Figure 1. Structures of sphingosine (a), ceramide (b), galactosylceramide (c), glucosylceramide (d) and ganglioside GM3 (e).

Figure 2. Structures of diacylglycerol, -galactosyl diacylglycerol and seminolipid.

Figure 3. Ganglio-series GSLs, having o-, a-, b- and c- subseries as indicated. Enzymes and genes involved in each synthetic step (indicated by red numbers) are described under ‘Synthesis and Degradation/(1) Ganglio-series pathway’

Figure 4. Lacto-series GSLs, having type 1 and type 2 chain subseries as indicated.

Figure 5. Globo-series GSLs.

Figure 6. Sulfated glycolipids.

Figure 7. Core structure of the glycosylphosphatidylinositol (GPI) anchor. Arrows indicate cleavage sites for PI-phospholipase C and GPI-phospholipase D.

Figure 8. Basic synthetic pathway of ceramide and glycosphingolipids. The first four steps indicate the synthetic process from l-serine and palmitoyl–CoA to ceramide. Note that the double bond of sphingosine is introduced at ceramide. These processes take place at the endoplasmic reticulum (ER). Ceramide is converted into sphingomyelin by transfer of phosphorylcholine from phosphatidylcholine. Conversely, sphingomyelin is hydrolysed by sphingomyelinase and converted into ceramide. Subsequent ceramide glycosylation (glucose addition by -glucosyltransferase, followed by addition of galactose by -Gal transferase I to form LacCer) takes place on the Golgi membrane. Subsequent synthesis of ganglio-, globo- and lacto-series GSLs is initiated by 1,4 GalNAc-T, 1,4 Gal-T and 1,3 GlcNAc-T, respectively.

Figure 9. Balance of synthesis, degradation and recycling of sphingolipids and glycosphingolipids. New (de novo) synthesis of sphingosine and ceramide is catalysed by a series of enzymes associated with the ER (‘1’), followed by glycosylation to form GSL or transfer of phosphorylcholine to form sphingomyelin (SM) at the Golgi membrane (‘1’). GSLs are further processed by the trans-Golgi network (TGN), and finally incorporated in the plasma membrane and clustered in the glycosignalling domain (GSD) (‘2’). GSLs are internalized to reach early endosome, then late endosome and are finally degraded at lysosome. Sphingosine and ceramide thus produced are reutilized for synthesis of GSLs and SM at the Golgi (recycling mechanism ‘3’). GSLs are ‘shuttled’ between late endosome and TGN by another recycling mechanism (‘4’). GSLs of some animal cells are synthesized mainly by recycling mechanisms 2 and 3. GSLs in other cells depend on de novo synthesis (1). The idea of de novo synthesis versus recycling of GSLs comes from the data of Gillard et al. (1999).

Figure 10. Possible modulation by GSLs of signal transduction through growth factor receptors. Signal transduction is initiated when growth factors or death-causing factors are bound to specific receptors. Receptors for growth factors are generally associated with cytoplasmic tyrosine kinases, which are activated upon binding of the factor to the receptor. Susceptibility of tyrosine kinase activity associated with each type of receptor to sphingolipids or GSLs is different. Known examples are shown schematically in this figure. Circled+and – signs represent, respectively, positive and negative effects of sphingolipid or GSL on the tyrosine kinase activity of the receptor. For example, tyrosine kinase associated with epidermal growth factor (EGF) receptor is promoted by N,N-dimethylsphingosine (DMS) and by de-N-acetyl-GM3, but inhibited by GM3 ganglioside. Tyrosine phosphorylation associated with the insulin receptor in human cells is inhibited by sialylparagloboside (SPG), and that in mice is inhibited by GM3. Other abbreviations: NGF, nerve growth factor; PSY, plasmalopsychosine; PDGF, platelet-derived growth factor; FGF, fibroblast growth factor; VEGF, vascular endothelial growth factor.

Figure 11. Schematic illustration of proposed function of GEM subfraction (glycosignalling domain) in cell adhesion coupled with signalling. (a) The minimum-energy conformational structure of a typical GSL (globoside) axis of the oligosaccharide is perpendicular to the axis of ceramide (N-fatty acyl sphingosine). Antibodies, lectins and complementary GSLs interact with the outer surface profile of oligosaccharide. (b) Proposed self-aggregation of GSLs in the lipid bilayer of the plasma membrane (‘GSL patch’). The ceramide moiety holds GSL carbohydrates in defined orientation through insertion in the plasma membrane. GSL patches are separated from clusters of glycoprotein (Gp). (c) GSLs are self-assembled in microdomains, which constitute a major component of the GEM, and transducers are associated with these GSL microdomains. Glycoprotein clusters (Gp) are physically separate from GSL microdomains, as revealed by electron microscopy with a freeze-fracture technique. GSL microdomains are subject to binding by lectins, antibodies and complementary GSLs. These GSL microdomains, separated from caveolae, may contain transbilayer lipophilic proteins. Such proteins may mediate functional connections between GSLs and transducers (TDa, TDb). (d) GSLs in the GEM subfraction (glycosignalling domain) are associated with inactive TD (1). Stimulation of GSLs in GEM by GSL ligands (antibody, complementary GSL, lectin) induces conformational change of TDa, b, c, which triggers signal transduction (2). Caveolae (invaginations of plasma membrane) may contain GEM-like components (G), transducers (TDa, b, c), growth factor receptors (x), and caveolin (y). They are involved mainly in growth factor receptor-mediated signal transduction and not in cell adhesion (3).