• 1
    Lawler A (2004) Archaeology. The Indus script – write or wrong? Science 306, 20262029.
  • 2
    Rao RP, Yadav N, Vahia MN, Joglekar H, Adhikari R & Mahadevan I (2009) Entropic evidence for linguistic structure in the Indus script. Science 324, 1165.
  • 3
    Searls DB (2013). A primer in macromolecular linguistics. Biopolymers 99, 203217.
  • 4
    Searls DB (2002) The language of genes. Nature 420, 211217.
  • 5
    Pilobello KT & Mahal LK (2007) Deciphering the glycocode: the complexity and analytical challenge of glycomics. Curr Opin Chem Biol 11, 300305.
  • 6
    Gupta G & Surolia A (2012) Glycomics: an overview of the complex glycocode. Adv Exp Med Biol 749, 113.
  • 7
    Merrill AH Jr (2011) Sphingolipid and glycosphingolipid metabolic pathways in the era of sphingolipidomics. Chem Rev 111, 63876422.
  • 8
    Schulze H & Sandhoff K (2011) Lysosomal lipid storage diseases. Cold Spring Harb Perspect Biol 3, pii:004804.
  • 9
    Ichikawa S, Nakajo N, Sakiyama H & Hirabayashi Y (1994) A mouse B16 melanoma mutant deficient in glycolipids. Proc Natl Acad Sci USA 91, 27032707.
  • 10
    Yamashita T, Wada R, Sasaki T, Deng C, Bierfreund U, Sandhoff K & Proia RL (1999) A vital role for glycosphingolipid synthesis during development and differentiation. Proc Natl Acad Sci USA 96, 91429147.
  • 11
    Yamashita T, Wu YP, Sandhoff R, Werth N, Mizukami H, Ellis JM, Dupree JL, Geyer R, Sandhoff K & Proia RL (2005) Interruption of ganglioside synthesis produces central nervous system degeneration and altered axon-glial interactions. Proc Natl Acad Sci USA 102, 27252730.
  • 12
    Okuda T, Tokuda N, Numata S, Ito M, Ohta M, Kawamura K, Wiels J, Urano T, Tajima O & Furukawa K (2006) Targeted disruption of Gb3/CD77 synthase gene resulted in the complete deletion of globo-series glycosphingolipids and loss of sensitivity to verotoxins. J Biol Chem 281, 1023010235.
  • 13
    Hakomori SI (2008) Structure and function of glycosphingolipids and sphingolipids: recollections and future trends. Biochim Biophys Acta 1780, 325346.
  • 14
    Hannun YA & Obeid LM (2008) Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Biol 9, 139150.
  • 15
    van Meer G, Voelker DR & Feigenson GW (2008) Membrane lipids: where they are and how they behave. Nat Rev Mol Cell Biol 9, 112124.
  • 16
    Mullen TD, Hannun YA & Obeid LM (2012) Ceramide synthases at the centre of sphingolipid metabolism and biology. Biochem J 441, 789802.
  • 17
    Holthuis JC, Pomorski T, Raggers RJ, Sprong H & Van Meer G (2001) The organizing potential of sphingolipids in intracellular membrane transport. Physiol Rev 81, 16891723.
  • 18
    Hanada K, Kumagai K, Yasuda S, Miura Y, Kawano M, Fukasawa M & Nishijima M (2003) Molecular machinery for non-vesicular trafficking of ceramide. Nature 426, 803809.
  • 19
    Gault CR, Obeid LM & Hannun YA (2010) An overview of sphingolipid metabolism: from synthesis to breakdown. Adv Exp Med Biol 688, 123.
  • 20
    Funakoshi T, Yasuda S, Fukasawa M, Nishijima M & Hanada K (2000) Reconstitution of ATP- and cytosol-dependent transport of de novo synthesized ceramide to the site of sphingomyelin synthesis in semi-intact cells. J Biol Chem 275, 2993829945.
  • 21
    Buton X, Herve P, Kubelt J, Tannert A, Burger KN, Fellmann P, Muller P, Herrmann A, Seigneuret M & Devaux PF (2002) Transbilayer movement of monohexosylsphingolipids in endoplasmic reticulum and Golgi membranes. Biochemistry 41, 1310613115.
  • 22
    D'Angelo G, Polishchuk E, Di Tullio G, Santoro M, Di Campli A, Godi A, West G, Bielawski J, Chuang CC, van der Spoel AC, et al. (2007) Glycosphingolipid synthesis requires FAPP2 transfer of glucosylceramide. Nature 449, 6267.
  • 23
    Halter D, Neumann S, van Dijk SM, Wolthoorn J, de Maziere AM, Vieira OV, Mattjus P, Klumperman J, van Meer G & Sprong H (2007) Pre- and post-Golgi translocation of glucosylceramide in glycosphingolipid synthesis. J Cell Biol 179, 101115.
  • 24
    D'Angelo G, Uemura T, Chuang CC, Polishchuk E, Santoro M, Ohvo-Rekila H, Sato T, Di Tullio G, Varriale A, D'Auria S, et al. (2013) Vesicular and non-vesicular transport feed distinct glycosylation pathways in the Golgi. Nature 501, 116120.
  • 25
    De Rosa MF, Sillence D, Ackerley C & Lingwood C (2004) Role of multiple drug resistance protein 1 in neutral but not acidic glycosphingolipid biosynthesis. J Biol Chem 279, 78677876.
  • 26
    Maccioni HJ, Quiroga R & Ferrari ML (2011a) Cellular and molecular biology of glycosphingolipid glycosylation. J Neurochem 117, 589602.
  • 27
    Nishie T, Hikimochi Y, Zama K, Fukusumi Y, Ito M, Yokoyama H, Naruse C & Asano M (2010) Beta4-galactosyltransferase-5 is a lactosylceramide synthase essential for mouse extra-embryonic development. Glycobiology 20, 13111322.
  • 28
    Nomura T, Takizawa M, Aoki J, Arai H, Inoue K, Wakisaka E, Yoshizuka N, Imokawa G, Dohmae N, Takio K, et al. (1998) Purification, cDNA cloning, and expression of UDP-Gal: glucosylceramide beta-1,4-galactosyltransferase from rat brain. J Biol Chem 273, 1357013577.
  • 29
    Kumagai T, Sato T, Natsuka S, Kobayashi Y, Zhou D, Shinkai T, Hayakawa S & Furukawa K (2010) Involvement of murine beta-1,4-galactosyltransferase V in lactosylceramide biosynthesis. Glycoconj J 27, 685695.
  • 30
    Nagata Y, Yamashiro S, Yodoi J, Lloyd KO, Shiku H & Furukawa K (1992) Expression cloning of beta 1,4 N-acetylgalactosaminyltransferase cDNAs that determine the expression of GM2 and GD2 gangliosides. J Biol Chem 267, 1208212089.
  • 31
    Hidari JK, Ichikawa S, Furukawa K, Yamasaki M & Hirabayashi Y (1994) beta 1-4N-acetylgalactosaminyltransferase can synthesize both asialoglycosphingolipid GM2 and glycosphingolipid GM2 in vitro and in vivo: isolation and characterization of a beta 1-4N-acetylgalactosaminyltransferase cDNA clone from rat ascites hepatoma cell line AH7974F. Biochem J 303, 957965.
  • 32
    Ishii A, Ohta M, Watanabe Y, Matsuda K, Ishiyama K, Sakoe K, Nakamura M, Inokuchi J, Sanai Y & Saito M (1998) Expression cloning and functional characterization of human cDNA for ganglioside GM3 synthase. J Biol Chem 273, 3165231655.
  • 33
    Kojima Y, Fukumoto S, Furukawa K, Okajima T, Wiels J, Yokoyama K, Suzuki Y, Urano T & Ohta M (2000) Molecular cloning of globotriaosylceramide/CD77 synthase, a glycosyltransferase that initiates the synthesis of globo series glycosphingolipids. J Biol Chem 275, 1515215156.
  • 34
    Biellmann F, Hulsmeier AJ, Zhou D, Cinelli P & Hennet T (2008) The Lc3-synthase gene B3gnt5 is essential to pre-implantation development of the murine embryo. BMC Dev Biol 8, 109.
  • 35
    Aureli M, Loberto N, Chigorno V, Prinetti A & Sonnino S (2011) Remodeling of sphingolipids by plasma membrane associated enzymes. Neurochem Res 36, 16361644.
  • 36
    Kitatani K, Idkowiak-Baldys J & Hannun YA (2008) The sphingolipid salvage pathway in ceramide metabolism and signaling. Cell Signal 20, 10101018.
  • 37
    Sud M, Fahy E, Cotter D, Brown A, Dennis EA, Glass CK, Merrill AH Jr, Murphy RC, Raetz CR, Russell DW, et al. (2007) LMSD: LIPID MAPS structure database. Nucleic Acids Res 35, D527D532.
  • 38
    Kozomara A & Griffiths-Jones S (2011) miRBase: integrating microRNA annotation and deep-sequencing data. Nucleic Acids Res 39, D152D157.
  • 39
    Shannon CE (1948) A mathematical theory of communication. Bell Sys Tech J 27, 379423.
  • 40
    Gabius HJ (2008) Glycans: bioactive signals decoded by lectins. Biochem Soc Trans 36, 14911496.
  • 41
    Merrill AH Jr, Stokes TH, Momin A, Park H, Portz BJ, Kelly S, Wang E, Sullards MC & Wang MD (2009) Sphingolipidomics: a valuable tool for understanding the roles of sphingolipids in biology and disease. J Lipid Res 50 (Suppl), S97S102.
  • 42
    Hannun YA & Obeid LM (2011) Many ceramides. J Biol Chem 286, 2785527862.
  • 43
    Mizutani Y, Kihara A & Igarashi Y (2005) Mammalian Lass6 and its related family members regulate synthesis of specific ceramides. Biochem J 390, 263271.
  • 44
    Hornemann T, Penno A, Rutti MF, Ernst D, Kivrak-Pfiffner F, Rohrer L & von Eckardstein A (2009) The SPTLC3 subunit of serine palmitoyltransferase generates short chain sphingoid bases. J Biol Chem 284, 2632226330.
  • 45
    Han G, Gupta SD, Gable K, Niranjanakumari S, Moitra P, Eichler F, Brown RH Jr, Harmon JM & Dunn TM (2009) Identification of small subunits of mammalian serine palmitoyltransferase that confer distinct acyl-CoA substrate specificities. Proc Natl Acad Sci USA 106, 81868191.
  • 46
    Varki A, Freeze HH & Manzi AE (2001) Overview of glycoconjugate analysis. Curr Protoc Protein Sci Chapter 12, Unit 12 11.
  • 47
    Liang YJ, Kuo HH, Lin CH, Chen YY, Yang BC, Cheng YY, Yu AL, Khoo KH & Yu J (2010) Switching of the core structures of glycosphingolipids from globo- and lacto- to ganglio-series upon human embryonic stem cell differentiation. Proc Natl Acad Sci USA 107, 2256422569.
  • 48
    Liang YJ, Yang BC, Chen JM, Lin YH, Huang CL, Cheng YY, Hsu CY, Khoo KH, Shen CN & Yu J (2011) Changes in glycosphingolipid composition during differentiation of human embryonic stem cells to ectodermal or endodermal lineages. Stem Cells 29, 19952004.
  • 49
    Liu H, Kojima N, Kurosawa N & Tsuji S (1997) Regulated expression system for GD3 synthase cDNA and induction of differentiation in Neuro2a cells. Glycobiology 7, 10671076.
  • 50
    Osanai T, Watanabe Y & Sanai Y (1997) Glycolipid sialyltransferases are enhanced during neural differentiation of mouse embryonic carcinoma cells, P19. Biochem Biophys Res Commun 241, 327333.
  • 51
    Hirschberg K, Zisling R, van Echten-Deckert G & Futerman AH (1996) Ganglioside synthesis during the development of neuronal polarity. Major changes occur during axonogenesis and axon elongation, but not during dendrite growth or synaptogenesis. J Biol Chem 271, 1487614882.
  • 52
    Jacewicz MS, Acheson DW, Mobassaleh M, Donohue-Rolfe A, Balasubramanian KA & Keusch GT (1995) Maturational regulation of globotriaosylceramide, the Shiga-like toxin 1 receptor, in cultured human gut epithelial cells. J Clin Invest 96, 13281335.
  • 53
    Ngamukote S, Yanagisawa M, Ariga T, Ando S & Yu RK (2007) Developmental changes of glycosphingolipids and expression of glycogenes in mouse brains. J Neurochem 103, 23272341.
  • 54
    Hettmer S, McCarter R, Ladisch S & Kaucic K (2004) Alterations in neuroblastoma ganglioside synthesis by induction of GD1b synthase by retinoic acid. Br J Cancer 91, 389397.
  • 55
    Sampaio JL, Gerl MJ, Klose C, Ejsing CS, Beug H, Simons K & Shevchenko A (2011) Membrane lipidome of an epithelial cell line. Proc Natl Acad Sci USA 108, 19031907.
  • 56
    Zuberbier T, Guhl S, Hantke T, Hantke C, Welker P, Grabbe J & Henz BM (1999) Alterations in ganglioside expression during the differentiation of human mast cells. Exp Dermatol 8, 380387.
  • 57
    Maccioni HJ, Quiroga R & Spessott W (2011b) Organization of the synthesis of glycolipid oligosaccharides in the Golgi complex. FEBS Lett 585, 16911698.
  • 58
    Uliana AS, Crespo PM, Martina JA, Daniotti JL & Maccioni HJ (2006) Modulation of GalT1 and SialT1 sub-Golgi localization by SialT2 expression reveals an organellar level of glycolipid synthesis control. J Biol Chem 281, 3285232860.
  • 59
    Sprong H, Degroote S, Nilsson T, Kawakita M, Ishida N, van der Sluijs P & van Meer G (2003) Association of the Golgi UDP-galactose transporter with UDP-galactose:ceramide galactosyltransferase allows UDP-galactose import in the endoplasmic reticulum. Mol Biol Cell 14, 34823493.
  • 60
    Takematsu H, Yamamoto H, Naito-Matsui Y, Fujinawa R, Tanaka K, Okuno Y, Tanaka Y, Kyogashima M, Kannagi R & Kozutsumi Y (2011) Quantitative transcriptomic profiling of branching in a glycosphingolipid biosynthetic pathway. J Biol Chem 286, 2721427224.
  • 61
    Giraudo CG, Daniotti JL & Maccioni HJ (2001) Physical and functional association of glycolipid N-acetyl-galactosaminyl and galactosyl transferases in the Golgi apparatus. Proc Natl Acad Sci USA 98, 16251630.
  • 62
    Giraudo CG & Maccioni HJ (2003) Ganglioside glycosyltransferases organize in distinct multienzyme complexes in CHO-K1 cells. J Biol Chem 278, 4026240271.
  • 63
    Chia J, Goh G, Racine V, Ng S, Kumar P & Bard F (2012) RNAi screening reveals a large signaling network controlling the Golgi apparatus in human cells. Mol Syst Biol 8, 629.
  • 64
    Snijder B, Sacher R, Ramo P, Damm EM, Liberali P & Pelkmans L (2009) Population context determines cell-to-cell variability in endocytosis and virus infection. Nature 461, 520523.
  • 65
    Kumagai T, Tanaka M, Yokoyama M, Sato T, Shinkai T & Furukawa K (2009) Early lethality of beta-1,4-galactosyltransferase V-mutant mice by growth retardation. Biochem Biophys Res Commun 379, 456459.
  • 66
    Yamashita T, Hashiramoto A, Haluzik M, Mizukami H, Beck S, Norton A, Kono M, Tsuji S, Daniotti JL, Werth N, et al. (2003) Enhanced insulin sensitivity in mice lacking ganglioside GM3. Proc Natl Acad Sci USA 100, 34453449.
  • 67
    Niimi K, Nishioka C, Miyamoto T, Takahashi E, Miyoshi I, Itakura C & Yamashita T (2011) Impairment of neuropsychological behaviors in ganglioside GM3-knockout mice. Biochem Biophys Res Commun 406, 524528.
  • 68
    Yoshikawa M, Go S, Takasaki K, Kakazu Y, Ohashi M, Nagafuku M, Kabayama K, Sekimoto J, Suzuki S, Takaiwa K, et al. (2009) Mice lacking ganglioside GM3 synthase exhibit complete hearing loss due to selective degeneration of the organ of Corti. Proc Natl Acad Sci USA 106, 94839488.
  • 69
    Takamiya K, Yamamoto A, Furukawa K, Yamashiro S, Shin M, Okada M, Fukumoto S, Haraguchi M, Takeda N, Fujimura K, et al. (1996) Mice with disrupted GM2/GD2 synthase gene lack complex gangliosides but exhibit only subtle defects in their nervous system. Proc Natl Acad Sci USA 93, 1066210667.
  • 70
    Takamiya K, Yamamoto A, Furukawa K, Zhao J, Fukumoto S, Yamashiro S, Okada M, Haraguchi M, Shin M, Kishikawa M, et al. (1998) Complex gangliosides are essential in spermatogenesis of mice: possible roles in the transport of testosterone. Proc Natl Acad Sci USA 95, 1214712152.
  • 71
    Sheikh KA, Sun J, Liu Y, Kawai H, Crawford TO, Proia RL, Griffin JW & Schnaar RL (1999) Mice lacking complex gangliosides develop Wallerian degeneration and myelination defects. Proc Natl Acad Sci USA 96, 75327537.
  • 72
    Chiavegatto S, Sun J, Nelson RJ & Schnaar RL (2000) A functional role for complex gangliosides: motor deficits in GM2/GD2 synthase knockout mice. Exp Neurol 166, 227234.
  • 73
    Wu G, Lu ZH, Kulkarni N, Amin R & Ledeen RW (2011) Mice lacking major brain gangliosides develop parkinsonism. Neurochem Res 36, 17061714.
  • 74
    Handa Y, Ozaki N, Honda T, Furukawa K, Tomita Y, Inoue M, Okada M & Sugiura Y (2005) GD3 synthase gene knockout mice exhibit thermal hyperalgesia and mechanical allodynia but decreased response to formalin-induced prolonged noxious stimulation. Pain 117, 271279.
  • 75
    Okada M, Itoh Mi M, Haraguchi M, Okajima T, Inoue M, Oishi H, Matsuda Y, Iwamoto T, Kawano T, Fukumoto S, et al. (2002) b-series Ganglioside deficiency exhibits no definite changes in the neurogenesis and the sensitivity to Fas-mediated apoptosis but impairs regeneration of the lesioned hypoglossal nerve. J Biol Chem 277, 16331636.
  • 76
    Kawai H, Allende ML, Wada R, Kono M, Sango K, Deng C, Miyakawa T, Crawley JN, Werth N, Bierfreund U, et al. (2001) Mice expressing only monosialoganglioside GM3 exhibit lethal audiogenic seizures. J Biol Chem 276, 68856888.
  • 77
    Inoue M, Fujii Y, Furukawa K, Okada M, Okumura K, Hayakawa T & Sugiura Y (2002) Refractory skin injury in complex knock-out mice expressing only the GM3 ganglioside. J Biol Chem 277, 2988129888.
  • 78
    Coetzee T, Fujita N, Dupree J, Shi R, Blight A, Suzuki K & Popko B (1996) Myelination in the absence of galactocerebroside and sulfatide: normal structure with abnormal function and regional instability. Cell 86, 209219.
  • 79
    Kuan CT, Chang J, Mansson JE, Li J, Pegram C, Fredman P, McLendon RE & Bigner DD (2010) Multiple phenotypic changes in mice after knockout of the B3gnt5 gene, encoding Lc3 synthase – a key enzyme in lacto-neolacto ganglioside synthesis. BMC Dev Biol 10, 114.
  • 80
    Patwardhan GA & Liu YY (2011) Sphingolipids and expression regulation of genes in cancer. Prog Lipid Res 50, 104114.
  • 81
    Mirkin BL, Clark SH & Zhang C (2002) Inhibition of human neuroblastoma cell proliferation and EGF receptor phosphorylation by gangliosides GM1, GM3, GD1A and GT1B. Cell Prolif 35, 105115.
  • 82
    Kovbasnjuk O, Mourtazina R, Baibakov B, Wang T, Elowsky C, Choti MA, Kane A & Donowitz M (2005) The glycosphingolipid globotriaosylceramide in the metastatic transformation of colon cancer. Proc Natl Acad Sci USA 102, 1908719092.
  • 83
    Furukawa K, Hamamura K, Ohkawa Y & Ohmi Y (2012) Disialyl gangliosides enhance tumor phenotypes with differential modalities. Glycoconj J 29, 579584.
  • 84
    Hamamura K, Furukawa K, Hayashi T, Hattori T, Nakano J, Nakashima H, Okuda T, Mizutani H, Hattori H, Ueda M, et al. (2005) Ganglioside GD3 promotes cell growth and invasion through p130Cas and paxillin in malignant melanoma cells. Proc Natl Acad Sci USA 102, 1104111046.
  • 85
    Hamamura K, Tsuji M, Ohkawa Y, Nakashima H, Miyazaki S, Urano T, Yamamoto N, Ueda M & Furukawa K (2008) Focal adhesion kinase as well as p130Cas and paxillin is crucially involved in the enhanced malignant properties under expression of ganglioside GD3 in melanoma cells. Biochim Biophys Acta 1780, 513519.
  • 86
    Ohkawa Y, Miyazaki S, Miyata M, Hamamura K & Furukawa K (2008) Essential roles of integrin-mediated signaling for the enhancement of malignant properties of melanomas based on the expression of GD3. Biochem Biophys Res Commun 373, 1419.
  • 87
    Hamamura K, Tsuji M, Hotta H, Ohkawa Y, Takahashi M, Shibuya H, Nakashima H, Yamauchi Y, Hashimoto N, Hattori H, et al. (2011) Functional activation of Src family kinase yes protein is essential for the enhanced malignant properties of human melanoma cells expressing ganglioside GD3. J Biol Chem 286, 1852618537.
  • 88
    Yoshida S, Fukumoto S, Kawaguchi H, Sato S, Ueda R & Furukawa K (2001) Ganglioside G(D2) in small cell lung cancer cell lines: enhancement of cell proliferation and mediation of apoptosis. Cancer Res 61, 42444252.
  • 89
    Shibuya H, Hamamura K, Hotta H, Matsumoto Y, Nishida Y, Hattori H, Furukawa K & Ueda M (2012) Enhancement of malignant properties of human osteosarcoma cells with disialyl gangliosides GD2/GD3. Cancer Sci 103, 16561664.
  • 90
    Hyuga S, Yamagata S, Tai T & Yamagata T (1997) Inhibition of highly metastatic FBJ-LL cell migration by ganglioside GD1a highly expressed in poorly metastatic FBJ-S1 cells. Biochem Biophys Res Commun 231, 340343.
  • 91
    Hu D, Man Z, Wang P, Tan X, Wang X, Takaku S, Hyuga S, Sato T, Yao X, Yamagata S, et al. (2007) Ganglioside GD1a negatively regulates matrix metalloproteinase-9 expression in mouse FBJ cell lines at the transcriptional level. Connect Tissue Res 48, 198205.
  • 92
    Wang L, Wang Y, Sato T, Yamagata S & Yamagata T (2008) Ganglioside GD1a suppresses TNFalpha expression via Pkn1 at the transcriptional level in mouse osteosarcoma-derived FBJ cells. Biochem Biophys Res Commun 371, 230235.
  • 93
    Cao T, Zhang T, Wang L, Zhang L, Adachi T, Sato T, Yamagata S & Yamagata T (2010) Ganglioside GD1a suppression of NOS2 expression via ERK1 pathway in mouse osteosarcoma FBJ cells. J Cell Biochem 110, 11651174.
  • 94
    Zhang L, Wang Y, Wang L, Cao T, Hyuga S, Sato T, Wu Y, Yamagata S & Yamagata T (2011) Ganglioside GD1a negatively regulates hepatocyte growth factor expression through caveolin-1 at the transcriptional level in murine osteosarcoma cells. Biochim Biophys Acta 1810, 759768.
  • 95
    Hyuga S, Kawasaki N, Hyuga M, Ohta M, Shibayama R, Kawanishi T, Yamagata S, Yamagata T & Hayakawa T (2001) Ganglioside GD1a inhibits HGF-induced motility and scattering of cancer cells through suppression of tyrosine phosphorylation of c-Met. Int J Cancer 94, 328334.
  • 96
    Wang X, Sun P, Al-Qamari A, Tai T, Kawashima I & Paller AS (2001) Carbohydrate–carbohydrate binding of ganglioside to integrin alpha(5) modulates alpha(5)beta(1) function. J Biol Chem 276, 84368444.
  • 97
    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, 3554535553.
  • 98
    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, 81238133.
  • 99
    Coskun U, Grzybek M, Drechsel D & Simons K (2011) Regulation of human EGF receptor by lipids. Proc Natl Acad Sci USA 108, 90449048.
  • 100
    Liu Y, Su Y, Wiznitzer M, Epifano O & Ladisch S (2008) Ganglioside depletion and EGF responses of human GM3 synthase-deficient fibroblasts. Glycobiology 18, 593601.
  • 101
    Park SY, Kwak CY, Shayman JA & Kim JH (2012) Globoside promotes activation of ERK by interaction with the epidermal growth factor receptor. Biochim Biophys Acta 1820, 11411148.
  • 102
    Guan F, Handa K & Hakomori SI (2011) Regulation of epidermal growth factor receptor through interaction of ganglioside GM3 with GlcNAc of N-linked glycan of the receptor: demonstration in ldlD cells. Neurochem Res 36, 16451653.
  • 103
    Huang X, Li Y, Zhang J, Xu Y, Tian Y & Ma K (2013) Ganglioside GM3 inhibits hepatoma cell motility via down-regulating activity of EGFR and PI3K/AKT signaling pathway. J Cell Biochem 114, 16161624.
  • 104
    Milani S, Sottocornola E, Zava S, Galbiati M, Berra B & Colombo I (2010) Gangliosides influence EGFR/ErbB2 heterodimer stability but they do not modify EGF-dependent ErbB2 phosphorylation. Biochim Biophys Acta 1801, 617624.
  • 105
    Bremer EG & 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, 711718.
  • 106
    Toledo MS, Suzuki E, Handa K & Hakomori S (2004) Cell growth regulation through GM3-enriched microdomain (glycosynapse) in human lung embryonal fibroblast WI38 and its oncogenic transformant VA13. J Biol Chem 279, 3465534664.
  • 107
    Bremer EG, Hakomori S, Bowen-Pope DF, Raines E & Ross R (1984) Ganglioside-mediated modulation of cell growth, growth factor binding, and receptor phosphorylation. J Biol Chem 259, 68186825.
  • 108
    Farooqui T, Kelley T, Coggeshall KM, Rampersaud AA & Yates AJ (1999) GM1 inhibits early signaling events mediated by PDGF receptor in cultured human glioma cells. Anticancer Res 19, 50075013.
  • 109
    Mutoh T, Tokuda A, Miyadai T, Hamaguchi M & Fujiki N (1995) Ganglioside GM1 binds to the Trk protein and regulates receptor function. Proc Natl Acad Sci USA 92, 50875091.
  • 110
    Kimura M, Hidari KI, Suzuki T, Miyamoto D & Suzuki Y (2001) Engagement of endogenous ganglioside GM1a induces tyrosine phosphorylation involved in neuron-like differentiation of PC12 cells. Glycobiology 11, 335343.
  • 111
    Saha N, Kolev MV, Semavina M, Himanen J & Nikolov DB (2011) Ganglioside mediate the interaction between Nogo receptor 1 and LINGO-1. Biochem Biophys Res Commun 413, 9297.
  • 112
    Chung TW, Kim SJ, Choi HJ, Kim KJ, Kim MJ, Kim SH, Lee HJ, Ko JH, Lee YC, Suzuki A, et al. (2009) Ganglioside GM3 inhibits VEGF/VEGFR-2-mediated angiogenesis: direct interaction of GM3 with VEGFR-2. Glycobiology 19, 229239.
  • 113
    Kim SJ, Chung TW, Choi HJ, Kwak CH, Song KH, Suh SJ, Kwon KM, Chang YC, Park YG, Chang HW, et al. (2013) Ganglioside GM3 participates in the TGF-beta1-induced epithelial-mesenchymal transition of human lens epithelial cells. Biochem J 449, 241251.
  • 114
    Kabayama K, Sato T, Saito K, Loberto N, Prinetti A, Sonnino S, Kinjo M, Igarashi Y & Inokuchi J (2007) Dissociation of the insulin receptor and caveolin-1 complex by ganglioside GM3 in the state of insulin resistance. Proc Natl Acad Sci USA 104, 1367813683.
  • 115
    Tagami S, Inokuchi Ji J, Kabayama K, Yoshimura H, Kitamura F, Uemura S, Ogawa C, Ishii A, Saito M, Ohtsuka Y, et al. (2002) Ganglioside GM3 participates in the pathological conditions of insulin resistance. J Biol Chem 277, 30853092.
  • 116
    Sekino-Suzuki N, Yuyama K, Miki T, Kaneda M, Suzuki H, Yamamoto N, Yamamoto T, Oneyama C, Okada M & Kasahara K (2013) Involvement of gangliosides in the process of Cbp/PAG phosphorylation by Lyn in developing cerebellar growth cones. J Neurochem 124, 514522.
  • 117
    Bremer EG, Schlessinger J & 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, 24342440.
  • 118
    Hanai N, Nores GA, MacLeod C, Torres-Mendez CR & Hakomori S (1988) Ganglioside-mediated modulation of cell growth. Specific effects of GM3 and lyso-GM3 in tyrosine phosphorylation of the epidermal growth factor receptor. J Biol Chem 263, 1091510921.
  • 119
    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, 1620416209.
  • 120
    Park SY, Yoon SJ, Freire-de-Lima L, Kim JH & Hakomori SI (2009) Control of cell motility by interaction of gangliosides, tetraspanins, and epidermal growth factor receptor in A431 versus KB epidermoid tumor cells. Carbohydr Res 344, 14791486.
  • 121
    Toledo MS, Suzuki E, Handa K & Hakomori S (2005) Effect of ganglioside and tetraspanins in microdomains on interaction of integrins with fibroblast growth factor receptor. J Biol Chem 280, 1622716234.
  • 122
    Nakayama H, Ogawa H, Takamori K & Iwabuchi K (2013) GSL-enriched membrane microdomains in innate immune responses. Arch Immunol Ther Exp (Warsz) 61, 217228.
  • 123
    Wang XQ, Yan Q, Sun P, Liu JW, Go L, McDaniel SM & Paller AS (2007) Suppression of epidermal growth factor receptor signaling by protein kinase C-alpha activation requires CD82, caveolin-1, and ganglioside. Cancer Res 67, 99869995.
  • 124
    Wang XQ, Sun P & Paller AS (2002) Ganglioside induces caveolin-1 redistribution and interaction with the epidermal growth factor receptor. J Biol Chem 277, 4702847034.
  • 125
    Duan J, Zhang J, Zhao Y, Yang F & Zhang X (2006) Ganglioside GM2 modulates the erythrocyte Ca2+-ATPase through its binding to the calmodulin-binding domain and its ‘receptor’. Arch Biochem Biophys 454, 155159.
  • 126
    Boscher C, Zheng YZ, Lakshminarayan R, Johannes L, Dennis JW, Foster LJ & Nabi IR (2012) Galectin-3 protein regulates mobility of N-cadherin and GM1 ganglioside at cell-cell junctions of mammary carcinoma cells. J Biol Chem 287, 3294032952.
  • 127
    Wang J, Lu ZH, Gabius HJ, Rohowsky-Kochan C, Ledeen RW & Wu G (2009) Cross-linking of GM1 ganglioside by galectin-1 mediates regulatory T cell activity involving TRPC5 channel activation: possible role in suppressing experimental autoimmune encephalomyelitis. J Immunol 182, 40364045.
  • 128
    Handa K & Hakomori SI (2012) Carbohydrate to carbohydrate interaction in development process and cancer progression. Glycoconj J 29, 627637.
  • 129
    Kojima N & Hakomori S (1991) Cell adhesion, spreading, and motility of GM3-expressing cells based on glycolipid-glycolipid interaction. J Biol Chem 266, 1755217558.
  • 130
    Santacroce PV & Basu A (2003) Probing specificity in carbohydrate–carbohydrate interactions with micelles and Langmuir monolayers. Angew Chem Int Ed Engl 42, 9598.
  • 131
    Simons K & Ikonen E (1997) Functional rafts in cell membranes. Nature 387, 569572.
  • 132
    Regina Todeschini A & Hakomori SI (2008) Functional role of glycosphingolipids and gangliosides in control of cell adhesion, motility, and growth, through glycosynaptic microdomains. Biochim Biophys Acta 1780, 421433.
  • 133
    Munro S (2003) Lipid rafts: elusive or illusive? Cell 115, 377388.
  • 134
    Simons K & Gerl MJ (2010) Revitalizing membrane rafts: new tools and insights. Nat Rev Mol Cell Biol 11, 688699.
  • 135
    Eggeling C, Ringemann C, Medda R, Schwarzmann G, Sandhoff K, Polyakova S, Belov VN, Hein B, von Middendorff C, Schonle A, et al. (2009) Direct observation of the nanoscale dynamics of membrane lipids in a living cell. Nature 457, 11591162.
  • 136
    Toulmay A & Prinz WA (2013) Direct imaging reveals stable, micrometer-scale lipid domains that segregate proteins in live cells. J Cell Biol 202, 3544.
  • 137
    Mishra S & Joshi PG (2007) Lipid raft heterogeneity: an enigma. J Neurochem 103 (Suppl 1), 135142.
  • 138
    Vyas KA, Patel HV, Vyas AA & Schnaar RL (2001) Segregation of gangliosides GM1 and GD3 on cell membranes, isolated membrane rafts, and defined supported lipid monolayers. Biol Chem 382, 241250.
  • 139
    Gomez-Mouton C, Abad JL, Mira E, Lacalle RA, Gallardo E, Jimenez-Baranda S, Illa I, Bernad A, Manes S & Martinez AC (2001) Segregation of leading-edge and uropod components into specific lipid rafts during T cell polarization. Proc Natl Acad Sci USA 98, 96429647.
  • 140
    Kiyokawa E, Baba T, Otsuka N, Makino A, Ohno S & Kobayashi T (2005) Spatial and functional heterogeneity of sphingolipid-rich membrane domains. J Biol Chem 280, 2407224084.
  • 141
    Tivodar S, Paladino S, Pillich R, Prinetti A, Chigorno V, van Meer G, Sonnino S & Zurzolo C (2006) Analysis of detergent-resistant membranes associated with apical and basolateral GPI-anchored proteins in polarized epithelial cells. FEBS Lett 580, 57055712.
  • 142
    Ohmi Y, Tajima O, Ohkawa Y, Mori A, Sugiura Y & Furukawa K (2009) Gangliosides play pivotal roles in the regulation of complement systems and in the maintenance of integrity in nerve tissues. Proc Natl Acad Sci USA 106, 2240522410.
  • 143
    Kaiser HJ, Lingwood D, Levental I, Sampaio JL, Kalvodova L, Rajendran L & Simons K (2009) Order of lipid phases in model and plasma membranes. Proc Natl Acad Sci USA 106, 1664516650.
  • 144
    Contreras FX, Ernst AM, Haberkant P, Bjorkholm P, Lindahl E, Gonen B, Tischer C, Elofsson A, von Heijne G, Thiele C, et al. (2012) Molecular recognition of a single sphingolipid species by a protein's transmembrane domain. Nature 481, 525529.
  • 145
    Park H, Haynes CA, Nairn AV, Kulik M, Dalton S, Moremen K & Merrill AH Jr (2010) Transcript profiling and lipidomic analysis of ceramide subspecies in mouse embryonic stem cells and embryoid bodies. J Lipid Res 51, 480489.
  • 146
    Pagano RE & Chen CS (1998) Use of BODIPY-labeled sphingolipids to study membrane traffic along the endocytic pathway. Ann N Y Acad Sci 845, 152160.
  • 147
    Marks DL, Bittman R & Pagano RE (2008) Use of Bodipy-labeled sphingolipid and cholesterol analogs to examine membrane microdomains in cells. Histochem Cell Biol 130, 819832.
  • 148
    Levery SB (2005) Glycosphingolipid structural analysis and glycosphingolipidomics. Methods Enzymol 405, 300369.
  • 149
    Sugiura Y & Setou M (2010) Imaging mass spectrometry for visualization of drug and endogenous metabolite distribution: toward in situ pharmacometabolomes. J Neuroimmune Pharmacol 5, 3143.
  • 150
    Heyningen SV (1974) Cholera toxin: interaction of subunits with ganglioside GM1. Science 183, 656657.
  • 151
    Jacewicz M, Clausen H, Nudelman E, Donohue-Rolfe A & Keusch GT (1986) Pathogenesis of shigella diarrhea. XI. Isolation of a shigella toxin-binding glycolipid from rabbit jejunum and HeLa cells and its identification as globotriaosylceramide. J Exp Med 163, 13911404.
  • 152
    Psotka MA, Obata F, Kolling GL, Gross LK, Saleem MA, Satchell SC, Mathieson PW & Obrig TG (2009) Shiga toxin 2 targets the murine renal collecting duct epithelium. Infect Immun 77, 959969.
  • 153
    Haberkant P, Schmitt O, Contreras FX, Thiele C, Hanada K, Sprong H, Reinhard C, Wieland FT & Brugger B (2008) Protein-sphingolipid interactions within cellular membranes. J Lipid Res 49, 251262.
  • 154
    Brustle O (2013) Developmental neuroscience: miniature human brains. Nature 501, 319320.