolipids in transmembrane signalling and cell—cell interactions, Biochem. Soc. Trans. 21: 583–595.PubMedGoogle Scholar
  15. Hakomori, S., and Igarashi, Y., 1993, Gangliosides and glycosphingolipids as modulators of cell growth, adhesion, and transmembrane signaling, Adv. Lipid Res. 25: 147–162.PubMedGoogle Scholar
  16. Hakomori, S., Igarashi, Y., Nojiri, H., Bremer, E. G., Hanai, N., and Nores, G. A., 1990, Bioactive gangliosides modulating transmembrane signaling, in: Trophic Factors and the Nervous System, ( L. A. Horrocks, N. H. Neff, A. J. Yates, and M. Hadjiconstantinou, eds.), Raven Press, New York, pp. 135–158.Google Scholar
  17. Hanai, N., Dohi, T., Nores, G. A., and Hakomori, S., 1988a, A novel ganglioside, de-N-acetylGM3 (II3NeuNH2LacCer), acting as a strong promoter for epidermal growth factor receptor kinase and as a stimulator for cell growth, J. Biol. Chem. 263: 6296–6301.PubMedGoogle Scholar
  18. Hanai, N., Nores, G. A., MacLeod, C., Torres-Mendez, C.-R., and Hakomori, S., 1988b, Gangliosidemediated modulation of cell growth: Specific effects of GM3 and lyso-GM3 in tyrosine phosphorylation of the epidermal growth factor receptor, J. Biol. Chem. 263: 10915–10921.PubMedGoogle Scholar
  19. Handa, K., Nudelman, E. D., Stroud, M. R., Shiozawa, T., and Hakomori, S., 1991, Selectin GMP-140 (CD62; PADGEM) binds to sialosyl-Lea and sialosyl-Lex, and sulfated glycans modulate this binding, Biochem. Biophys. Res. Commun. 181: 1223–1230.PubMedCrossRefGoogle Scholar
  20. Heldin, C.-H., Ek, B., and Ronnstrand, L., 1983, Characterization of the receptor for platelet-derived growth factor on human fibroblasts: Demonstration of an intimate relationship with a 185,000-dalton substrate for the plate-derived growth factor-stimulated kinase, J. Biol. Chem. 258: 10054–10061.PubMedGoogle Scholar
  21. Igarashi, Y., Nojiri, H., Hanai, N., and Hakomori, S., 1989, Gangliosides that modulate membrane protein function, Methods Enzymol. 179: 521–541.PubMedCrossRefGoogle Scholar
  22. Igarashi, Y., Kitamura, K., Zhou, Q., and Hakomori, S., 1990, A role of lyso-phosphatidylcholine in GM3-dependent inhibition of epidermal growth factor receptor autophosphorylation in A431 plasma membranes, Biochem. Biophys. Res. Commun. 172: 77–84.PubMedCrossRefGoogle Scholar
  23. Jacobs, S., Kull, F. C., Jr., Earp, H. S., Svoboda, M. E., Van Wyk, J. J., and Cuatrecasas, P., 1983, Somatomedin-C stimulates the phosphorylation of the beta-subunit of its own receptor, J. Biol. Chem. 258: 9581–9584.PubMedGoogle Scholar
  24. Kasuga, M., Hedo, J. A., Yamada, K. M., and Kahn, C. R., 1982a, The structure of insulin receptor and its subunits: Evidence for multiple non-reduced forms and a 210,000 possible proreceptor, J. Biol. Chem. 257: 10392–10399.PubMedGoogle Scholar
  25. Kasuga, M., Karlsson, F. A., and Kahn, C. R., 1982b, Insulin stimulates the phosphorylation of the 95,000-dalton subunit of its own receptor, Science 215: 185–187.PubMedCrossRefGoogle Scholar
  26. Kasuga, M., Zick, Y., Blithe, D. L., Crettaz, M., and Kahn, C. R., 1982e, Insulin stimulates tyrosine phosphorylation of the insulin receptor in a cell-free system, Nature 298: 667–669.PubMedCrossRefGoogle Scholar
  27. Kleinman, H. K., Martin, G. R., and Fishman, P. H., 1979, Ganglioside inhibition of fibronectinmediated cell adhesion to collagen, Proc. Natl. Acad. Sci. USA 76: 3367–3371.PubMedCrossRefGoogle Scholar
  28. Klenk, E., 1942, Über die Ganglioside, eine neue Gruppe von zuckerhaltigen Gehirnlipoiden, Hoppe-Seyler’s Z. Physiol. Chem. 273: 76–86.CrossRefGoogle Scholar
  29. Kojima, N., and Hakomori, S., 1989, Specific interaction between gangliotriaosylceramide (Gg3) and sialosyllactosylceramide (GM3) as a basis for specific cellular recognition between lymphoma and melanoma cells, J. Biol. Chem. 264: 20159–20162.PubMedGoogle Scholar
  30. Kojima, N., and Hakomori, S., 1991, Cell adhesion, spreading, and motility of G3-expressing cells based on glycolipid—glycolipid interaction, J. Biol. Chem. 266: 17552–17558.PubMedGoogle Scholar
  31. Kojima, N., Handa, K., Newman, W., and Hakomori, S., 1992a, Multi-recognition capability of E-selectin in a dynamic flow system, as evidenced by differential effects of sialidases and anti-carbohydrate antibodies on selectin-mediated cell adhesion at low vs. high wall shear stress: A preliminary note, Biochem. Biophys. Res. Commun. 189: 1686–1694.PubMedCrossRefGoogle Scholar
  32. Kojima, N., Handa, K., Newman, W., and Hakomori, S., 1992b, Inhibition of selectin-dependent tumor cell adhesion to endothelial cells and platelets by blocking O-glycosylation of these cells, Biochem. Biophys. Res. Commun. 182: 1288–1295.PubMedCrossRefGoogle Scholar
  33. Kojima, N., Shiota, M., Sadahira, Y., Handa, K., and Hakomori, S., 1992c, Cell adhesion in a dynamic flow system as compared to static system: Glycosphingolipid—glycosphingolipid interaction in the dynamic system predominates over lectin-or integrin-based mechanisms in adhesion of B16 melanoma cells to non-activated endothelial cells, J. Biol. Chem. 267: 17264–17270.PubMedGoogle Scholar
  34. Lawrence, M. B., and Springer, T. A., 1991, Leukocytes roll on a selectin at physiologic flow rates: Distinction from and prerequisite for adhesion through integrins, Cell 65: 859–873.PubMedCrossRefGoogle Scholar
  35. Lawrence, M. B., Smith, C. W., Eskin, S. G., and McIntire, L. V., 1990, Effect of venous shear stress on CD18-mediated neutrophil adhesion to cultured endothelium, Blood 75: 227–237.PubMedGoogle Scholar
  36. Lingwood, C., and Hakomori, S., 1977, Selective inhibition of cell growth and associated changes in glycolipid metabolism induced by monovalent antibodies to glycolipids, Exp. Cell Res. 108: 385–391.PubMedCrossRefGoogle Scholar
  37. Lowe, J. B., Stoolman, L. M., Nair, R. P., Larsen, R. D., Berhend, T. L., and Marks, R. M., 1990, ELAM-1-dependent cell adhesion to vascular endothelium determined by a transfected human fucosyltransferase cDNA, Cell 63: 475–484.PubMedCrossRefGoogle Scholar
  38. Mulligan, M. S., Lowe, J. B., Larsen, R. D., Paulson, J. C., Zheng, Z.-L., DeFrees, S., Maemura, K., Fukuda, M., and Ward, P. A., 1993a, Protective effects of sialylated oligosaccharides in immune complex-induced acute lung injury, J. Exp. Med. 178: 623–631.PubMedCrossRefGoogle Scholar
  39. Mulligan, M. S., Paulson, J. C., DeFrees, S., Zheng, Z.-L., Lowe, J. B., and Ward, P. A., 1993b, Protective effects of oligosaccharides in P-selectin-dependent lung injury, Nature 364: 149–151.PubMedCrossRefGoogle Scholar
  40. Nojiri, H., Stroud, M. R., and Hakomori, S., 1991, A specific type of ganglioside as a modulator of insulin-dependent cell growth and insulin receptor tyrosine kinase activity: Possible association of ganglioside-induced inhibition of insulin receptor function and monocytic differentiation induction in HL60 cells, J. Biol. Chem. 266: 4531–4537.PubMedGoogle Scholar
  41. Okada, Y., Mugnai, G., Bremer, E. G., and Hakomori, S., 1984, Glycosphingolipids in detergent-insoluble substrate attachment matrix (DISAM) prepared from substrate attachment material (SAM): Their possible role in regulating cell adhesion, Exp. Cell Res. 155: 448–456.PubMedCrossRefGoogle Scholar
  42. Paulson, J. C., 1992, Selectin/carbohydrate-mediated adhesion of leukocytes, in: Adhesion: Its Role in Inflammatory Disease, ( J. M. Harlan and D. Y. Liu, eds.), Freeman, San Francisco, pp. 1942.Google Scholar
  43. Phillips, M. L., Nudelman, E. D., Gaeta, F.C.A., Perez, M., Singhal, A. K., Hakomori, S., and Paulson, J. C., 1990, ELAM-1 mediates cell adhesion by recognition of a carbohydrate ligand, sialyl-Le“, Science 250: 1130–1132.PubMedCrossRefGoogle Scholar
  44. Polley, M. J., Phillips, M. L., Wayner, E. A., Nudelman, E. D., Singhal, A. K., Hakomori, S., and Paulson, J. C., 1991, CD62 and endothelial cell—leukocyte adhesion molecule I (ELAM-1) recognize the same carbohydrate ligand, sialyl-Lewis x, Proc. Natl. Acad. Sci. USA 88: 6224–6228.PubMedCrossRefGoogle Scholar
  45. Rauvala, H., Carter, W. G., and Hakomori, S., 1981, Studies on cell adhesion and recognition: I. Extent and specificity of cell adhesion triggered by carbohydrate-reactive proteins (glycosidases and lectins) and by fibronectin, J. Cell Biol. 88: 127–137.PubMedCrossRefGoogle Scholar
  46. Schlessinger, J., 1988, Signal transduction by allosteric receptor oligomerization, Trends Biochem. Sci. 13: 443–447.PubMedCrossRefGoogle Scholar
  47. Song, W., Vacca, M. F., Welti, R., and Rintoul, D. A., 1991, Effects of gangliosides GM3 and de-Nacetyl GM3 on epidermal growth factor receptor kinase activity and cell growth, J. Biol. Chem. 266: 10174–10181.PubMedGoogle Scholar
  48. Takada, A., Ohmori, K., Takahashi, N., Tsuyuoka, K., Yago, A., Zenita, K., Hasegawa, A., and Kannagi, R., 1991, Adhesion of human cancer cells to vascular endothelium mediated by a carbohydrate antigen, sialyl Lewis A, Biochem. Biophys. Res. Commun. 179: 713–719.PubMedCrossRefGoogle Scholar
  49. Ullrich, A., and Schlessinger, J., 1990, Signal transduction by receptors with tyrosine kinase activity, Cell 61: 203–212.PubMedCrossRefGoogle Scholar
  50. Ushiro, H., and Cohen, S., 1980, Identification of phosphotyrosine as a product of epidermal growth factor-activated protein kinase in A43I cell membranes, J. Biol. Chem. 255: 8363–8365.PubMedGoogle Scholar
  51. Weis, F.M.B., and Davis, R. J., 1990, Regulation of epidermal growth factor receptor signal transduction: Role of gangliosides, J. Biol. Chem. 265: 12059–12066.PubMedGoogle Scholar
  52. Yates, A. J., VanBrocklyn, J., Saqr, H. E., Guan, Z., Stokes, B. T., and O’Dorisio, M. S., 1993, Mechanisms through which gangliosides inhibit PDGF-stimulated mitogenesis in intact Swiss 3T3 cells: Receptor tyrosine phosphorylation, intracellular calcium, and receptor binding, Exp. Cell Res. 204: 38–45.PubMedCrossRefGoogle Scholar
  53. Zheng, M., Tsuruoka, T., Tsuji, T., and Hakomori, S., 1992, Regulatory role of GM3 ganglioside in integrin function, as evidenced by its effect on function of a513 1-liposomes: A preliminary note, Biochem. Biophys. Res. Commun. 186: 1397–1402.PubMedCrossRefGoogle Scholar
  54. Zheng, M., Fang, H., Tsuruoka, T., Tsuji, T., Sasaki, T., and Hakomori, S., 1993, Regulatory role of GM3 ganglioside in 05131 integrin receptor for fibronectin-mediated adhesion of FUA169 cells, J. Biol. Chem. 268: 2217–2222.PubMedGoogle Scholar
  55. Zhou, Q., Hakomori, S., Kitamura, K., and Igarashi, Y., 1994, GM3 directly inhibits tyrosine phosphorylation and de-N-acetyl-GM3 directly enhances serine phosphorylation of epidermal growth factor receptor, independently of receptor—receptor interaction, J. Biol. Chem. 269: 1959–1965.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1995

Authors and Affiliations

  • Sen-itiroh Hakomori
    • 1
  1. 1.The Biomembrane Institute, and Departments of Pathobiology and MicrobiologyUniversity of WashingtonSeattleUSA

Personalised recommendations