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Ganglioside modulation of the PDGF receptor

A model for ganglioside functions

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Summary

Gangliosides are a family of glycolipids that are present at the cell surface of all mammalian cells. Patterns of gangliosides are different in gliomas than normal brain, and exogenously added gangliosides affect the growth of cultured glioma cells. Gangliosides inhibit the activities of several kinases, including protein kinase C (PKC) and cAMP-kinase. U-1242 MG cells (derived from a human malignant glioma) have receptors for platelet-derived growth factor (PDGF) that become phosphorylated on tyrosine when exposed to PDGF. Exposure of these cells to PDGF also causes an increase in intracellular calcium concentration ([Ca2+]i) and induces a translocation of PKC to the membrane. Preincubation of U-1242 MG cells with several species of gangliosides inhibits the increase in ([Ca2+]i) and PKC translocation in response to PDGF, but GM3 is much less effective than other species tested. This is due to a lack of activation of the receptor tyrosine kinase as monitored by phosphorylation of the receptor on tyrosine residues, but is not due to an inhibition of binding of PDGF to its receptors. The lack of activation of the PDGF receptor tyrosine kinase is due to an inhibition of dimerization of the receptor monomers by gangliosides GM1, GM2, GD1a, GT1b, but not GM3. Therefore, gangliosides may be involved in coordinating the activities of multiple trophic factors simultaneously acting on a cell by regulating the dimerization of their respective receptor monomers.

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Article 23 January 2015

Sen-Itiroh Hakomori & Kazuko Handa

References

  1. Stults CLM, Sweeley CC, Macher BA: Glycosphingolipids: Structure, biological source, and properties. Methods Enzymol 179: 167–214, 1989

    Google Scholar 

  2. Ledeen RW, Yu RK: Gangliosides: Structure, isolation, and analysis. Methods in enzymology 83: 139–191, 1982

    Google Scholar 

  3. Svennerholm L: Ganglioside designation. Adv Exp Med Biol 125: 11, 1980

    Google Scholar 

  4. Ledeen RW: Biosynthesis, metabolism, and biological effects of gangliosides. In: Margolis RU, Margolis RK (eds) Neurobiology of Glycoconjugates. Plenum, New York, 1989, pp 43–83

    Google Scholar 

  5. Byrne MC, Farooq M, Sbaschnig-Agler M, Norton WT, Ledeen RW: Ganglioside content of astroglia and neurons isolated from maturing rat brain: consideration of the source of astroglial gangliosides. Brain Res 461: 87–97, 1988

    Google Scholar 

  6. Van nEchten G, Sandhoff K: Ganglioside metabolism. Enzymology, topology, and regulation. J Biol Chem 268: 5341–5344, 1993

    Google Scholar 

  7. Fishman PH, Brady RO: Biosynthesis and function of gangliosides. Science 194: 906–915, 1976

    Google Scholar 

  8. Hakomori SI: Glycosphingolipids as differentiation and tumor markers and as regulators of cell proliferation. In: B. Wahern, Hammarstrom S, Holm G, Perlmann P (eds) Molecular biology of tumor cells. Raven Press, New York, 1985, pp 139–156

    Google Scholar 

  9. Yogeeswaran G: Cell surface glycolipids and glycoproteins in malignant transformation. Adv Cancer Res 38: 289–350, 1983

    Google Scholar 

  10. Hakomori SI: Aberrant glycosylation in cancer cell membranes as focused on glycolipids: overview and perspectives. Cancer Res 45: 2405–2414, 1985

    Google Scholar 

  11. Hakomori SI: Glycosphinglipids in cellular interaction, differentiation, and oncogenesis. Ann Rev Biochem 50: 733–764, 1981

    Google Scholar 

  12. Ladisch S: Tumor cell gangliosides. Adv Pediatr 34: 45–58, 1987

    Google Scholar 

  13. Fredman P, von Holst H, Collins P, Granholm L, Svennerholm L: Siallyllactotetraosylceramide, a ganglioside marker for human malignant gliomas. J Neurochem 50: 912–919, 1988

    Google Scholar 

  14. Fredman P, Dumanski J, Davidsson P, Svennerholm L, Collins VP: Expression of the ganglioside GD3 in human meningiomas is associated with monosomy of chromosome 22. J Neurochem 55: 1838–1840, 1990

    Google Scholar 

  15. Davidsson P, Fredman P, Collins VP, von Holst H, Mansson J-E, Svennerholm L: Ganglioside composition in human meningiomas. J Neurochem 53: 705–7091, 1989

    Google Scholar 

  16. Gottfries J, Fredman P, Mansson J-E, Collins VP, von Holst H, Armstrong DD, Percy AK, Wikstrand CJ, Bigner DD, Svennerholm L: Determination of gangliosides in six human primary medulloblastomas. J Neurochem 55: 1322–1326, 1990

    Google Scholar 

  17. Fredman P, von Holst H, Collins VP, Dellheden B, Svennerholm L: Expression of gangliosides GD3 and 3′-isoLM1 in autopsy brains from patients with malignant tumors. J Neurochem 60: 99–105, 1993

    Google Scholar 

  18. Traylor TD, Hogan EL: Gangliosides of human cerebral astrocytomas. J Neurochem 34: 126–131, 1980

    Google Scholar 

  19. Yates AJ, Thompson DK, Boesel CP, Albrightson C, Hart RW: Lipid composition of human neural tumors. J Lipid Res 20: 428–436, 1979

    Google Scholar 

  20. Berra B, Gaini SM, Riboni L: Correlation between ganglioside distribution and histological grading of human astrocytomas. Int J Cancer 36: 363–366, 1985

    Google Scholar 

  21. Sung CC, Pearl DK, Coons SW, Scheithauer BW, Johnson PC, Yates AJ: Gangliosides as diagnostic markers of human astrocytomas and primitive neuroectodermal tumors. Cancer 1994

  22. Svennerholm L, Rynmark B-M, Vilbergsson G, Fredman P, Gottfries J, Mansson J-E, Percy A: Gangliosides in human fetal brain. J Neurochem 56: 1763–1768, 1991

    Google Scholar 

  23. Wikstrand CJ, He X, Fuller GN, Bigner SH, Fredman P, Svennerholm L, Bigner DD: Occurrence of lacto series gangliosides 3′-isoLM1 and 3′,6′-isoLD1 in human gliomas in vitro and in vivo. J Neuropathol Exp Neurol 50: 756–769, 1991

    Google Scholar 

  24. De Cristan G, Morbidelli L, Alessandri G, Ziche M, Cappa APM, Gullino PM: Synergism between gangliosides and basic fibroblastic growth factor in favouring survival, growth, and motility of capillary endothelium. J Cell Physiol 144: 505–510, 1990

    Google Scholar 

  25. Keenan TW, Schmid E, Franke WW, Wiegandt H: Exogenous glycosphingolipids suppress growth rate of transformed and untransformed 3T3 mouse cells. Exp Cell Res 92: 259–270, 1975

    Google Scholar 

  26. Ohsawa T, Senshu T: Exogenous GM1 ganglioside caused G1-arrest of human diploid fibroblasts. flow cytometric studies. Exp Cell Res 173: 49–55, 1987

    Google Scholar 

  27. Icard-Liepkalns C, Liepkalns VA, Yates AJ, Rodriguez ZR, Stephens RE: Effect of exogenous gangliosides on human neural cell division. J Cell Physiol 113: 186–191, 1982

    Google Scholar 

  28. Icard-Liepkalns C, Liepkalns VA, Yates AJ, Stephens RE: Cell cycle phases of a novel human neural cell line and the effect of exogenous gangliosides. Biochem Biophys Res Comm 105: 225–230, 1982

    Google Scholar 

  29. Liepkalns VA, Icard-Liepkalns C, Yates AJ, Thompson DK, Hart RW: Effects of cell density on lipids of human glioma and fetal neural cells. J Neurochem 36: 1959–1965, 1981

    Google Scholar 

  30. Coleman MT, Allred LE, Hart RW, Yates AJ: Relationship between gangliosides and doubling times in cultured human brain and brain tumor cells. Cancer Letters 8: 255–262, 1980

    Google Scholar 

  31. Doherty P, Dickerson JG, Flanigan TP, Walsh FS: Ganglioside GM1 does not initiate, but enhances neurite regeneration of nerve growth factor-dependent sensory neurones. J Neurochem 44: 1259–1265, 1985

    Google Scholar 

  32. Ferrari G, Fabris M, Gorio A: Gangliosides enhance neurite outgrowth in PC12 cells. Dev Brain Res 8: 215–221, 1983

    Google Scholar 

  33. Bremer EG, Hakomori SI: 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, 1982

    Google Scholar 

  34. Bremer EG, Hakomori SI, Bowen-Pope DF, Raines E, Ross R: Ganglioside-mediated modulation of cell growth, growth factor binding, and receptor phosphorylation. J Biol Chem 259: 6818–6825, 1984

    Google Scholar 

  35. Yates AJ, Van Brocklyn J, Saqr HE, Guan Z, Stokes BT, O'Dorisio MS: 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, 1993

    Google Scholar 

  36. Goldenring JR, Otis LC, Yu RK, Delorenzo RJ: Calcium/ganglioside-dependent protein kinase activity in rat brain membrane. J Neurochem 44: 1229–1234, 1985

    Google Scholar 

  37. Kreutter D, Kim JYH, Goldenring JR, Rasmussen H, Ukomadu C, Delorenzo RJ, Yu RK: Regulation of protein kinase C activity by gangliosides. J Biol Chem 262: 1633–1637, 1970

    Google Scholar 

  38. Yates AJ, Walters JD, Wood CL, Johnson JD: Ganglioside modulation of cyclic AMP-dependent protein kinase and cyclic nucleotide phosphodiesterase in vitro. J Neurochem 53: 162–167, 1989

    Google Scholar 

  39. Yates AJ, Wood CL, Halterman RK, Stock SM, Walters JD, Johnson JD: Effects of gangliosides, calmodulin, protein kinase C and copper on phosphorylation of protein in membranes of normal and transected sciatic nerve. In: Ledeen RW, Hogan EL, Tettamanti G, Yates AJ, Yu RK (eds) New Trends in Ganglioside Research: Neurochemical and Neuroregenerative Aspects. Liviana Press/Springer Verlag, Padova, 1988, pp 495–511

    Google Scholar 

  40. Eccleston PA, Funa K, Heldin C-H: Expression of platelet-derived growth factor (PDGF) and PDGF α-and β-receptors in the peripheral nervous system: An analysis of sciatic nerve and dorsal root ganglia. Dev Biol 155: 459–470, 1993

    Google Scholar 

  41. Westermark B, Heldin CH: Platelet-derived growth factor. Acta Oncologica 32: 101–105, 1993

    Google Scholar 

  42. Heidaran MA, Pierce JH, Yu J-C, Lombardi D, Artrip JE, Fleming TP, Thomason A, Aaronson SA: Role of αβ receptor heterodimer formation in β platelet-derived growth factor (PDGF) receptor activation by PDGF-AB. J Biol Chem 266: 20232–20237, 1991

    Google Scholar 

  43. Westermark B: PDGF and its receptors in human tumor cells. Cytokines 5: 146–162, 1993

    Google Scholar 

  44. Maxwell M, Naber SP, Wolfe HJ, Galanopolous T, Hedley-Whyte ET, Black PM, Antoniades HN: Coexpression of platelet-derived growth factor (PDGF) and PDGF-receptor genes by primary human astrocytomas may contribute to their development and maintenance. J Clin Invest 86: 131–140, 1990

    Google Scholar 

  45. Hermansson M, Nister M, Betsholtz C, Heldin C-H, Westermark B, Funa K: Endothelial cell hyperplasia in human glioblastoma: Coexpression of mRNA for platelet-derived growth factor (PDGF) B chain and PDGF receptor suggests autocrine growth stimulation. Proc Natl Acad Sci USA 85: 7748–7752, 1988

    Google Scholar 

  46. Mapstone TB: Expression of platelet-derived growth factor and transforming growth factor and their correlation with cellular morphology in glial tumors. J Neurosurg 75: 447–451, 1991

    Google Scholar 

  47. Fleming TP, Saxena A, Clark WC, Robertson JT, Oldfield OH, Aaronson SA, Ali IU: Amplification and/or overex-pression of platelet-derived growth factor receptors and epidermal growth factor receptor in human glial tumors. Cancer Res 52: 4550–4553, 1992

    Google Scholar 

  48. Nister M, Liermann TA, Betsholtz C, Petterson M, Claesson-Welsh L, Heldin C-H, Schlessinger J, Westermark B: Expression of messenger RNAs for platelet-derived growth factor and transforming growth factor-alpha and their receptors in human malignant glioma cell lines. Cancer Res 48: 3910–3918, 1988

    Google Scholar 

  49. Nister M, Wedell B, Betsholtz C, Bywater M, Pettersson M, Westermark B, Mark J: Evidence for progressional changes in the human malignant glioma line U343 MGa: analysis of karyotype and expression of genes encoding the subunit chains of platelet-derived growth factor. Cancer Res 47: 4953–4960, 1987

    Google Scholar 

  50. Westphal M, Brunken M, Rohde E, Herrmann H-D: Growth factors in cultured human glioma cells: Differential effects of FGF, EGF and PDGF. Cancer Letters 38: 283–296, 1988

    Google Scholar 

  51. Nister M, Heldin C-H, Westermark B: Clonal variation in the production of a platelet-derived growth factor-like protein and expression of corresponding receptors in a human malignant glioma. Cancer Res 46: 322–340, 1986

    Google Scholar 

  52. Nistér M, Claesson-Welsh L, Eriksson A, Heldin C-H, Westermark B: Differential expression of platelet-derived growth factor receptors in human malignant glioma cell lines. J Biol Chem 266: 16755–16763, 1991

    Google Scholar 

  53. Vassbotn FS, Östman A, Langeland N, Holmsen H, Westermark B, Heldin C-H, Nistér M: Activated platelet-derived growth factor autocrine pathway drives the transformed phenotype of a human glioblastoma cell line. J Cell Physiol 158: 381–389, 1994

    Google Scholar 

  54. Van Brocklyn J, Bremer EG, Yates AJ: Gangliosides inhibit platelet-derived growth factor-stimulated receptor dimerization in human glioma U-1242MG and Swiss 3T3 cells. J Neurochem 61: 371–374, 1993

    Google Scholar 

  55. Chen W-W, O'Dorisio MS, Pearl DK, Yates AJ: Gangliosides inhibit platelet-derived growth factor stimulated growth of U-1242MG human glioma cells. Brain Tumor Pathol 9: 51–54, 1992

    Google Scholar 

  56. Couldwell WT, Uhm JH, Antel JP, Yong VW: Enhanced protein kinase C activity correlates with the growth rate of malignant gliomas in vitro. Neurosurgery 29: 880–887, 1991

    Google Scholar 

  57. Pollack IF, Randall MS, Kristofik MP, Kelly RH, Selker RG, Vertosick FT, Jr.: Response of malignant glioma cell lines to activation and inhibition of protein kinase C-mediated pathways. J Neurosurg 73: 98–105, 1990

    Google Scholar 

  58. Pollack IF, Randall MS, Kristofik MP, Kelly RH, Selker RG, Vertosick FT, Jr.: Effect of tamoxifen on DNA synthesis and proliferation of human malignant glioma lines in vitro. Cancer Res 50: 7134–7138, 1990

    Google Scholar 

  59. Couldwell WT, Antel JP, Yong VW: Protein kinase C activity correlates with the growth rate of malignant gliomas: Part II. Effects of glioma mitogens and modulators of protein kinase C. Neurosurgery 31: 717–724, 1992

    Google Scholar 

  60. Baltuch GH, Couldwell WT, Villemure J-G, Yong VW: Protein kinase C inhibitors suppress cell growth in established and low-passage glioma cell lines. A comparison between staurosporine and tamoxifen. Neurosurgery 33: 495–501, 1993

    Google Scholar 

  61. Farooqui AA, Farooqui T, Yates AJ, Horrocks LA: Regulation of protein kinase C activity by various lipids. Neurochem Res 13: 499–511, 1988

    Google Scholar 

  62. Guan Z, Stokes BT, Van Brocklyn J, Yates AJ: Gangliosides inhibit platelet-derived growth factor stimulated increases in intracellular calcium in Swiss 3T3 cells. Biochim Biophys Acta 1136: 315–318, 1992

    Google Scholar 

  63. Herren B, Rooney B, Weyer KA, Iberg N, Schmid G, Pech M: Dimerization of extracellular domains of platelet-derived growth factor receptors. A revised model of receptor-ligand interaction. J Biol Chem 268: 15088–15095, 1993

    Google Scholar 

  64. Bremer EG, Schlessinger J, Hakomori SI: Ganglioside-mediated modulation of cell growth. Specific effects of GM3 of tryosine phosphorylation of the epidermal growth factor receptor. J Biol Chem 261: 2434–2440, 1986

    Google Scholar 

  65. Saqr HE, Pearl DK, Yates AJ: A review and predictive models of ganglioside uptake by biological membranes. J Neurochem 61: 395–411, 1994

    Google Scholar 

  66. Yates AJ, Agudelo JD, Sung C-C: Glycolipids of a human glioma cell line bearing receptors for platelet-derived growth factor (PDGF). Lipids 27: 308–310, 1992

    Google Scholar 

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Authors and Affiliations

  1. Division of Neuropathology, The Ohio State University, 43210, Columbus, Ohio, USA

    Allan J. Yates, Hany E. Saqr & James Van Brocklyn

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  1. Allan J. Yates
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  2. Hany E. Saqr
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Yates, A.J., Saqr, H.E. & Van Brocklyn, J. Ganglioside modulation of the PDGF receptor. J Neuro-Oncol 24, 65–73 (1995). https://doi.org/10.1007/BF01052661

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