Aberrant Glycosylation as Biomarker for Cancer: Focus on CD43

Figure 2

Mucin-type O-glycosylation. Different forms of O-glycosylation of proteins occur in animals. Mucin-type O-glycosylation is the most abundant form of protein O-glycosylation and consists of glycans attached via O-linked N-acetylgalactosamine (GalNAc) to serine and threonine residues. Other types of O-glycosylation include mannose-, galactose- (added to a residue of hydroxylysine), fucose-, glucose-, xylose-, and N-acetylglucosamine-O-glycosylation. GalNAc-O-glycosylation originates in the Golgi apparatus after protein folding, while other types of O-glycosylation of proteins in the secretory pathway initiate in the ER. Mucin-type O-glycosylation is initiated by a large family of homologous proteins, named N-acetylgalactosamine (GalNAc)-transferase that catalyses the transfer of GalNAc from UDP-GalNAc to Ser or Thr residues of target glycoprotein. These enzymes are sequentially and functionally conserved across species and their expression is time and tissue specific, suggesting a very complex regulation. Up to 20 different isoforms of polypeptide N-acetyl-α-D-galactosaminyltransferases are known and many are specific for the sites of attachment of the GalNAc to serine/threonine residues, influencing the density and the specific position of the O-glycosylation of target proteins. Thereafter, specific glycosyltransferases can catalyse the addition to GalNAc of specific monosaccharides generating four common subtypes (Core-1-, Core-2-, Core-3-, and Core-4-O-glycan structures) based on differential monosaccharide linkage reactions to the GalNAc (GalNAcα-Ser/Thr). Most O-glycans contain the Core-1 subtype (a), which is generated by the addition of galactose to the GalNAc through a β1–3 linkage by the Core-1-(β1–3) galactosyltransferase. This structure is usually further extended by the addition of monosaccharides such as N-acetylglucosamine, galactose, N-acetylneuraminic acid, and fucose. (b) Core-2-O-glycans are generated by the addition of GlcNAc to the GalNAc through a β1–6 linkage. In order to generate Core-2-O-glycans, Core-1 structure is required as a substrate; thus, the Core-2 structure includes the Core-1 structure. The Core-2-O-glycan can be further extended into either a mono- or biantennary form by addition of multiple galactose (Gal(β1–4)GlcNAc) units and terminal linkages of fucose and sialic acid. (c) Core-3 subtype is generated by the addition of GlcNAc in a β1–3 linkage to the GalNAc, and it can be extended by the addition of GlcNAc in a β1–6 linkage, generating the Core-4-O-glycan (d), which also can be extended by addition of monosaccharides, such as galactose, fucose, and sialic acid, which results in the synthesis of a wide spectrum of O-glycan structures. In some cases, the biosynthesis of O-glycans is stopped by the addition of sialic acid residues in early biosynthesis leading to “dead ends” of O-glycan structures that cannot be further modified ((e), (f)). Truncated O-glycan structures are frequently found in cancer cells as tumour antigens, suggesting that aberrant glycosylation may contribute to cancer progression by modifying cell signalling, adhesion, and antigenicity. (g) Graphic legend of described structures.