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The Molecular Immunology of Complex Carbohydrates-3 pp 643–667Cite as

Aberrant Glycosphingolipid Expression and Membrane Organization in Tumor Cells: Consequences on Tumor–Host Interactions

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Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 705))

Abstract

More than 20 years ago [1], the pioneering work of Dr. Sen-itiroh Hakomori formed the basis for the concept that aberrant glycosylation is a general feature of human cancer. The term “aberrant glycosylation” describes the altered expression of oligosaccharide epitopes associated with both glycolipid and glycoprotein antigens in human cancer. This event is the consequence of at least two different metabolic mechanisms: (1) the impairment of specific glycosylation steps (“incomplete synthesis”) and (2) the transcriptional induction of genes encoding for glycosyltransferases or carbohydrate transporters (“neosynthesis”) [2]. Both mechanisms contribute to the accumulation of antigen-carrying tumor-associated epitopes that were originally defined by their ability to raise the production of specific antibodies and subsequently characterized on the basis of their molecular structure. The discovery of oligosaccharide tumor-associated antigens provided useful diagnostic tools and opened the field of tumor glycobiology, which developed tremendously in the following decades.

Ganglioside and glycosphingolipid nomenclature is in accordance with Svennerholm L (1980) Ganglioside designation. Adv Exp Med Biol 125:11 and the IUPAC-IUBMB recommendations Nomenclature of glycolipids (1998) Carbohydr Res 312:167–175.

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Abbreviations

CHO:

Chinese hamster ovary

EGFR:

Epidermal growth factor receptor

EM:

Electron microscopy

GPI:

Glycosylphosphatidylinositol

GSL:

Glycosphingolipid(s)

References

  1. Hakomori SI (1985) Aberrant glycosylation in cancer cell membranes as focused on ­glycolipids: overview and perspectives. Cancer Res 45(6):2405–2414

    PubMed  CAS  Google Scholar 

  2. Hakomori SI (1996) Tumor malignancy defined by aberrant glycosylation and sphingo(glyco)lipid metabolism. Cancer Res 56(23):5309–5318

    PubMed  CAS  Google Scholar 

  3. Miotti S, Tomassetti A, Facetti I, Sanna E, Berno V, Canevari S (2005) Simultaneous expression of caveolin-1 and E-cadherin in ovarian carcinoma cells stabilizes adherens junctions through inhibition of src-related kinases. Am J Pathol 167(5):1411–1427

    PubMed  CAS  Google Scholar 

  4. Wary KK, Mariotti A, Zurzolo C, Giancotti FG (1998) A requirement for caveolin-1 and associated kinase fyn in integrin signaling and anchorage-dependent cell growth. Cell 94(5):625–634

    PubMed  CAS  Google Scholar 

  5. Nakashima H, Hamamura K, Houjou T, Taguchi R, Yamamoto N, Mitsudo K, Tohnai I, Ueda M, Urano T, Furukawa K, Furukawa K (2007) Overexpression of caveolin-1 in a human melanoma cell line results in dispersion of ganglioside GD3 from lipid rafts and alteration of leading edges, leading to attenuation of malignant properties. Cancer Sci 98(4):512–520

    PubMed  CAS  Google Scholar 

  6. Prinetti A, Basso L, Appierto V, Villani MG, Valsecchi M, Loberto N, Prioni S, Chigorno V, Cavadini E, Formelli F, Sonnino S (2003) Altered sphingolipid metabolism in N-(4-hydroxyphenyl)-retinamide-resistant A2780 human ovarian carcinoma cells. J Biol Chem 278(8):5574–5583

    PubMed  CAS  Google Scholar 

  7. Hakomori S (2002) Glycosylation defining cancer malignancy: new wine in an old bottle. Proc Natl Acad Sci USA 99(16):10231–10233

    PubMed  CAS  Google Scholar 

  8. Satoh M, Handa K, Saito S, Tokuyama S, Ito A, Miyao N, Orikasa S, Hakomori SI (1996) Disialosyl galactosylgloboside as an adhesion molecule expressed on renal cell carcinoma and its relationship to metastatic potential. Cancer Res 56(8):1932–1938

    PubMed  CAS  Google Scholar 

  9. Ohyama C, Orikasa S, Kawamura S, Satoh M, Saito S, Fukushi Y, Levery SB, Hakomori S (1995) Galactosylgloboside expression in seminoma. Inverse correlation with metastatic potential. Cancer 76(6):1043–1050

    PubMed  CAS  Google Scholar 

  10. Kawamura S, Ohyama C, Watanabe R, Satoh M, Saito S, Hoshi S, Gasa S, Orikasa S (2001) Glycolipid composition in bladder tumor: a crucial role of GM3 ganglioside in tumor invasion. Int J Cancer 94(3):343–347

    PubMed  CAS  Google Scholar 

  11. Watanabe R, Ohyama C, Aoki H, Takahashi T, Satoh M, Saito S, Hoshi S, Ishii A, Saito M, Arai Y (2002) Ganglioside GM3 overexpression induces apoptosis and reduces malignant potential in murine bladder cancer. Cancer Res 62(13):3850–3854

    PubMed  CAS  Google Scholar 

  12. Ladisch S, Kitada S, Hays EF (1987) Gangliosides shed by tumor cells enhance tumor formation in mice. J Clin Invest 79(6):1879–1882

    PubMed  CAS  Google Scholar 

  13. Deng W, Li R, Ladisch S (2000) Influence of cellular ganglioside depletion on tumor formation. J Natl Cancer Inst 92(11):912–917

    PubMed  CAS  Google Scholar 

  14. Ladisch S, Li R, Olson E (1994) Ceramide structure predicts tumor ganglioside immunosuppressive activity. Proc Natl Acad Sci USA 91(5):1974–1978

    PubMed  CAS  Google Scholar 

  15. Ladisch S, Fumin C, Ruixiang L, Cogen P, Johnson D (1997) Detection of medulloblastoma and astrocytoma-associated ganglioside GD3 in cerebrospinal fluid. Cancer Lett 120(1):71–78

    PubMed  CAS  Google Scholar 

  16. Chang F, Li R, Ladisch S (1997) Shedding of gangliosides by human medulloblastoma cells. Exp Cell Res 234(2):341–346

    PubMed  CAS  Google Scholar 

  17. Hakomori S, Handa K, Iwabuchi K, Yamamura S, Prinetti A (1998) New insights in glycosphingolipid function: “glycosignaling domain,” a cell surface assembly of glycosphingolipids with signal transducer molecules, involved in cell adhesion coupled with signaling. Glycobiology 8(10):xi–xix

    PubMed  CAS  Google Scholar 

  18. Satoh M, Ito A, Nojiri H, Handa K, Numahata K, Ohyama C, Saito S, Hoshi S, Hakomori S (2001) Enhanced GM3 expression, associated with decreased invasiveness, is induced by brefeldin A in bladder cancer cells. Int J Oncol 19(4):723–731

    PubMed  CAS  Google Scholar 

  19. Nojiri H, Yamana H, Shirouzu G, Suzuki T, Isono H (2002) Glycotherapy for cancer: remodeling of ganglioside pattern as an effective approach for cancer therapy. Cancer Detect Prev 26(2):114–120

    PubMed  CAS  Google Scholar 

  20. Prinetti A, Bettiga A, Prioni S, Aureli M, Nocco V, Chigorno V, Sonnino S (2007) Altered sphingolipid metabolism and membrane organization are associated with reduced invasivity in HPR-resistant human ovarian carcinoma cells. Glycobiology and Sphingolipidology, Hakomori Commemorative Forum Tokushima, Japan

    Google Scholar 

  21. Ono M, Handa K, Withers DA, Hakomori SI (1999) Motility inhibition and apoptosis are induced by metastasis-suppressing gene product CD82 and its analogue CD9, with concurrent glycosylation. Cancer Res 59(10):2335–2339

    PubMed  CAS  Google Scholar 

  22. Ono M, Handa K, Sonnino S, Withers DA, Nagai H, Hakomori S (2001) GM3 ganglioside inhibits CD9-facilitated haptotactic cell motility: coexpression of GM3 and CD9 is essential in the downregulation of tumor cell motility and malignancy. Biochemistry 40(21):6414–6421

    PubMed  CAS  Google Scholar 

  23. Iwabuchi K, Handa K, Hakomori S (1998) Separation of “glycosphingolipid signaling domain” from caveolin-containing membrane fraction in mouse melanoma B16 cells and its role in cell adhesion coupled with signaling. J Biol Chem 273(50):33766–33773

    PubMed  CAS  Google Scholar 

  24. Kojima N, Shiota M, Sadahira Y, Handa K, Hakomori S (1992) 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(24):17264–17270

    PubMed  CAS  Google Scholar 

  25. Hakomori S (2004) Glycosynapses: microdomains controlling carbohydrate-dependent cell adhesion and signaling. An Acad Bras Cienc 76(3):553–572

    PubMed  CAS  Google Scholar 

  26. Hakomori S, Handa K (2002) Glycosphingolipid-dependent cross-talk between glycosynapses interfacing tumor cells with their host cells: essential basis to define tumor malignancy. FEBS Lett 531(1):88–92

    PubMed  CAS  Google Scholar 

  27. Iwabuchi K, Yamamura S, Prinetti A, Handa K, Hakomori S (1998) GM3-enriched microdomain involved in cell adhesion and signal transduction through carbohydrate-carbohydrate interaction in mouse melanoma B16 cells. J Biol Chem 273(15):9130–9138

    PubMed  CAS  Google Scholar 

  28. Prinetti A, Iwabuchi K, Hakomori S (1999) Glycosphingolipid-enriched signaling domain in mouse neuroblastoma Neuro2a cells. Mechanism of ganglioside-dependent neuritogenesis. J Biol Chem 274(30):20916–20924

    PubMed  CAS  Google Scholar 

  29. Satoh M, Nejad FM, Ohtani H, Ito A, Ohyama C, Saito S, Orikasa S, Hakomori S (2000) Association of renal cell carcinoma antigen, disialylgalactosylgloboside, with c-Src and Rho A in clustered domains at the surface membrane. Int J Oncol 16(3):529–536

    PubMed  CAS  Google Scholar 

  30. Steelant WF, Kawakami Y, Ito A, Handa K, Bruyneel EA, Mareel M, Hakomori S (2002) Monosialyl-Gb5 organized with cSrc and FAK in GEM of human breast carcinoma MCF-7 cells defines their invasive properties. FEBS Lett 531(1):93–98

    PubMed  CAS  Google Scholar 

  31. Hemler ME (1998) Integrin associated proteins. Curr Opin Cell Biol 10(5):578–585

    PubMed  CAS  Google Scholar 

  32. Kawakami Y, Kawakami K, Steelant WFA, Ono M, Baek RC, Handa K, Withers DA, Hakomori S (2002) Tetraspanin CD9 is a “proteolipid,” and its interaction with alpha 3 ­integrin in microdomain is promoted by GM3 ganglioside, leading to inhibition of laminin-5-dependent cell motility. J Biol Chem 277(37):34349–34358

    PubMed  CAS  Google Scholar 

  33. Miura Y, Kainuma M, Jiang H, Velasco H, Vogt PK, Hakomori S (2004) Reversion of the Jun-induced oncogenic phenotype by enhanced synthesis of sialosyllactosylceramide (GM3 ganglioside). Proc Natl Acad Sci USA 101(46):16204–16209

    PubMed  CAS  Google Scholar 

  34. Mitsuzuka K, Handa K, Satoh M, Arai Y, Hakomori S (2005) A specific microdomain (“glycosynapse 3”) controls phenotypic conversion and reversion of bladder cancer cells through GM3-mediated interaction of alpha3beta1 integrin with CD9. J Biol Chem 280(42):35545–35553

    PubMed  CAS  Google Scholar 

  35. Todeschini AR, Dos Santos JN, Handa K, Hakomori SI (2007) Ganglioside GM2-tetraspanin CD82 complex inhibits Met and its cross-talk with integrins, providing a basis for control of cell motility through glycosynapse. J Biol Chem 282(11):8123–8133

    PubMed  CAS  Google Scholar 

  36. Iwabuchi K, Zhang Y, Handa K, Withers DA, Sinay P, Hakomori SI (2000) Reconstitution of membranes simulating “glycosignaling domain” and their susceptibility to Lyso-GM3. J Biol Chem 275(20):15174–15181

    PubMed  CAS  Google Scholar 

  37. Ono M, Handa K, Withers DA, Hakomori SI (2000) Glycosylation effect on membrane domain (GEM) involved in cell adhesion and motility: a preliminary note on functional [alpha]3, [alpha]5-CD82 glycosylation complex in ldlD 14 cells. Biochem Biophys Res Commun 279(3):744–750

    PubMed  CAS  Google Scholar 

  38. Zhang Y, Iwabuchi K, Nunomura S, Hakomori S (2000) Effect of synthetic sialyl 21 sphingosine and other glycosylsphingosines on the structure and function of the “glycosphingolipid signaling domain (GSD)” in mouse melanoma B16 cells. Biochemistry 39(10):2459–2468

    PubMed  CAS  Google Scholar 

  39. Rothberg KG, Heuser JE, Donzell WC, Ying YS, Glenney JR, Anderson RG (1992) Caveolin, a protein component of caveolae membrane coats. Cell 68(4):673–682

    PubMed  CAS  Google Scholar 

  40. Williams TM, Lisanti MP (2004) The caveolin proteins. Genome Biol 5(3):214

    PubMed  Google Scholar 

  41. Anderson RG (1998) The caveolae membrane system. Annu Rev Biochem 67:199–225

    PubMed  CAS  Google Scholar 

  42. Harder T, Simons K (1997) Caveolae, DIGs, and the dynamics of sphingolipid-cholesterol microdomains. Curr Opin Cell Biol 9(4):534–542

    PubMed  CAS  Google Scholar 

  43. Song KS, Li S, Okamoto T, Quilliam LA, Sargiacomo M, Lisanti MP (1996) Co-purification and direct interaction of Ras with caveolin, an integral membrane protein of caveolae microdomains. Detergent-free purification of caveolae microdomains. J Biol Chem 271(16):9690–9697

    PubMed  CAS  Google Scholar 

  44. Couet J, Li S, Okamoto T, Ikezu T, Lisanti MP (1997) Identification of peptide and protein ligands for the caveolin-scaffolding domain. Implications for the interaction of caveolin with caveolae-associated proteins. J Biol Chem 272(10):6525–6533

    PubMed  CAS  Google Scholar 

  45. Couet J, Sargiacomo M, Lisanti MP (1997) Interaction of a receptor tyrosine kinase, EGF-R, with caveolins. Caveolin binding negatively regulates tyrosine and serine/threonine kinase activities. J Biol Chem 272(48):30429–30438

    PubMed  CAS  Google Scholar 

  46. Pike LJ (2005) Growth factor receptors, lipid rafts and caveolae: an evolving story. Biochim Biophys Acta 1746(3):260–273

    PubMed  CAS  Google Scholar 

  47. Sargiacomo M, Scherer PE, Tang Z, Kubler E, Song KS, Sanders MC, Lisanti MP (1995) Oligomeric structure of caveolin: implications for caveolae membrane organization. Proc Natl Acad Sci USA 92(20):9407–9411

    PubMed  CAS  Google Scholar 

  48. Liu J, Oh P, Horner T, Rogers RA, Schnitzer JE (1997) Organized endothelial cell surface signal transduction in caveolae distinct from glycosylphosphatidylinositol-anchored protein microdomains. J Biol Chem 272(11):7211–7222

    PubMed  CAS  Google Scholar 

  49. Engelman JA, Zhang XL, Razani B, Pestell RG, Lisanti MP (1999) p42/44 MAP kinase-dependent and -independent signaling pathways regulate caveolin-1 gene expression. Activation of Ras-MAP kinase and protein kinase A signaling cascades transcriptionally down-regulates caveolin-1 promoter activity. J Biol Chem 274(45):32333–32341

    PubMed  CAS  Google Scholar 

  50. Williams TM, Medina F, Badano I, Hazan RB, Hutchinson J, Muller WJ, Chopra NG, Scherer PE, Pestell RG, Lisanti MP (2004) Caveolin-1 gene disruption promotes mammary tumorigenesis and dramatically enhances lung metastasis in vivo: role of cav-1 in cell invasiveness and matrix metalloproteinase (MMP-2/9) secretion. J Biol Chem 279(49):51630–51646

    PubMed  CAS  Google Scholar 

  51. Wiechen K, Diatchenko L, Agoulnik A, Scharff KM, Schober H, Arlt K, Zhumabayeva B, Siebert PD, Dietel M, Schafer R, Sers C (2001) Caveolin-1 is down-regulated in human ovarian carcinoma and acts as a candidate tumor suppressor gene. Am J Pathol 159(5):1635–1643

    PubMed  CAS  Google Scholar 

  52. Lee SW, Reimer CL, Oh P, Campbell DB, Schnitzer JE (1998) Tumor cell growth inhibition by caveolin re-expression in human breast cancer cells. Oncogene 16(11):1391–1397

    PubMed  CAS  Google Scholar 

  53. Bender FC, Reymond MA, Bron C, Quest AFG (2000) Caveolin-1 levels are down-regulated in human colon tumors, and ectopic expression of caveolin-1 in colon carcinoma cell lines reduces cell tumorigenicity. Cancer Res 60(20):5870–5878

    PubMed  CAS  Google Scholar 

  54. Ho CC, Huang PH, Huang HY, Chen YH, Yang PC, Hsu SM (2002) Up-regulated caveolin-1 accentuates the metastasis capability of lung adenocarcinoma by inducing filopodia formation. Am J Pathol 161(5):1647–1656

    PubMed  CAS  Google Scholar 

  55. Timme TL, Golstsov A, Tahir S, Li L, Wang J, Ren C, Johnston RN, Thompson TC (2000) Caveolin-1 is regulated by c-myc and suppresses c-myc-induced apoptosis. Oncogene 19(29):3256–3265

    PubMed  CAS  Google Scholar 

  56. Roche S, Koegl M, Barone M, Roussel M, Courtneidge S (1995) DNA synthesis induced by some but not all growth factors requires Src family protein tyrosine kinases. Mol Cell Biol 15(2):1102–1109

    PubMed  CAS  Google Scholar 

  57. Roche S, Fumagalli S, Courtneidge S (1995) Requirement for Src family protein tyrosine kinases in G2 for fibroblast cell division. Science 269(5230):1567–1569

    PubMed  CAS  Google Scholar 

  58. Roche S, McGlade J, Jones M, Gish GD, Pawson T, Courtneidge S (1996) Requirement of phospholipase C gamma, the tyrosine phosphatase Syp and the adaptor proteins Shc and Nck for PDGF-induced DNA synthesis: evidence for the existence of Ras-dependent and Ras-independent pathways. EMBO J 15(18):4940–4948

    PubMed  CAS  Google Scholar 

  59. Roche S, Downward J, Raynal P, Courtneidge SA (1998) A function for phosphatidylinositol 3-kinase beta (p85alpha -p110beta) in fibroblasts during mitogenesis: requirement for insulin- and lysophosphatidic acid-mediated signal transduction. Mol Cell Biol 18(12):7119–7129

    PubMed  CAS  Google Scholar 

  60. Manes G, Bello P, Roche S (2000) Slap negatively regulates Src mitogenic function but does not revert Src-induced cell morphology changes. Mol Cell Biol 20(10):3396–3406

    PubMed  CAS  Google Scholar 

  61. Furstoss O, Dorey K, Simon V, Barilà D, Superti-Furga G, Roche S (2002) c-Abl is an effector of Src for growth factor-induced c-myc expression and DNA synthesis. EMBO J 21(4):514–524

    PubMed  CAS  Google Scholar 

  62. Boureux A, Furstoss O, Simon V, Roche S (2005) Abl tyrosine kinase regulates a Rac/JNK and a Rac/Nox pathway for DNA synthesis and Myc expression induced by growth factors. J Cell Sci 118(16):3717–3726

    PubMed  CAS  Google Scholar 

  63. Franco M, Furstoss O, Simon V, Benistant C, Hong WJ, Roche S (2006) The adaptor protein Tom1L1 is a negative regulator of Src mitogenic signaling induced by growth factors. Mol Cell Biol 26(5):1932–1947

    PubMed  CAS  Google Scholar 

  64. Veracini L, Franco M, Boureux A, Simon V, Roche S, Benistant C (2006) Two distinct pools of Src family tyrosine kinases regulate PDGF-induced DNA synthesis and actin dorsal ruffles. J Cell Sci 119(14):2921–2934

    PubMed  CAS  Google Scholar 

  65. Boyer B, Roche S, Denoyelle M, Thiery JP (1997) Src and Ras are involved in separate pathways in epithelial cell scattering. EMBO J 16:5904–5913

    PubMed  CAS  Google Scholar 

  66. Benistant C, Chapuis H, Mottet N, Noletti J, Crapez E, Bali JP, Roche S (2000) Deregulation of the cytoplasmic tyrosine kinase cSrc in the absence of a truncating mutation at codon 531 in human bladder carcinoma. Biochem Biophys Res Commun 273(2):425–430

    PubMed  CAS  Google Scholar 

  67. Benistant C, Bourgaux JF, Chapuis H, Mottet N, Roche S, Bali JP (2001) The COOH-terminal Src kinase Csk is a tumor antigen in human carcinoma. Cancer Res 61(4):1415–1420

    PubMed  CAS  Google Scholar 

  68. Mastick C, Brady M, Saltiel A (1995) Insulin stimulates the tyrosine phosphorylation of caveolin. J Cell Biol 129(6):1523–1531

    PubMed  CAS  Google Scholar 

  69. Li S, Seitz R, Lisanti MP (1996) Phosphorylation of caveolin by Src tyrosine kinases. J Biol Chem 271(7):3863–3868

    PubMed  CAS  Google Scholar 

  70. Aoki T, Nomura R, Fujimoto T (1999) Tyrosine phosphorylation of caveolin-1 in the endothelium. Exp Cell Res 253(2):629–636

    PubMed  CAS  Google Scholar 

  71. Lu TL, Kuo FT, Lu TJ, Hsu CY, Fu HW (2006) Negative regulation of protease-activated receptor 1-induced Src kinase activity by the association of phosphocaveolin-1 with Csk. Cell Signal 18(11):1977–1987

    PubMed  CAS  Google Scholar 

  72. Echarri A, Del Pozo A (2006) Caveolae internalization regulates integrin-dependent signaling pathways. Cell Cycle 5(19):2179–2182

    PubMed  CAS  Google Scholar 

  73. Del Pozo MA, Balasubramanian N, Alderson NB, Kiosses WB, Grande-Garcia A, Anderson RG, Schwartz MA (2005) Phospho-caveolin-1 mediates integrin-regulated membrane domain internalisation. Nat Cell Biol 7(9):901–908

    PubMed  Google Scholar 

  74. Del Pozo MA, Schwartz MA (2007) Rac, membrane heterogeneity, caveolin and regulation of growth by integrins. Trends Cell Biol 17(5):246–250

    PubMed  Google Scholar 

  75. Palade GE (1953) An electron microscope study of the mitochondrial structure. J Histochem Cytochem 1(4):188–211

    PubMed  CAS  Google Scholar 

  76. Yamada E (1955) The fine structure of the gall bladder epithelium of the mouse. J Biophys Biochem Cytol 1(5):445–458

    PubMed  CAS  Google Scholar 

  77. Lisanti MP, Scherer PE, Tang Z, Sargiacomo M (1994) Caveolae, caveolin and caveolin-rich membrane domains: a signalling hypothesis. Trends Cell Biol 4(7):231–235

    PubMed  CAS  Google Scholar 

  78. Okamoto T, Schlegel A, Scherer PE, Lisanti MP (1998) Caveolins, a family of scaffolding proteins for organizing “preassembled signaling complexes” at the plasma membrane. J Biol Chem 273(10):5419–5422

    PubMed  CAS  Google Scholar 

  79. Fielding CJ (2001) Caveolae and signaling. Curr Opin Lipidol 12(3):281–287

    PubMed  CAS  Google Scholar 

  80. Chini B, Parenti M (2004) G-protein coupled receptors in lipid rafts and caveolae: how, when and why do they go there? J Mol Endocrinol 32(2):325–338

    PubMed  CAS  Google Scholar 

  81. Drab M, Verkade P, Elger M, Kasper M, Lohn M, Lauterbach B, Menne J, Lindschau C, Mende F, Luft FC, Schedl A, Haller H, Kurzchalia TV (2001) Loss of caveolae, vascular dysfunction, and pulmonary defects in caveolin-1 gene-disrupted mice. Science 293(5539):2449–2452

    PubMed  CAS  Google Scholar 

  82. Galbiati F, Engelman JA, Volonte D, Zhang XL, Minetti C, Li M, Hou H Jr, Kneitz B, Edelmann W, Lisanti MP (2001) Caveolin-3 null mice show a loss of caveolae, changes in the microdomain distribution of the dystrophin-glycoprotein complex, and t-tubule abnormalities. J Biol Chem 276(24):21425–21433

    PubMed  CAS  Google Scholar 

  83. Fra AM, Williamson E, Simons K, Parton RG (1995) De novo formation of caveolae in lymphocytes by expression of VIP21-caveolin. Proc Natl Acad Sci USA 92(19):8655–8659

    PubMed  CAS  Google Scholar 

  84. Sowa G, Pypaert M, Sessa WC (2001) Distinction between signaling mechanisms in lipid rafts vs. caveolae. Proc Natl Acad Sci USA 98(24):14072–14077

    PubMed  CAS  Google Scholar 

  85. Westermann M, Leutbecher H, Meyer HW (1999) Membrane structure of caveolae and isolated caveolin-rich vesicles. Histochem Cell Biol 111(1):71–81

    PubMed  CAS  Google Scholar 

  86. Kurzchalia TV, Dupree P, Parton RG, Kellner R, Virta H, Lehnert M, Simons K (1992) VIP21, a 21-kD membrane protein is an integral component of trans-Golgi-network-derived transport vesicles. J Cell Biol 118(5):1003–1014

    PubMed  CAS  Google Scholar 

  87. Li WP, Liu P, Pilcher BK, Anderson RG (2001) Cell-specific targeting of caveolin-1 to caveolae, secretory vesicles, cytoplasm or mitochondria. J Cell Sci 114(Pt 7):1397–1408

    PubMed  CAS  Google Scholar 

  88. Fujimoto T (1996) GPI-anchored proteins, glycosphingolipids, and sphingomyelin are sequestered to caveolae only after crosslinking. J Histochem Cytochem 44(8):929–941

    PubMed  CAS  Google Scholar 

  89. Stan RV (2002) Structure and function of endothelial caveolae. Microsc Res Tech 57(5):350–364

    PubMed  Google Scholar 

  90. Nabi IR, Le PU (2003) Caveolae/raft-dependent endocytosis. J Cell Biol 161(4):673–677

    PubMed  CAS  Google Scholar 

  91. Nichols B (2003) Caveosomes and endocytosis of lipid rafts. J Cell Sci 116(Pt 23):4707–4714

    PubMed  CAS  Google Scholar 

  92. Parton RG, Richards AA (2003) Lipid rafts and caveolae as portals for endocytosis: new insights and common mechanisms. Traffic 4(11):724–738

    PubMed  CAS  Google Scholar 

  93. Kenworthy A (2002) Peering inside lipid rafts and caveolae. Trends Biochem Sci 27(9):435–438

    PubMed  CAS  Google Scholar 

  94. Hooper NM (1999) Detergent-insoluble glycosphingolipid/cholesterol-rich membrane domains, lipid rafts and caveolae (review). Mol Membr Biol 16(2):145–156

    PubMed  CAS  Google Scholar 

  95. Sargiacomo M, Sudol M, Tang Z, Lisanti MP (1993) Signal transducing molecules and glycosyl-phosphatidylinositol-linked proteins form a caveolin-rich insoluble complex in MDCK cells. J Cell Biol 122(4):789–807

    PubMed  CAS  Google Scholar 

  96. Prinetti A, Chigorno V, Prioni S, Loberto N, Marano N, Tettamanti G, Sonnino S (2001) Changes in the lipid turnover, composition, and organization, as sphingolipid-enriched membrane domains, in rat cerebellar granule cells developing in vitro. J Biol Chem 276(24):21136–21145

    PubMed  CAS  Google Scholar 

  97. Fra AM, Williamson E, Simons K, Parton RG (1994) Detergent-insoluble glycolipid microdomains in lymphocytes in the absence of caveolae. J Biol Chem 269(49):30745–30748

    PubMed  CAS  Google Scholar 

  98. Kasahara K, Watanabe K, Takeuchi K, Kaneko H, Oohira A, Yamamoto T, Sanai Y (2000) Involvement of gangliosides in glycosylphosphatidylinositol-anchored neuronal cell adhesion molecule TAG-1 signaling in lipid rafts. J Biol Chem 275(44):34701–34709

    PubMed  CAS  Google Scholar 

  99. Kasahara K, Watanabe Y, Yamamoto T, Sanai Y (1997) Association of Src family tyrosine kinase Lyn with ganglioside GD3 in rat brain. Possible regulation of Lyn by glycosphingolipid in caveolae-like domains. J Biol Chem 272(47):29947–29953

    PubMed  CAS  Google Scholar 

  100. Prinetti A, Prioni S, Chigorno V, Karagogeos D, Tettamanti G, Sonnino S (2001) Immunoseparation of sphingolipid-enriched membrane domains enriched in Src family protein tyrosine kinases and in the neuronal adhesion molecule TAG-1 by anti-GD3 ganglioside monoclonal antibody. J Neurochem 78(5):1162–1167

    PubMed  CAS  Google Scholar 

  101. Quest AF, Leyton L, Parraga M (2004) Caveolins, caveolae, and lipid rafts in cellular transport, signaling, and disease. Biochem Cell Biol 82(1):129–144

    PubMed  CAS  Google Scholar 

  102. Prinetti A, Marano N, Prioni S, Chigorno V, Mauri L, Casellato R, Tettamanti G, Sonnino S (2000) Association of Src-family protein tyrosine kinases with sphingolipids in rat cerebellar granule cells differentiated in culture. Glycoconj J 17(3–4):223–232

    PubMed  CAS  Google Scholar 

  103. Scheiffele P, Verkade P, Fra AM, Virta H, Simons K, Ikonen E (1998) Caveolin-1 and -2 in the exocytic pathway of MDCK cells. J Cell Biol 140(4):795–806

    PubMed  CAS  Google Scholar 

  104. Maggi R, Pimpinelli F, Molteni L, Milani M, Martini L, Piva F (2000) Immortalized luteinizing hormone-releasing hormone neurons show a different migratory activity in vitro. Endocrinology 141(6):2105–2112

    PubMed  CAS  Google Scholar 

  105. Prioni S, Loberto N, Prinetti A, Chigorno V, Guzzi F, Maggi R, Parenti M, Sonnino S (2002) Sphingolipid metabolism and caveolin expression in gonadotropin-releasing hormone-expressing GN11 and gonadotropin-releasing hormone-secreting GT1-7 neuronal cells. Neurochem Res 27(7–8):831–840

    PubMed  CAS  Google Scholar 

  106. Mayor S, Rothberg K, Maxfield F (1994) Sequestration of GPI-anchored proteins in caveolae triggered by cross-linking. Science 264(5167):1948–1951

    PubMed  CAS  Google Scholar 

  107. Stan RV, Roberts WG, Predescu D, Ihida K, Saucan L, Ghitescu L, Palade GE (1997) Immunoisolation and partial characterization of endothelial plasmalemmal vesicles (caveolae). Mol Biol Cell 8(4):595–605

    PubMed  CAS  Google Scholar 

  108. Waugh MG, Lawson D, Hsuan JJ (1999) Epidermal growth factor receptor activation is localized within low-buoyant density, non-caveolar membrane domains. Biochem J 337(Pt 3):591–597

    PubMed  CAS  Google Scholar 

  109. Waugh MG, Minogue S, Anderson JS, dos Santos M, Hsuan JJ (2001) Signalling and non-caveolar rafts. Biochem Soc Trans 29(Pt 4):509–511

    PubMed  CAS  Google Scholar 

  110. Ringerike T, Blystad FD, Levy FO, Madshus IH, Stang E (2002) Cholesterol is important in control of EGF receptor kinase activity but EGF receptors are not concentrated in caveolae. J Cell Sci 115(6):1331–1340

    PubMed  CAS  Google Scholar 

  111. Roepstorff K, Thomsen P, Sandvig K, van Deurs B (2002) Sequestration of epidermal growth factor receptors in non-caveolar lipid rafts inhibits ligand binding. J Biol Chem 277(21):18954–18960

    PubMed  CAS  Google Scholar 

  112. Fujimoto T, Hayashi M, Iwamoto M, Ohno-Iwashita Y (1997) Crosslinked plasmalemmal cholesterol is sequestered to caveolae: analysis with a new cytochemical probe. J Histochem Cytochem 45(9):1197–1205

    PubMed  CAS  Google Scholar 

  113. Murata M, Peranen J, Schreiner R, Wieland F, Kurzchalia TV, Simons K (1995) VIP21/caveolin is a cholesterol-binding protein. Proc Natl Acad Sci USA 92(22):10339–10343

    PubMed  CAS  Google Scholar 

  114. Li S, Song KS, Lisanti MP (1996) Expression and characterization of recombinant caveolin. J Biol Chem 271(1):568–573

    PubMed  CAS  Google Scholar 

  115. Thiele C, Hannah MJ, Fahrenholz F, Huttner WB (2000) Cholesterol binds to synaptophysin and is required for biogenesis of synaptic vesicles. Nat Cell Biol 2(1):42–49

    PubMed  CAS  Google Scholar 

  116. Parton RG (1994) Ultrastructural localization of gangliosides; GM1 is concentrated in caveolae. J Histochem Cytochem 42(2):155–166

    PubMed  CAS  Google Scholar 

  117. Schnitzer JE, McIntosh DP, Dvorak AM, Liu J, Oh P (1995) Separation of caveolae from associated microdomains of GPI-anchored proteins. Science 269(5229):1435–1439

    PubMed  CAS  Google Scholar 

  118. Liu P, Anderson RG (1995) Compartmentalized production of ceramide at the cell surface. J Biol Chem 270(45):27179–27185

    PubMed  CAS  Google Scholar 

  119. Chigorno V, Palestini P, Sciannamblo M, Dolo V, Pavan A, Tettamanti G, Sonnino S (2000) Evidence that ganglioside enriched domains are distinct from caveolae in MDCK II and human fibroblast cells in culture. Eur J Biochem 267(13):4187–4197

    PubMed  CAS  Google Scholar 

  120. Fra AM, Masserini M, Palestini P, Sonnino S, Simons K (1995) A photo-reactive derivative of ganglioside GM1 specifically cross-links VIP21-caveolin on the cell surface. FEBS Lett 375(1–2):11–14

    PubMed  CAS  Google Scholar 

  121. Resh MD (1999) Fatty acylation of proteins: new insights into membrane targeting of myristoylated and palmitoylated proteins. Biochim Biophys Acta 1451(1):1–16

    PubMed  CAS  Google Scholar 

  122. Robbins S, Quintrell N, Bishop J (1995) Myristoylation and differential palmitoylation of the HCK protein-tyrosine kinases govern their attachment to membranes and association with caveolae. Mol Cell Biol 15(7):3507–3515

    PubMed  CAS  Google Scholar 

  123. Shenoy-Scaria A, Dietzen D, Kwong J, Link D, Lublin D (1994) Cysteine3 of Src family protein tyrosine kinase determines palmitoylation and localization in caveolae. J Cell Biol 126(2):353–363

    PubMed  CAS  Google Scholar 

  124. Wolven A, Okamura H, Rosenblatt Y, Resh M (1997) Palmitoylation of p59fyn is reversible and sufficient for plasma membrane association. Mol Biol Cell 8(6):1159–1173

    PubMed  CAS  Google Scholar 

  125. Janes PW, Ley SC, Magee AI, Kabouridis PS (2000) The role of lipid rafts in T cell antigen receptor (TCR) signalling. Semin Immunol 12(1):23–34

    PubMed  CAS  Google Scholar 

  126. Mukherjee A, Arnaud L, Cooper JA (2003) Lipid-dependent recruitment of neuronal Src to lipid rafts in the brain. J Biol Chem 278(42):40806–40814

    PubMed  CAS  Google Scholar 

  127. Melkonian KA, Ostermeyer AG, Chen JZ, Roth MG, Brown DA (1999) Role of lipid modifications in targeting proteins to detergent-resistant membrane rafts. Many raft proteins are acylated, while few are prenylated. J Biol Chem 274(6):3910–3917

    PubMed  CAS  Google Scholar 

  128. Lee H, Volonte D, Galbiati F, Iyengar P, Lublin DM, Bregman DB, Wilson MT, Campos-Gonzalez R, Bouzahzah B, Pestell RG, Scherer PE, Lisanti MP (2000) Constitutive and growth factor-regulated phosphorylation of caveolin-1 occurs at the same site (Tyr-14) in vivo: identification of a c-Src/Cav-1/Grb7 signaling cassette. Mol Endocrinol 14(11):1750–1775

    PubMed  CAS  Google Scholar 

  129. Sharma DK, Brown JC, Choudhury A, Peterson TE, Holicky E, Marks DL, Simari R, Parton RG, Pagano RE (2004) Selective stimulation of caveolar endocytosis by glycosphingolipids and cholesterol. Mol Biol Cell 15(7):3114–3122

    PubMed  CAS  Google Scholar 

  130. Shajahan AN, Timblin BK, Sandoval R, Tiruppathi C, Malik AB, Minshall RD (2004) Role of Src-induced dynamin-2 phosphorylation in caveolae-mediated endocytosis in endothelial cells. J Biol Chem 279(19):20392–20400

    PubMed  CAS  Google Scholar 

  131. Pelkmans L, Zerial M (2005) Kinase-regulated quantal assemblies and kiss-and-run recycling of caveolae. Nature 436(7047):128–133

    PubMed  CAS  Google Scholar 

  132. Da Silva JS, Hasegawa T, Miyagi T, Dotti CG, Abad-Rodriguez J (2005) Asymmetric membrane ganglioside sialidase activity specifies axonal fate. Nat Neurosci 8(5):606–615

    PubMed  Google Scholar 

  133. Kakugawa Y, Wada T, Yamaguchi K, Yamanami H, Ouchi K, Sato I, Miyagi T (2002) Up-regulation of plasma membrane-associated ganglioside sialidase (Neu3) in human colon cancer and its involvement in apoptosis suppression. Proc Natl Acad Sci USA 99(16):10718–10723

    PubMed  CAS  Google Scholar 

  134. Ueno S, Saito S, Wada T, Yamaguchi K, Satoh M, Arai Y, Miyagi T (2006) Plasma membrane-associated sialidase is up-regulated in renal cell carcinoma and promotes interleukin-6-induced apoptosis suppression and cell motility. J Biol Chem 281(12):7756–7764

    PubMed  CAS  Google Scholar 

  135. Kalka D, von Reitzenstein C, Kopitz J, Cantz M (2001) The plasma membrane ganglioside sialidase cofractionates with markers of lipid rafts. Biochem Biophys Res Commun 283(4):989–993

    PubMed  CAS  Google Scholar 

  136. Wang Y, Yamaguchi K, Wada T, Hata K, Zhao X, Fujimoto T, Miyagi T (2002) A close association of the ganglioside-specific sialidase Neu3 with caveolin in membrane microdomains. J Biol Chem 277(29):26252–26259

    PubMed  CAS  Google Scholar 

  137. Papini N, Anastasia L, Tringali C, Croci G, Bresciani R, Yamaguchi K, Miyagi T, Preti A, Prinetti A, Prioni S, Sonnino S, Tettamanti G, Venerando B, Monti E (2004) The plasma membrane-associated sialidase MmNEU3 modifies the ganglioside pattern of adjacent cells supporting its involvement in cell-to-cell interactions. J Biol Chem 279(17):16989–16995

    PubMed  CAS  Google Scholar 

  138. Cremesti AE, Goni FM, Kolesnick R (2002) Role of sphingomyelinase and ceramide in modulating rafts: do biophysical properties determine biologic outcome? FEBS Lett 531(1):47–53

    PubMed  CAS  Google Scholar 

  139. Yu C, Alterman M, Dobrowsky RT (2005) Ceramide displaces cholesterol from lipid rafts and decreases the association of the cholesterol binding protein caveolin-1. J Lipid Res 46(8):1678–1691

    PubMed  CAS  Google Scholar 

  140. Kazui A, Ono M, Handa K, Hakomori SI (2000) Glycosylation affects translocation of ­integrin, Src, and caveolin into or out of GEM. Biochem Biophys Res Commun 273(1):159–163

    PubMed  CAS  Google Scholar 

  141. Wang XQ, Sun P, Paller AS (2002) Ganglioside induces caveolin-1 redistribution and interaction with the epidermal growth factor receptor. J Biol Chem 277(49):47028–47034

    PubMed  CAS  Google Scholar 

  142. Hamamura K, Furukawa K, Hayashi T, Hattori T, Nakano J, Nakashima H, Okuda T, Mizutani H, Hattori H, Ueda M, Urano T, Lloyd KO, Furukawa K (2005) Ganglioside GD3 promotes cell growth and invasion through p130Cas and paxillin in malignant melanoma cells. Proc Natl Acad Sci USA 102(31):11041–11046

    PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by the Mizutani Foundation for Glycoscience, Grant 070002, to Alessandro Prinetti, and by the CARIPLO Foundation, Grant 2006, to Sandro Sonnino.

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  1. Department of Medical Chemistry, Biochemistry and Biotechnology, Center of Excellence on Neurodegenerative Diseases, University of Milan, Via Fratelli Cervi 93, 20090, Segrate, Milano, Italy

    Alessandro Prinetti

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  1. Alessandro Prinetti
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  2. Simona Prioni
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  3. Nicoletta Loberto
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Correspondence to Alessandro Prinetti .

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  1. College of Medicine, Institute of Molecular&Cellular Biology, Chang-Gung University, Kwei-San, Tao-Yuan, 333, Taiwan R.O.C.

    Albert M. Wu

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Prinetti, A. et al. (2011). Aberrant Glycosphingolipid Expression and Membrane Organization in Tumor Cells: Consequences on Tumor–Host Interactions. In: Wu, A. (eds) The Molecular Immunology of Complex Carbohydrates-3. Advances in Experimental Medicine and Biology, vol 705. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-7877-6_34

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