- freely available
Cells 2013, 2(4), 751-767; doi:10.3390/cells2040751
Abstract: Gangliosides, the glycosphingolipids carrying one or several sialic acid residues, are located on the outer leaflet of the plasma membrane in glycolipid-enriched microdomains, where they interact with molecules of signal transduction pathways including receptors tyrosine kinases (RTKs). The role of gangliosides in the regulation of signal transduction has been reported in many cases and in a large number of cell types. In this review, we summarize the current knowledge on the biosynthesis of gangliosides and the mechanism by which they regulate RTKs signaling.
Gangliosides are glycosphingolipids (GSL) carrying one or several sialic acid residues. According to Svennerholm, gangliosides are classified in four series (0-, a-, b-, and c-series) due to the number of sialic acid residues linked to the lactosylceramide (LacCer) (Figure 1) . Normal human tissues mainly express ‘simple’ gangliosides, from 0- and a-series, whereas ‘complex’ gangliosides from b- and c-series are essentially found in developing tissues, during embryogenesis, and mainly restricted to the nervous system of healthy adults . In humans, the expression of complex gangliosides increases uder pathological conditions including neurodegenerative disorders , immune diseases , and cacers . For example, GD3 and GD2 are over-expressed in neuroectoderm-derived tumors such as melanoma, neuroblastoma, and breast cancer, in which they mediate cell proliferation, migration, tumor growth, and angiogenesis . Gangliosides are located on the outer layer of the plasma membrane mainly in glycolipid-enriched microdomains (GEMs), also known as lipid rafts or gangliosides-rich lipid domains. As GEMs are insoluble in detergents at 4 °C, they are also known as detergent-resistant membrane domains. Together with cholesterol, transmembrane proteins, and other glycosphingolipids, gangliosides contribute to the maintenance and dynamic of the membrane organzation. Notably, ganglioside-rich lipid domains are described components of caveolae .
Quantitative or qualitative (i.e., changes in carbohydrate moiety) modifications of gangliosides can affect GEMs architecture and functions . Amongst the membrane-bound proteins associated to GEMs, many components of signal transduction pathways were identified. The role of GEMs-associated gangliosides in the regulation of signal transduction has been repeatedly reported in a variety of cell lines [9,10,11]. However, the molecular mechanisms sustaining these functions are poorly known. Apprehending the structural heterogeneity and the diversity of interactions between gangliosides and the other components of GEMs should therefore lead to a better understanding of the fine regulation of signal transduction. This has been eased by recent advances in structural analysis of GEMs glycolipids and by the identification of GEMs associated molecules, as reviewed herein.
2. Biosynthesis of Gangliosides
The first step of the biosynthesis of gangliosides is the transfer of a glucose residue onto ceramide (Cer) by the UDP-Glc: ceramide β-glucosyltransferase (GlcCer synthase) encoded by the UGCG gene (Table 1) . The next step is the conversion of the glucosylceramide (GlcCer) into lactosylceramide (LacCer), the precursor of the five series of GSL, by the UDP-Gal: GlcCer β1,4-galactosyltransferase (LacCer synthase) [13,14]. The transfer of sialic acid residue to LacCer is then catalyzed by the specific sialyltransferases ST3Gal V (GM3 synthase), ST8Sia I (GD3 synthase) and ST8Sia V (GT3 synthase), all being highly specific for glycolipid substrates . LacCer is the only known substrate for ST3Gal V activity  and a loss-of-function mutation in ST3GAL5 gene is associated with the infantile-onset symptomatic epilepsy syndrome . The GD3 synthase ST8Sia I is highly specific for GM3 as acceptor substrate . However, the human enzyme was also shown to resialylate its own product GD3 creating a chain of 3 (GT3), 4 (GQ3), or 5 (GP3) sialic acid residues, GQ3 and GP3 being unusual structures recently described [19,20]. The human ST8Sia V exhibits a broader activity toward gangliosides, using GD3, but also GM1b, GD1a or GT1b as acceptors . LacCer, GM3, GD3, and GT3 are the precursors for 0-, a-, b-, and c-series gangliosides, respectively (Figure 1). Further, monosaccharides can be transferred in a stepwise manner by the β1,4-N-acetyl-galactosaminyltransferase I (GM2/GD2 synthase)  and the β1,3-galactosyltransferase IV (GM1a/GD1b synthase) , both acting on the four series of gangliosides [24,25]. The terminal Gal residue of the Galβ1-3GalNAc disaccharide can be further sialylated by ST3Gal II [26,27] and ST8Sia V , and the GalNAc residue can be sialylated in α2,6-linkage by the sialyltransferases ST6GalNAc III  or V  to form α-gangliosides (Figure 1).
|Gene||Common name||Main acceptors||Accession #||Ref.|
|B4GALT6||LacCer synthase||Glucosylceramide||NM_004775||(13, 14)|
|ST8SIA1||GD3 synthase||GM3, GD3||NM_003034.2||(18)|
|ST8SIA5||GT3 synthase||GD3, GM1b, GD1a, GT1b||NM_013305||(21)|
|B4GALNACT1||GM2/GD2 synthase||GA3, GM3, GD3, GT3||NM_001478.2||(22)|
|B3GALT4||GM1a/GD1b synthase||GA2, GM2, GD2, GT2||NM_003782.3||(23)|
|ST3GAL2||ST3Gal II||Galβ1-3GalNAc-R||NM_006927||(26, 27)|
The first steps of gangliosides synthesis take place in the cis/median-Golgi and the later steps in the trans-Golgi and trans-Golgi network . The regulation of glycosyltransferases (GT) activity is mainly achieved at the transcriptional level  and GT genes expression is highly tissue-specific. For example, human B4GALNACT1 gene is essentially expressed in embryonic tissue and in adult brain, lung and testis. By contrast, ST3GAL5 is ubiquitously expressed in human tissues [16,32,33]. GT involved in the synthesis of gangliosides can be also regulated by post translational modifications such as N-glycosylation, phosphorylation, and dephosphorylation. For example, protein kinases PKA and PKC can activate the GM2/GD2 synthase while inhibiting the activity of ST3Gal II or GM1a/GD1b synthase [34,35,36].
3. Regulation of RTKs Signaling by Gangliosides
Receptor tyrosine kinases (RTKs) are key proteins involved in the control of cellular processes such as survival, proliferation, differentiation, migration and invasion. Fifty-eight RTKs have been identified in Humans. They all share a similar structural organization comprising of an extracellular domain containing the ligand-binding site, a unique transmembrane domain, and a cytoplasmic region containing the tyrosine kinase activity . Usually, RTKs are activated by the binding of the ligand that induces receptor dimerization and the autophosphorylation of the intracellular domain. The role of gangliosides as modulators of signal transduction was first analyzed in the 80’ by the addition of exogenous gangliosides in the medium of cultured cells . However, this approach was rather limited by the unavailability of some specific gangliosides and because it not only modifies the gangliosides pattern but also increases the total amount of cell-membrane-associated gangliosides that can result in non-physiological responses . From 2000, with the progress in the identification of gangliosides biosynthetic enzymes, an increasing number of papers have reported ectopic expression or antisense inhibition strategies targeting specific GT to finely analyze the role of specific gangliosides without modifying the total amount of GSLs. These different approaches have clearly demonstrated that gangliosides are fine regulators of RTKs signaling and that physio-pathological changes in cell membrane ganglioside composition result in different cellular responses [40,41] (Figure 2).
A number of growth factor receptors, including receptors for epidermal growth factor (EGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), nerve growth factor (NGF), hepatocyte growth factor (HGF), and insulin, were demonstrated to be regulated by gangliosides. RTKs are localized in GEMs with other lipid rafts associated proteins including integrins, tetraspanins, or plexins. Within lipid rafts, RTKs signaling can be negatively or positively regulated by gangliosides by either direct or indirect interactions [7,42]. Changes in gangliosides modify the molecular composition and the structure of glycolipid-enriched microdomains, leading to the reorganization and/or the exclsion of RTKs from GEMs [43,44,45]. Finally, it was also demonstrated that the crosstalk between RTKs subunits and other lipid rafts associated proteins is also regulated by gangliosides.
3.1. Epidermal Growth Factor Receptor (EGFR)
Several studies have shown that GM3 is able to bind to the extracellular domain and inhibit the kinase activity of EGFR in a variety of cell lines. The effect of gangliosides on EGF-dependent tyrosine phosphorylation of EGFR was first demonstrated in human epidermoid carcinoma cell line A431 . GM3 added exogenously to cells in culture was shown to inhibit EGFR autophosphorylation [38,46] whereas de-N-acetyl-GM3 (II3NeuNH2LacCer) enhances serine phosphorylation independently of receptor-receptor interaction [47,48]. Similarly, depletion of GM3 in A431 cells by PDMP (d-threo-1-phenyl-2-decannoylamino-3-morpholino-1-propanol), which inhibits the GlcCer synthase, increased EGFR autophosphorylation upon EGF stimulation . GM3 directly interacts with EGFR on a site distinct from the EGF-binding site  through direct carbohydrate-carbohydrate interactions between GM3 and terminal GlcNAc residues on EGFR N-glycans [51,52]. GM3 binding to EGFR is enhanced after glycosidase-treatment that exposes N-glycan terminal GlcNAc, whereas GM3 does not bind to EGFR from ManIB-knocked down cells that accumulates high mannose-type (i.e., immature form lacking terminal GlcNAc) N-glycans . This was further confirmed using UDP-Gal 4-epimerase defective ldlD cells transfected with EGFR gene, in which high amount of terminal GlcNAc residues (that accumulate due to the lack of UDP-Gal) is correlated with an inhibitory effect of GM3 on EGFR . GM3 was also shown to suppress murine hepatoma cell motility by inhibiting EGFR phosphorylation and the downstream PI3K/Akt signaling pathway .
More recently, it has been reported that GM3 and the tetraspanin tumor suppressor CD82 induce synergistic inhibition of migration Hepa1-6 cells by reducing EGFR phosphorylation . By reconstituting human EGFR into proteoliposomes, it was shown that GM3 inhibits the structural transition from inactive EGFR to signaling EGFR dimer, by preventing the autophosphorylation of the intracellular kinase domain in response to ligand binding . In parallel, stable transfection of the GD3 synthase in CHO-K1 cells induces cell surface expression of GD3 and decreases EGFR phosphorlation and Erk2 activation upon EGF stimulation . Inhibition of EGFR phosphorylation and cell proliferation due to GM3, GM1, GD1a, and GT1b treatment were also reported in human neuroblastoma cells . In normal human dermal fibroblasts, GD1a promotes the ligand-independent EGFR dimerization and enhances EGFR-mediated activation of the mitogen-activated protein kinase (MAPK) signaling pathway . Accordingly, it was also shown that EGFR phosphorylation is signiicantly reduced with the knockdown of ST3Gal II, the enzyme that converts GM1 to GD1a .
3.2. Fibroblast Growth Factor Receptor (FGFR)
FGFR participates in many developmental, homeostatic and healing processes including neurogenesis, axon growth, differentiation, and neuronal survival . The negative effect of GM3 on FGFR activation and tyrosine phosphorylation was first demonstrated in cultured retinal glial cells . The interaction of GM3 with FGFR was hinted by confocal microscopy analysis in human lung embryonic fibroblast WI38, showing co-localization of GM3 and FGFR in the GEM fraction . Moreover, GM3 depletion by GlcCer synthase inhibition enhances tyrosine phosphorylation of FGFR, activates PI3K/Akt pathway and increases the interactions of FGFR with α3/α5/β1 integrins . This demonstrated that integrin-FGFR cross-talk is regulated by GM3 within the ganglioside-enriched microdomains.
3.3. Neurotrophins Receptors
It has been clearly demonstrated that GM1 ganglioside regulates neurotrophins receptors both in vivo and in cell cultures [65,66,67]. In rat pheochromocytoma PC12 cells, the addition of exogenous GM1 to cell culture enhances NGF/TrkA signaling and protects neuronal cells from serum deprivation-induced apoptosis . On the contrary, the over-expression of GM1 by the transfection of β3GalT4 cDNA, the enzyme that converts GM2 in GM1, inhibited NGF-induced TrkA dimerization and phosphorylation as well as the downstream pathway . According to the authors, this opposite effect of GM1 in PC12 was due to the high concentration of GM1 at the plasma membrane in β3GalT4 expressing cells that modulated membrane fluidity, impeding the NGF receptor localization within the lipid rafts . In parallel, the introduction of the GD3 synthase gene into PC12 cells resulted in the over-expression of GD1b and GT1b. These gangliosides triggered a conformational change of TrkA that formed a constitutively active dimer, activating its downstream signal pathways, including Erk1/2 and PI3K/Akt, and leading to a marked enhancement of cell proliferation [69,70].
3.4. Hepatocyte Growth Factor Receptor c-Met
In HCV29 bladder epithelial cells, motility and growth are modulated by the expression of a-series gangliosides. In the presence of Ca2+, GM3, and GM2 form heterodimers that specifically interact with tetraspanin CD82, thus impairing the trans-phosphorylation of c-Met receptor, the recruiting of Grb2 and the activation of PI3K/Akt and MEK/Erk pathways [44,71]. Similarly, the ganglioside-dependent activation of c-Met receptor was also recently demonstrated in breast cancer cells . The expression of the GD3 synthase in MDA-MB-231 breast cancer cells induced the cell surface accumulation of b- and c- series gangliosides including GD3, GD2, and GT3 [73,74]. Of these complex gangliosides, GD2 was found to be involved in the activation of c-Met, and the subsequent activation of MEK/Erk and PI3K/Akt signaling pathways, leading to enhanced cell migration and proliferation. This was shown by competition assays using anti-GD2 mAb that inhibited c-Met phosphorylation (Figure 3), demonstrating the role of the GD2 glycan moiety in c-Met activation . Moreover, silencing of the GM2/GD2 synthase (β4GalNAc T1) efficiently reduced both GD2 expression and c-Met phosphorylation. Of importance, the GD2-dependent activation of c-Met occurred in the absence of HGF . On the other hand, the ganglioside GD1a that belongs to the a-series, was shown to inhibit HGF-induced motility and scattering of mouse osteosarcoma cell variant FBJ-LL cells through the suppression of phosphorylation of c-Met .
3.5. Platelet-Derived Growth Factor Receptor (PDGFR)
Various gangliosides were shown to inhibit PDGF-dependent tyrosine phosphorylation of PDGFR in several cell types including Swiss 3T3 , human glioma cells , and neuroblastoma SH-SY5Y cells . Of the tested gangliosides (GM1, GM2, GM3, GD1a, GD1b, GD3, and GT1b), only GM3 did not inhibit the dimerization of PDGFR  but could facilitate PDGF-dependent receptor activation, as an anti-GM3 antibody was found to inhibit PDGF receptor activation in T51B liver epithelial cells . Amongst the gangliosides inhibiting PDGFR, GM1 was the most studied. In human glioma cells, GM1 treatment resulted in reduced phosphorylation of specific tyrosine residues of the cytoplasmic tail of PDGFR . However, it was later shown that the cytoplasmic domain of PDGFR was not required for GM1-dependent inhibition of the receptor . Indeed, GM1 inhibition of PDGFR seems to be rather due to the exclusion of the receptor from glycolipid-enriched microdomains . Recently, it was shown that the Csk binding protein PAG (Phosphoprotein Associated with Glycosphingolipid-enriched micro-domains)  regulates PDGFR partitioning in caveolae and its association with SRC family protein tyrosine kinases (SFK) by controlling GM1 levels at the plasma membrane .
3.6. Vascular Endothelial Growth Factor Receptor (VEGFR)
Several pieces of evidence have suggested that gangliosides also modulate tumor angiogenesis by controlling the activation of VEGF receptors FLT1 (VEGFR-1) and FLK1/KDR (VEGFR-2). It has been shown that ganglioside enrichment in human umbilical vein vascular endothelial cells (HUVEC) induces VEGFR dimerization and autophosphorylation at very low VEGF concentrations  and icubation of HUVEC with exogenous GD1a increases VEGF-induced proliferation and migration . GM3 is implicated in the decrease of VEGFR-2 phosphorylation and subsequent inhibition of Akt downstream signaling pathway in HUVECs [88,89]. It was also shown that GM3 decreases VEGF-induced VEGFR-2 activation by blocking receptor dimerization and the binding of VEGF to VEGFR-2 through a GM3-specific interaction with the extracellular domain of VEGFR-2 . In contrast, the elevation of the proportion of GM3 in CT-2A malignant mouse astrocytoma cells using GM2/GD2 synthase shRNA reduces tumor-induced angiogenesis . Moreover, the antisense inhibition of β3GalT4 expression in the highly angiogenic CT-2A astrocytoma cells, which mainly express GD1a, increases GM3 content while reducing GD1a and reduces growth, VEGF gene and protein expression, and vascularity . Finally, it has been recently shown using a mass spectrometry-based approach that the soluble form of VEGFR-1 (sFLT1) binds to GM3 in lipid rafts on the surface of podocytes (kidney glomerular pericytes), promoting adhesion and rapid actin reorganization [92,93].
3.7. Insulin Receptor
GM3 has been described as a negative regulator of insulin signaling, partially responsible for insulin resistance. In 3T3-L1 adipocytes, insulin resistance induced by tumor necrosis factor (TNF) is accompanied by an increased expression of GM3 synthase activity and GM3 ganglioside . The increased interaction between insulin receptor and GM3 leads to the dissociation of insulin receptor (IR) from caveolae . Moreover, inhibition of ganglioside biosynthesis by PDMP, a specific inhibitor of the GlcCer synthase, restores insulin signaling, whereas addition of exogenous GM3 inhibits the IR substrate 1 (IRS-1) phosphorylation and IR signaling pathway [94,96]. Similar results were obtained with GM3 synthase mutant mice that show an enhanced IR phosphorylation and a heightened sensitivity to insulin . In parallel, hepatic over-expression of the membrane-associated sialidase NEU3 in C57BL/6 mice reduces GM3 level in the liver, improving insulin sensitivity . It was also demonstrated that GM3 interacts with a lysine residue of IR beta-subunit localized above the transmembrane domain and induces the dissociation of the IR-caveolin-1 complex, which is essential for insulin signaling . Finally, GM1 and GM2 were also shown to inhibit IR phosphorylation in in vitro assay .
To conclude, it is now clear that gangliosides regulate RTKs within glycolipid-enriched microdomains either by inhibiting the dimerization and autophosphorylation of the receptors induced by specific ligands, or activating receptors signaling without ligand binding. Moreover, the activation or inhibition of RTKs is dependent on the glycan structure of gangliosides and cellular context. From a general point of view, monosialogangliosides, such as GM3 or GM1 can be considered as negative regulators of RTKs signaling whereas disialogangliosides including GD2, GD1a, or GD1b mostly activated RTKs-mediated signal transduction. However, the molecular mechanisms by which gangliosides regulate RTKs remain poorly understood. Direct interactions between carbohydrate moiety of gangliosides and RTKs have been clearly identified as demonstrated for GM3 inhibition of EGFR, but direct carbohydrate-carbohydrate interactions cannot explain the different observed effects. Gangliosides regulation of RTKs also involved the reorganization of GEMs due to the change in ganglioside composition that induces the dissociation of RTKs from glycolipid-enriched microdomains, resulting in a reduced phosphorylation of the receptors as it has been demonstrated for insulin receptor. Indirect interactions with other GEMs associated transmembrane proteins including integrins and tetraspanins, can also be involved in the regulation of RTKs by gangliosides, as it has been demostrated for c-Met receptor. In parallel, the regulation of RTKs by gangliosides is highly depending on the carbohydrate moiety of gangliosides as shown for c-Met receptor, which is activated by GD2 whereas GD3 has no effect. The fine recognition of the glycan part of gangliosides should involve membrane lectin domains, able to discriminate between subtle changes in ganglioside glycans. The use of emergent technologies such as glycan arrays and photocrosslinking should enable to identification of such lectin domains [101,102]. Finally, changes in ganglioside composition occur in pathological conditions and are observed in a variety of cancers, mainly in neuro-ectoderm-related cancers. The understanding of the mechanisms by which gangliosides modify RTKs signaling is therefore of first importance to identify new targets in cancer therapy.
This work was supported by the University of Sciences and Technologies of Lille, the CNRS, the Association pour la Recherche sur le Cancer (Grant #7936 and 5023), le comité du Pas-de-Calais de La Ligue contre le Cancer and the GEFLUC Lille Flandres-Artois.
Conflicts of Interest
The authors declare no conflict of interest.
- Svennerholm, L. Ganglioside designation. Adv. Exp. Med. Biol. 1980, 125, 11. [Google Scholar] [CrossRef]
- Yamashita, T.; Wada, R.; Sasaki, T.; Deng, C.; Bierfreund, U.; Sandhoff, K.; Proia, R.L. A vital role for glycosphingolipid synthesis during development and differentiation. Proc. Natl. Acad. Sci. USA. 1999, 96, 9142–9147. [Google Scholar] [CrossRef]
- Hakomori, S.I. The glycosynapse. Proc. Natl. Acad. Sci. USA. 2002, 99, 225–232. [Google Scholar] [CrossRef]
- Regina, T.A.; Hakomori, S.I. Functional role of glycosphingolipids and gangliosides in control of cell adhesion, motility, and growth, through glycosynaptic microdomains. Biochim. Biophys. Acta. 2008, 1780, 421–433. [Google Scholar] [CrossRef]
- Ariga, T.; McDonald, M.P.; Yu, R.K. Role of ganglioside metabolism in the pathogenesis of Alzheimer's disease--a review. J. Lipid Res. 2008, 49, 1157–1175. [Google Scholar] [CrossRef]
- Shahrizaila, N.; Yuki, N. Guillain-Barré syndrome animal model: the first proof of molecular mimicry in human autoimmune disorder. J. Biomed. Biotechnol. 2011, 2011, 829129. [Google Scholar]
- Miljan, E.A.; Bremer, E.G. Regulation of growth factor receptors by gangliosides. Sci. STKE. 2002, 2002, re15. [Google Scholar]
- Ohmi, Y.; Tajima, O.; Ohkawa, Y.; Mori, A.; Sugiura, Y.; Furukawa, K.; Furukawa, K. Gangliosides play pivotal roles in the regulation of complement systems and in the maintenance of integrity in nerve tissues. Proc. Natl. Acad. Sci. USA. 2009, 106, 22405–22410. [Google Scholar] [CrossRef]
- Birklé, S.; Zeng, G.; Gao, L.; Yu, R.K.; Aubry, J. Role of tumor-associated gangliosides in cancer progression. Biochimie. 2003, 85, 455–463. [Google Scholar] [CrossRef]
- Bobowski, M.; Cazet, A.; Steenackers, A.; Delannoy, P. Role of complex gangliosides in cancer progression. Carbohydr. Chem. 2012, 37, 1–20. [Google Scholar]
- Harding, A.S.; Hancock, J.F. Using plasma membrane nanoclusters to build better signaling circuits. Trends Cell Biol. 2008, 18, 364–371. [Google Scholar] [CrossRef]
- Ichikawa, S.; Sakiyama, H.; Suzuki, G.; Hidari, K.I.; Hirabayashi, Y. Expression cloning of a cDNA for human ceramide glucosyltransferase that catalyzes the first glycosylation step of glycosphingolipid synthesis. Proc. Natl. Acad. Sci. USA. 1996, 93, 4638–4643. [Google Scholar] [CrossRef]
- Nomura, T.; Takizawa, M.; Aoki, J.; Arai, H.; Inoue, K.; Wakisaka, E.; Yoshizuka, N.; Imokawa, G.; Dohmae, N.; Takio, K.; et al. Purification, cDNA cloning, and expression of UDP-Gal: glucosylceramide beta-1,4-galactosyltransferase from rat brain. J. Biol. Chem. 1998, 273, 13570–13577. [Google Scholar] [CrossRef]
- Takizawa, M.; Nomura, T.; Wakisaka, E.; Yoshizuka, N.; Aoki, J.; Arai, H.; Inoue, K.; Hattori, M.; Matsuo, N. cDNA cloning and expression of human lactosylceramide synthase. Biochim. Biophys. Acta. 1999, 1438, 301–304. [Google Scholar] [CrossRef]
- Zeng, G.; Yu, R.K. Cloning and transcriptional regulation of genes responsible for synthesis of gangliosides. Curr. Drug Targets. 2008, 9, 317–324. [Google Scholar] [CrossRef]
- Ishii, A.; Ohta, M.; Watanabe, Y.; Matsuda, K.; Ishiyama, K.; Sakoe, K.; Nakamura, M.; Inokuchi, J.; Sanai, Y.; Saito, M. Expression cloning and functional characterization of human cDNA for ganglioside GM3 synthase. J. Biol. Chem. 1998, 273, 31652–31655. [Google Scholar] [CrossRef]
- Simpson, M.A.; Cross, H.; Proukakis, C.; Priestman, D.A.; Neville, D.C.; Reinkensmeier, G.; Wang, H.; Wiznitzer, M.; Gurtz, K.; Verganelaki, A.; et al. Infantile-onset symptomatic epilepsy syndrome caused by a homozygous loss-of-function mutation of GM3 synthase. Nat. Genet. 2004, 36, 1225–1229. [Google Scholar] [CrossRef]
- Haraguchi, M.; Yamashiro, S.; Yamamoto, A.; Furukawa, K.; Takamiya, K.; Lloyd, K.O.; Shiku, H.; Furukawa, K. Isolation of GD3 synthase gene by expression cloning of GM3 alpha-2,8-sialyltransferase cDNA using anti-GD2 monoclonal antibody. Proc. Natl. Acad. Sci. USA. 1994, 91, 10455–10459. [Google Scholar] [CrossRef]
- Nakayama, J.; Fukuda, M.N.; Hirabayashi, Y.; Kanamori, A.; Sasaki, K.; Nishi, T.; Fukuda, M. Expression cloning of a human GT3 synthase. GD3 and GT3 are synthesized by a single enzyme. J. Biol. Chem. 1996, 271, 3684–3691. [Google Scholar] [CrossRef]
- Steenackers, A.; Vanbeselaere, J.; Cazet, A.; Bobowski, M.; Rombouts, Y.; Colomb, F.; Le Bourhis, X.; Guérardel, Y.; Delannoy, P. Accumulation of unusual gangliosides G(Q3) and G(P3) in breast cancer cells expressing the G(D3) synthase. Molecules. 2012, 17, 9559–9572. [Google Scholar] [CrossRef]
- Kim, Y.J.; Kim, K.S.; Do, S.; Kim, C.H.; Kim, S.K.; Lee, Y.C. Molecular cloning and expression of human alpha2,8-sialyltransferase (hST8Sia V). Biochem. Biophys. Res. Commun. 1997, 235, 327–330. [Google Scholar] [CrossRef]
- Nagata, Y.; Yamashiro, S.; Yodoi, J.; Lloyd, K.O.; Shiku, H.; Furukawa, K. Expression cloning of beta 1,4 N-acetylgalactosaminyltransferase cDNAs that determine the expression of GM2 and GD2 gangliosides. J. Biol. Chem. 1992, 267, 12082–12089. [Google Scholar]
- Amado, M.; Almeida, R.; Carneiro, F.; Levery, S.B.; Holmes, E.H.; Nomoto, M.; Hollingsworth, M.A.; Hassan, H.; Schwientek, T.; Nielsen, P.A.; et al. A family of human beta3-galactosyltransferases. Characterization of four members of a UDP-galactose: beta-N-acetyl-glucosamine/beta-N-acetyl-galactosamine beta-1,3-galactosyltransferase family. J. Biol. Chem. 1998, 273, 12770–12778. [Google Scholar] [CrossRef]
- Iber, H.; Zacharias, C.; Sandhoff, K. The c-series gangliosides GT3, GT2 and GP1c are formed in rat liver Golgi by the same set of glycosyltransferases that catalyse the biosynthesis of asialo-, a- and b-series gangliosides. Glycobiology. 1992, 2, 137–142. [Google Scholar] [CrossRef]
- Yamashiro, S.; Haraguchi, M.; Furukawa, K.; Takamiya, K.; Yamamoto, A.; Nagata, Y.; Lloyd, K.O.; Shiku, H.; Furukawa, K. Substrate specificity of beta 1,4-N-acetylgalactosaminyltransferase in vitro and in cDNA-transfected cells. GM2/GD2 synthase efficiently generates asialo-GM2 in certain cells. J. Biol. Chem. 1995, 270, 6149–6155. [Google Scholar] [CrossRef]
- Giordanengo, V.; Bannwarth, S.; Laffont, C.; Van Miegem, V.; Harduin-Lepers, A.; Delannoy, P.; Lefebvre, J.C. Cloning and expression of cDNA for a human Gal(beta1–3)GalNAc alpha2,3-sialyltransferase from the CEM T-cell line. Eur. J. Biochem. 1997, 247, 558–566. [Google Scholar]
- Sturgill, E.R.; Aoki, K.; Lopez, P.H.; Colacurcio, D.; Vajn, K.; Lorenzini, I.; Majić, S.; Yang, W.H.; Heffer, M.; Tiemeyer, M.; et al. Biosynthesis of the major brain gangliosides GD1a and GT1b. Glycobiology. 2012, 22, 1289–1301. [Google Scholar] [CrossRef]
- Tsuchida, A.; Ogiso, M.; Nakamura, Y.; Kiso, M.; Furukawa, K.; Furukawa, K. Molecular cloning and expression of human ST6GalNAc III: restricted tissue distribution and substrate specificity. J. Biochem. 2005, 138, 237–243. [Google Scholar] [CrossRef]
- Okajima, T.; Fukumoto, S.; Ito, H.; Kiso, M.; Hirabayashi, Y.; Urano, T.; Furukawa, K. Molecular cloning of brain-specific GD1alpha synthase (ST6GalNAc V) containing CAG/Glutamine repeats. J. Biol. Chem. 1999, 274, 30557–30562. [Google Scholar] [CrossRef]
- Maccioni, H.J.; Daniotti, J.L.; Martina, J.A. Organization of ganglioside synthesis in the Golgi apparatus. Biochim. Biophys. Acta. 1999, 1437, 101–118. [Google Scholar] [CrossRef]
- Nairn, A.V.; York, W.S.; Harris, K.; Hall, E.M.; Pierce, J.M.; Moremen, K.W. Regulation of gly-can structures in animal tissues: transcript profiling of glycan-related genes. J. Biol. Chem. 2008, 283, 17298–17313. [Google Scholar] [CrossRef]
- Hidari, J.K.; Ichikawa, S.; Furukawa, K.; Yamasaki, M.; Hirabayashi, Y. 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. 1994, 303, 957–965. [Google Scholar]
- Fukumoto, S.; Miyazaki, H.; Goto, G.; Urano, T.; Furukawa, K.; Furukawa, K. Expression cloning of mouse cDNA of CMP-NeuAc: Lactosylceramide alpha2,3-sialyltransferase, an enzyme that imitates the synthesis of gangliosides. J. Biol. Chem. 1999, 274, 9271–9276. [Google Scholar] [CrossRef]
- Gu, X.; Preuss, U.; Gu, T.; Yu, R.K. Regulation of sialyltransferase activities by phosphorylation and dephosphorylation. J. Neurochem. 1995, 64, 2295–2302. [Google Scholar]
- Bieberich, E.; Freischütz, B.; Liour, S.S.; Yu, R.K. Regulation of ganglioside metabolism by phosphorylation and dephosphorylation. J. Neurochem. 1998, 71, 972–979. [Google Scholar]
- Yu, R.K.; Bieberich, E. Regulation of glycosyltransferases in ganglioside biosynthesis by phosphorylation and dephosphorylation. Mol. Cell. Endocrinol. 2001, 177, 19–24. [Google Scholar] [CrossRef]
- Lemmon, M.A.; Schlessinger, J. Cell signaling by receptor tyrosine kinases. Cell 2010, 141, 1117–1134. [Google Scholar] [CrossRef]
- Bremer, E.G.; Schlessinger, J.; Hakomori, S. Ganglioside-mediated modulation of cell growth. Specific effects of GM3 on tyrosine phosphorylation of the epidermal growth factor receptor. J. Biol. Chem. 1986, 261, 2434–2440. [Google Scholar]
- Zhou, J.; Shao, H.; Cox, N.R.; Baker, H.J.; Ewald, S.J. Gangliosides enhance apoptosis of thymocytes. Cell. Immunol. 1998, 183, 90–98. [Google Scholar] [CrossRef]
- Bremer, E.G.; Hakomori, S.I. Gangliosides as receptor modulators. Adv. Exp. Med. Biol. 1984, 174, 381–394. [Google Scholar] [CrossRef]
- Hakomori, S.; Igarashi, Y. Functional role of glycosphingolipids in cell recognition and signaling. J. Biochem. 1995, 118, 1091–1103. [Google Scholar]
- Kaucic, K.; Liu, Y.; Ladisch, S. Modulation of growth factor signaling by gangliosides: positive or negative? Methods Enzymol. 2006, 417, 168–185. [Google Scholar] [CrossRef]
- Lai, A.Z.; Abella, J.V.; Park, M. Crosstalk in Met receptor oncogenesis. Trends Cell Biol. 2009, 19, 542–551. [Google Scholar] [CrossRef]
- Park, S.Y.; Yoon, S.J.; Freire-de-Lima, L.; Kim, J.H.; Hakomori, S.I. Control of cell motility by interaction of gangliosides, tetraspanins, and epidermal growth factor receptor in A431 versus KB epidermoid tumor cells. Carbohydr. Res. 2009, 344, 1479–1486. [Google Scholar] [CrossRef]
- Todeschini, A.R.; Dos Santos, J.N.; Handa, K.; Hakomori, S.I. 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. 2007, 282, 8123–8133. [Google Scholar] [CrossRef]
- Rebbaa, A.; Hurh, J.; Yamamoto, H.; Kersey, D.S.; Bremer, E.G. Ganglioside GM3 inhibition of EGF receptor mediated signal transduction. Glycobiology. 1996, 6, 399–406. [Google Scholar] [CrossRef]
- Hanai, N.; Dohi, T.; Nores, G.A.; Hakomori, S. A novel ganglioside, de-N-acetyl-GM3 (II3NeuNH2LacCer), acting as a strong promoter for epidermal growth factor receptor kinase and as a stimulator for cell growth. J. Biol. Chem. 1988, 263, 6296–6301. [Google Scholar]
- Zhou, Q.; Hakomori, S.; Kitamura, K.; Igarashi, Y. 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. 1994, 269, 1959–1965. [Google Scholar]
- Meuillet, E.J.; Mania-Farnell, B.; George, D.; Inokuchi, J.I.; Bremer, E.G. Modulation of EGF receptor activity by changes in the GM3 content in a human epidermoid carcinoma cell line, A431. Exp. Cell Res. 2000, 256, 74–82. [Google Scholar] [CrossRef]
- Miljan, E.A.; Meuillet, E.J.; Mania-Farnell, B.; George, D.; Yamamoto, H.; Simon, H.G.; Bremer, E.G. Interaction of the extracellular domain of the epidermal growth factor receptor with gangliosides. J. Biol. Chem. 2002, 277, 10108–10113. [Google Scholar] [CrossRef]
- Yoon, S.J.; Nakayama, K.; Hikita, T.; Handa, K.; Hakomori, S.I. Epidermal growth factor receptor tyrosine kinase is modulated by GM3 interaction with N-linked GlcNAc termini of the receptor. Proc. Natl. Acad. Sci. USA. 2006, 103, 18987–18991. [Google Scholar] [CrossRef]
- Kawashima, N.; Yoon, S.J.; Itoh, K.; Nakayama, K. Tyrosine kinase activity of epidermal growth factor receptor is regulated by GM3 binding through carbohydrate to carbohydrate interactions. J. Biol. Chem. 2009, 284, 6147–6155. [Google Scholar] [CrossRef]
- Guan, F.; Handa, K.; Hakomori, S.I. 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. 2011, 36, 1645–1653. [Google Scholar] [CrossRef]
- Huang, X.; Li, Y.; Zhang, J.; Xu, Y.; Tian, Y.; Ma, K. Ganglioside GM3 inhibits hepatoma cell motility via down-regulating activity of EGFR and PI3K/AKT signaling pathway. J. Cell. Biochem. 2013, 114, 1616–1624. [Google Scholar] [CrossRef]
- Li, Y.; Huang, X.; Zhang, J.; Li, Y.; Ma, K. Synergistic inhibition of cell migration by tetraspanin CD82 and gangliosides occurs via the EGFR or cMet-activated Pl3K/Akt signalling pathway. Int. J. Biochem. Cell. Biol. 2013, 45, 2349–2358. [Google Scholar] [CrossRef]
- Coskun, Ü.; Grzybek, M.; Drechsel, D.; Simons, K. Regulation of human EGF receptor by lipids. Proc. Natl. Acad. Sci. USA. 2011, 108, 9044–9048. [Google Scholar] [CrossRef]
- Zurita, A.R.; Maccioni, H.J.; Daniotti, J.L. Modulation of epidermal growth factor receptor phosphorylation by endogenously expressed gangliosides. Biochem. J. 2001, 355, 465–472. [Google Scholar] [CrossRef]
- Mirkin, B.L.; Clark, S.H.; Zhang, C. Inhibition of human neuroblastoma cell proliferation and EGF receptor phosphorylation by gangliosides GM1, GM3, GD1A and GT1B. Cell Prolif. 2002, 35, 105–115. [Google Scholar] [CrossRef]
- Liu, Y.; Li, R.; Ladisch, S. Exogenous ganglioside GD1a enhances epidermal growth factor receptor binding and dimerization. J. Biol. Chem. 2004, 279, 36481–36489. [Google Scholar] [CrossRef]
- Yang, H.J.; Jung, K.Y.; Kwak, D.H.; Lee, S.H.; Ryu, J.S.; Kim, J.S.; Chang, K.T.; Lee, J.W.; Choo, Y.K. Inhibition of ganglioside GD1a synthesis suppresses the differentiation of human mesenchymal stem cells into osteoblasts. Dev. Growth Differ. 2011, 53, 323–332. [Google Scholar] [CrossRef]
- Mudò, G.; Bonomo, A.; Di Liberto, V.; Frinchi, M.; Fuxe, K.; Belluardo, N. The FGF-2/FGFRs neurotrophic system promotes neurogenesis in the adult brain. J. Neural Transm. 2009, 116, 995–1005. [Google Scholar] [CrossRef]
- Meuillet, E.; Cremel, G.; Dreyfus, H.; Hicks, D. Differential modulation of basic fibroblast and epidermal growth factor receptor activation by ganglioside GM3 in cultured retinal Müller glia. Glia. 1996, 17, 206–216. [Google Scholar] [CrossRef]
- Toledo, M.S.; Suzuki, E.; Handa, K.; Hakomori, S. Cell growth regulation through GM3-enriched microdomain (glycosynapse) in human lung embryonal fibroblast WI38 and its oncogenic transformant VA13. J. Biol. Chem. 2004, 279, 34655–34664. [Google Scholar] [CrossRef]
- Toledo, M.S.; Suzuki, E.; Handa, K.; Hakomori, S. Effect of ganglioside and tetraspanins in microdomains on interaction of integrins with fibroblast growth factor receptor. J. Biol. Chem. 2005, 280, 16227–16234. [Google Scholar] [CrossRef]
- Mutoh, T.; Tokuda, A.; Miyadai, T.; Hamaguchi, M.; Fujiki, N. Ganglioside GM1 binds to the Trk protein and regulates receptor function. Proc. Natl. Acad. Sci. USA. 1995, 92, 5087–5091. [Google Scholar] [CrossRef]
- Rabin, S.J.; Mocchetti, I. GM1 ganglioside activates the high affinity nerve growth factor receptor trkA. J. Neurochem. 1995, 65, 347–354. [Google Scholar] [CrossRef]
- Duchemin, A.M.; Ren, Q.; Mo, L.; Neff, N.H.; Hajiconstantinou, M. GM1 ganglioside induces phosphorylation and activation of Trk and Erk in brain. J. Neurochem. 2002, 81, 696–707. [Google Scholar] [CrossRef]
- Nishio, M.; Fukumoto, S.; Furukawa, K.; Ichimura, A.; Miyazaki, H.; Kusunoki, S.; Urano, T.; Furukawa, K. Overexpressed GM1 suppresses nerve growth factor (NGF) signals by modulating the intracellular localization of NGF receptors and membrane fluidity in PC12 cells. J. Biol. Chem. 2004, 279, 33368–33378. [Google Scholar] [CrossRef]
- Fukumoto, S.; Mutoh, T.; Hasegawa, T.; Miyazaki, H.; Okada, M.; Goto, G.; Furukawa, K.; Urano, T. GD3 synthase gene expression in PC12 cells results in the continuous activation of TrkA and ERK1/2 and enhanced proliferation. J. Biol. Chem. 2000, 275, 5832–5838. [Google Scholar] [CrossRef]
- Duchemin, A.M.; Ren, Q.; Neff, N.H.; Hadjiconstantinou, M. GM1-induced activation of phosphatidylinositol 3-kinase: Involvement of Trk receptors. J. Neurochem. 2008, 104, 1466–1477. [Google Scholar] [CrossRef]
- Todeschini, A.R.; Dos Santos, J.N.; Handa, K.; Hakomori, S.I. Ganglioside GM2/GM3 complex affixed on silica nanospheres strongly inhibits cell motility through CD82/cMet-mediated pathway. Proc. Natl. Acad. Sci. USA. 2008, 105, 1925–1930. [Google Scholar] [CrossRef]
- Cazet, A.; Lefebvre, J.; Adriaenssens, E.; Julien, S.; Bobowski, M.; Grigoriadis, A.; Tutt, A.; Tulasne, D.; Le Bourhis, X.; Delannoy, P. GD3 synthase expression enhances proliferation and tumor growth of MDA-MB-231 breast cancer cells through c-Met activation. Mol. Cancer Res. 2010, 8, 1526–1535. [Google Scholar] [CrossRef]
- Cazet, A.; Groux-Degroote, S.; Teylaert, B.; Kwon, K.M.; Lehoux, S.; Slomianny, C.; Kim, C.H.; Le Bourhis, X.; Delannoy, P. GD3 synthase overexpression enhances proliferation and migration of MDA-MB-231 breast cancer cells. Biol. Chem. 2009, 390, 601–609. [Google Scholar]
- Cazet, A.; Bobowski, M.; Rombouts, Y.; Lefebvre, J.; Steenackers, A.; Popa, I.; Guérardel, Y.; Le Bourhis, X.; Tulasne, D.; Delannoy, P. The ganglioside G(D2) induces the constitutive activation of c-Met in MDA-MB-231 breast cancer cells expressing the G(D3) synthase. Glycobiology 2012, 22, 806–816. [Google Scholar] [CrossRef]
- Hyuga, S.; Kawasaki, N.; Hyuga, M.; Ohta, M.; Shibayama, R.; Kawanishi, T.; Yamagata, S.; Yamagata, T.; Hayakawa, T. Ganglioside GD1a inhibits HGF-induced motility and scattering of cancer cells through suppression of tyrosine phosphorylation of c-Met. Int. J. Cancer. 2001, 94, 328–334. [Google Scholar] [CrossRef]
- Bremer, E.G.; Hakomori, S.; Bowen-Pope, D.F.; Raines, E.; Ross, R. Ganglioside-mediated modulation of cell growth, growth factor binding, and receptor phosphorylation. J. Biol. Chem. 1984, 259, 6818–6825. [Google Scholar]
- Yates, A.J.; Saqr, H.E.; Van Brocklyn, J. Ganglioside modulation of the PDGF receptor. A model for ganglioside functions. J. Neurooncol. 1995, 24, 65–73. [Google Scholar] [CrossRef]
- Hynds, D.L.; Summers, M.; Van Brocklyn, J.; O'Dorisio, M.S.; Yates, A.J. Gangliosides inhibit platelet-derived growth factor-stimulated growth, receptor phosphorylation, and dimerization in neuroblastoma SH-SY5Y cells. J. Neurochem. 1995, 65, 2251–2258. [Google Scholar]
- Van Brocklyn, J.; Bremer, E.G.; Yates, A.J. Gangliosides inhibit platelet-derived growth factor-stimulated receptor dimerization in human glioma U-1242MG and Swiss 3T3 cells. J. Neurochem. 1993, 61, 371–374. [Google Scholar] [CrossRef]
- Golard, A. Anti-GM3 antibodies activate calcium inflow and inhibit platelet-derived growth factor beta receptors (PDGFbetar) in T51B rat liver epithelial cells. Glycobiology 1998, 8, 1221–1225. [Google Scholar] [CrossRef]
- Farooqui, T.; Kelley, T.; Coggeshall, K.M.; Rampersaud, A.A.; Yates, A.J. GM1 inhibits early signaling events mediated by PDGF receptor in cultured human glioma cells. Anticancer Res. 1999, 19, 5007–5013. [Google Scholar]
- Oblinger, J.L.; Boardman, C.L.; Yates, A.J.; Burry, R.W. Domain-dependent modulation of PDGFRbeta by ganglioside GM1. J. Mol. Neurosci. 2003, 20, 103–114. [Google Scholar] [CrossRef]
- Mitsuda, T.; Furukawa, K.; Fukumoto, S.; Miyazaki, H.; Urano, T.; Furukawa, K. Overexpression of ganglioside GM1 results in the dispersion of platelet-derived growth factor receptor from glycolipid-enriched microdomains and in the suppression of cell growth signals. J. Biol. Chem. 2002, 277, 11239–11246. [Google Scholar] [CrossRef]
- Brdicka, T.; Pavlistova, D.; Leo, A.; Bruyns, E.; Korinek, V.; Angelisova, P.; Scherer, J.; Shevchenko, A.; Hilgert, I.; Cerný, J.; et al. Phosphoprotein associated with glycosphingolipid-enriched microdomains (PAG), a novel ubiquitously expressed transmembrane adaptor protein, binds the protein tyrosine kinase csk and is involved in regulation of T cell activation. J. Exp. Med. 2000, 191, 1591–1604. [Google Scholar] [CrossRef]
- Veracini, L.; Simon, V.; Richard, V.; Schraven, B.; Horejsi, V.; Roche, S.; Benistant, C. The Csk-binding protein PAG regulates PDGF-induced Src mitogenic signaling via GM1. J. Cell Biol. 2008, 182, 603–614. [Google Scholar] [CrossRef]
- Liu, Y.; McCarthy, J.; Ladisch, S. Membrane ganglioside enrichment lowers the threshold for vascular endothelial cell angiogenic signaling. Cancer Res. 2006, 66, 10408–10414. [Google Scholar] [CrossRef]
- Lang, Z.; Guerrera, M.; Li, R.; Ladisch, S. Ganglioside GD1a enhances VEGF-induced endothelial cell proliferation and migration. Biochem. Biophys. Res. Commun. 2001, 282, 1031–1037. [Google Scholar] [CrossRef]
- Seyfried, T.N.; Mukherjee, P. Ganglioside GM3 Is Antiangiogenic in Malignant Brain Cancer. J. Oncol. 2010, 2010, 961243. [Google Scholar]
- Mukherjee, K.; Chava, A.K.; Mandal, C.; Dey, S.N.; Kniep, B.; Chandra, S.; Mandal, C. O-acetylation of GD3 prevents its apoptotic effect and promotes survival of lymphoblasts in childhood acute lymphoblastic leukaemia. J. Cell. Biochem. 2008, 105, 724–734. [Google Scholar] [CrossRef]
- Chung, T.W.; Kim, S.J.; Choi, H.J.; Kim, K.J.; Kim, M.J.; Kim, S.H.; Lee, H.J.; Ko, J.H.; Lee, Y.C.; Suzuki, A.; et al. Ganglioside GM3 inhibits VEGF/VEGFR-2-mediated angiogenesis: direct interaction of GM3 with VEGFR-2. Glycobiology 2009, 19, 229–239. [Google Scholar]
- Abate, L.E.; Mukherjee, P.; Seyfried, T.N. Gene-linked shift in ganglioside distribution influences growth and vascularity in a mouse astrocytoma. J. Neurochem. 2006, 98, 1973–1984. [Google Scholar] [CrossRef]
- Jin, J.; Sison, K.; Li, C.; Tian, R.; Wnuk, M.; Sung, H.K.; Jeansson, M.; Zhang, C.; Tucholska, M.; Jones, N.; et al. Soluble FLT1 binds lipid microdomains in podocytes to control cell morphology and glomerular barrier function. Cell 2012, 151, 384–399. [Google Scholar] [CrossRef]
- Tian, R.; Jin, J.; Taylor, L.; Larsen, B.; Quaggin, S.E.; Pawson, T. Rapid and sensitive MRM-based mass spectrometry approach for systematically exploring ganglioside-protein interactions. Proteomics 2013, 13, 1334–1338. [Google Scholar]
- Tagami, S.; Inokuchi, J.; Kabayama, K.; Yoshimura, H.; Kitamura, F.; Uemura, S.; Ogawa, C.; Ishii, A.; Saito, M.; Ohtsuka, Y.; et al. Ganglioside GM3 participates in the pathological conditions of insulin resistance. J. Biol. Chem. 2002, 277, 3085–3092. [Google Scholar] [CrossRef]
- Sekimoto, J.; Kabayama, K.; Gohara, K.; Inokuchi, J. Dissociation of the insulin receptor from caveolae during TNFα-induced insulin resistance and its recovery by D-PDMP. FEBS Lett. 2012, 586, 191–195. [Google Scholar] [CrossRef]
- Kabayama, K.; Sato, T.; Kitamura, F.; Uemura, S.; Kang, B.W.; Igarashi, Y.; Inokuchi, J. TNFalpha-induced insulin resistance in adipocytes as a membrane microdomain disorder: Involvement of ganglioside GM3. Glycobiology 2005, 15, 21–29. [Google Scholar]
- Yamashita, T.; Hashiramoto, A.; Haluzik, M.; Mizukami, H.; Beck, S.; Norton, A.; Kono, M.; Tsuji, S.; Daniotti, J.L.; Werth, N.; et al. Enhanced insulin sensitivity in mice lacking ganglioside GM3. Proc. Natl. Acad. Sci. USA. 2003, 100, 3445–3449. [Google Scholar] [CrossRef]
- Yoshizumi, S.; Suzuki, S.; Hirai, M.; Hinokio, Y.; Yamada, T.; Yamada, T.; Tsunoda, U.; Aburatani, H.; Yamaguchi, K.; Miyagi, T.; Oka, Y. Increased hepatic expression of ganglioside-specific sialidase, NEU3, Improves insulin sensitivity and glucose tolerance in mice. Metabolism 2007, 56, 420–429. [Google Scholar] [CrossRef]
- Kabayama, K.; Sato, T.; Saito, K.; Loberto, N.; Prinetti, A.; Sonnino, S.; Kinjo, M.; Igarashi, Y.; Inokuchi, J. Dissociation of the insulin receptor and caveolin-1 complex by ganglioside GM3 in the state of insulin resistance. Proc. Natl. Acad. Sci. USA. 2007, 104, 13678–13683. [Google Scholar] [CrossRef]
- Sasaki, A.; Hata, K.; Suzuki, S.; Sawada, M.; Wada, T.; Yamaguchi, K.; Obinata, M.; Tateno, H.; Suzuki, H.; Miyagi, T. Overexpression of plasma membrane-associated sialidase attenuates insulin signaling in transgenic mice. J. Biol. Chem. 2003, 278, 27896–27902. [Google Scholar] [CrossRef]
- Rillahan, C.D.; Paulson, J.C. Glycan microarrays for decoding the glycome. Annu. Rev. Biochem. 2011, 80, 797–823. [Google Scholar] [CrossRef]
- Bond, M.R.; Whitman, C.M.; Kohler, J.J. Metabolically incorporated photocrosslinking sialic acid covalently captures a ganglioside-protein complex. Mol. Biosyst. 2010, 6, 1796–1799. [Google Scholar] [CrossRef]
© 2013 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).