Biosynthesis of HNK-1 Glycans on O-Linked Oligosaccharides Attached to the Neural Cell Adhesion Molecule (NCAM)

Ong, Edgar; Suzuki, Misa; Bélot, Frédéric; Yeh, Jeunliang; Franceschini, Isabelle; Angata, Kiyohiko; Hindsgaul, Ole; Fukuda, Minoru

doi:10.1074/jbc.m201312200

Cited by 34 publications

(12 citation statements)

References 61 publications

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“…A similar difference was also found in the HNK-1 epitope, a sulfated-glycan with the structure of sulfo>3GlcAβ1->3Galβ1->4GlcNA-cβ1->R [64][65][66][67][68], between melanomas and prostate cancer tissues when the anti-HNK-1 monoclonal antibody Leu 7 was used for the test [69]. The expression level of the HNK-1 epitope is parallel to that of human METCAM/MUC18 in human melanoma, and both are predominantly expressed on the plasma membrane of melanoma cells.…”

Section: The Possible Role Of Glycosylation In the Humet-cam/muc18-mesupporting

confidence: 55%

METCAM/MUC18 Expression and Cancer Metastasis

Wu¹

2005

134

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The aberrant expression of cell adhesion molecules (CAMs) is correlated with the malignant progression of many tumors. MUC18/CD146/A32/MelCAM/S-endo, an integral membrane glycoprotein, is a CAM in the immunoglobulin gene superfamily. MUC18 has often been mistaken as a mucin because of the misleading nomenclature. Based on its biological functions and other known biochemical properties, we propose to re-name it as METCAM (metastasis CAM). METCAM/MUC18 expression has a very interesting effect on tumor formation and metastasis. The overexpression of METCAM/MUC18 has been correlated with the malignant progression of human melanoma and human prostate cancer. In melanoma, the ectopic over-expression of METCAM/MUC18 has no effect on tumorigenesis, but augments the metastasis of cancer cells. In prostate cancer, the ectopic over-expression of human METCAM/MUC18 has an even greater effect, increasing tumorigenesis and initiating the metastasis of cancer cells. However, an opposite effect of METCAM/MUC18 on tumorigenesis and metastasis of breast cancer, some mouse melanoma cell lines, and perhaps haemangioma and nasopharygeal carcinoma has also been suggested. Taken together, we suggest that the different effect of METCAM/MUC18 on tumor formation and metastasis is dependent on the intrinsic properties of each tumor cell line. This paper will review previous experiments and results and present some possible mechanisms of METCAM/MUC18-mediated tumorigenesis and metastasis for future studies.

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Section: The Possible Role Of Glycosylation In the Humet-cam/muc18-mesupporting

confidence: 55%

METCAM/MUC18 Expression and Cancer Metastasis

Wu¹

2005

134

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“…On the other hand, from the results shown above (Fig. 2B) and from previous reports (4,26), it can be concluded that O-glycans are attached to the MSD. Therefore, based on the structure of GPI anchoring isoforms present in nature, we constructed cDNAs encoding chimeric proteins of NCAM with and without N-glycosylation sites for polysialylation and with and without the MSD (Fig.…”

Section: Ncam-msd and Polysialic Acid Are Sequentially Expressed On Tcontrasting

confidence: 34%

“…Indeed, we demonstrate in the present study that O-glycosylation takes place only on an MSD that contains multiple O-glycosylation sites. The structure of those O-glycans contains Gal␤1-3GalNAc␣1-Ser/Thr, and some of them are sialylated (4,26).…”

Section: Discussionmentioning

confidence: 99%

Polysialic Acid and Mucin Type O-Glycans on the Neural Cell Adhesion Molecule Differentially Regulate Myoblast Fusion

Suzuki

Angata

Nakayama

et al. 2003

Journal of Biological Chemistry

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Polysialic acid attached to the neural cell adhesion molecule (NCAM) is thought to play a critical role in development. NCAM in muscle tissue contains a muscle-specific domain (MSD) to which mucin type O-glycans are attached. In the present study, using the C2C12 myoblast system, we show that NCAM containing MSD is increasingly expressed on the cell surface as myotubes form. Polysialic acid is primarily attached to N-glycans of NCAM, and polysialylated NCAM is expressed on the outer surface of myotube bundles. By transfecting cDNAs encoding wild type and mutant forms of NCAM, we found that NCAM containing MSD facilitates myoblast fusion, and this effect is diminished by mutating O-glycosylation sites at MSD. By contrast, forced expression of polysialic acid in early differentiation stages reduces myotube formation and delays the expression of NCAM containing the MSD domain. Strikingly, inhibition of polysialic acid synthesis by antisense DNA approach induced differentiation in both human rhabdomyosarcoma cells, which overexpress polysialic acid, and C2C12 cells. These results indicate that polysialic acid and mucin type O-glycans on NCAM differentially regulate myoblast fusion, playing critical roles in muscle development.During mammalian embryonic development, muscle development is initiated once mesenchymal cells commit to become myoblasts. Myoblasts then align and fuse, forming multinucleated myotubes, and mature myotubes are bundled together, forming sarcolemma. In parallel, each myotube starts contraction, receives innervation from motor and sensory neurons, and eventually forms muscle tissue. In this process, one of the most intriguing steps is myoblast fusion. Myoblast fusion consists of multiple steps: expression of the fusion competent phenotype, specific myoblast-myoblast recognition and alignment, cell adhesion and electrical coupling, and fusion of lipid bilayer membrane (1). It has been reported that anti-NCAM 1 antibody inhibits aggregation of fusion-competent chick embryo myoblasts (2), indicating that cell-cell adhesion via NCAM apparently initiates myoblast fusion. In addition, integrins, N-cadherin, VCAM, and VLA4 are thought to be involved (see Ref. 3 and references herein).NCAM is found in several isoforms due to alternative mRNA splicing of more than 19 exons. In mammalian brain, the glycosylphosphatidylinositol (GPI)-anchored 120-kDa isoform and transmembrane 140-and 180-kDa isoforms are primarily expressed. In muscles, three isoforms have been reported: a GPIanchored 125-kDa isoform and transmembrane 140-and 155-kDa isoforms (4). Muscle-specific domain (MSD) was identified in the cDNA of the 125-kDa NCAM isoform obtained from human skeletal muscle (5). MSD is encoded by four different exons, MSD1a, MSD1b, MSD1c, and codon AAG. The fulllength MSD sequence consists of 35 amino acids inserted between two fibronectin type III domains of NCAM. MSD insertion is observed only in skeletal muscle and heart and not in other tissues. O-Glycosylation of MSD was shown by peanut agglutinin (PNA) lecti...

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“…The HNK-1 epitope is found on glycolipids (20,21), N-linked glycans (13,22), and O-linked glycans (23); however, recent evidence suggests that a significant portion of the HNK-1 epitope is linked to proteins via an N-glycanase-insensitive linkage, likely on O-mannose glycans (15), which can be detected by the monoclonal antibody Cat-315. Interestingly, the Cat-315 antibody has been shown to react with different perisynaptic extracellular matrix components during synapse formation, suggesting a role for O-mannosyl-linked HNK-1 in synaptogenesis (15).…”

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confidence: 99%

Receptor Tyrosine Phosphatase β (RPTPβ) Activity and Signaling Are Attenuated by Glycosylation and Subsequent Cell Surface Galectin-1 Binding

Abbott

Matthews

Pierce

2008

Journal of Biological Chemistry

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O-Mannosyl-linked glycosylation is abundant within the central nervous system, yet very few glycoproteins with this glycan modification have been identified. Congenital diseases with significant neurological defects arise from inactivating mutations found within the glycosyltransferases that act early in the O-mannosyl glycosylation pathway. The N-acetylglucosaminyltransferase known as GnT-Vb or -IX is highly expressed in brain and branches O-mannosyl-linked glycans. Our results using SH-SY5Y neuroblastoma cells indicate that GnT-Vb activity promotes the addition of the O-mannosyl-linked HNK-1 modification found on the developmentally regulated and neuronspecific receptor protein-tyrosine phosphatase ␤ (RPTP␤). These changes in glycosylation accompany decreased cell-cell adhesion and increased rates of migration on laminin. In addition, we show that expression of GnT-Vb promotes its dimerization and inhibits RPTP␤ intrinsic phosphatase activity, resulting in higher levels of phosphorylated ␤-catenin, suggesting a mechanism by which GnT-Vb glycosylation couples to changes in cell adhesion. GnT-Vb-mediated glycosylation of RPTP␤ promotes galectin-1 binding and RPTP␤ levels of retention on the cell surface. N-Acetyllactosamine, but not sucrose, treatment of cells results in decreased RPTP retention, showing that galectin-1 binding contributes to the increased retention after GnT-Vb expression. These results place GnT-Vb as a regulator of RPTP␤ signaling that influences cell-cell and cell-matrix interactions in the developing nervous system. Glycosylation is regulated spatially and temporally during the development of the nervous system (1). In particular, sulfated glycoconjugates, such as the human natural killer-1 epitope, are important for proper migration and adhesion during neural development (2, 3). The human natural killer-1 (HNK-1) 3 epitope was originally discovered using a monoclonal antibody raised against a specific T-lymphoblastoid cell type (4). Since its discovery in lymphocytes, the HNK-1 (also known as CD57) antibody has been shown to react with many neural cell types, including glial, neuroectoderm, and neuroendocrine cells (5-8). The HNK-1 epitope consists of a glucuronic acid, transferred by glucuronyltransferases (GlcATs), that is 3-sulfated by HNK-1 sulfotransferase (HNK1st), linked to a precursor N-acetyllactosamine structure (Fig. 1). Numerous glycoproteins bearing the HNK-1 epitope have been identified in the nervous system, such as neural cell adhesion molecule (9), L1 (10), neural-glia cell adhesion molecule (11), myelinassociated glycoprotein (12), tenascin R (13), and RPTP (receptor protein-tyrosine phosphatase) (14, 15). In certain cell types, such as neural crest cells, the expression of the HNK-1 antigen is highly regulated during development (2) and is often found on migratory cells (3). The HNK-1 antigen is linked to critical functions during the formation of the nervous system, such as cell-matrix interactions (16), cell-cell adhesion (17), memory, and synaptic plasticity (15,18,19...

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Biosynthesis of HNK-1 Glycans on O-Linked Oligosaccharides Attached to the Neural Cell Adhesion Molecule (NCAM)

Cited by 34 publications

References 61 publications

METCAM/MUC18 Expression and Cancer Metastasis

METCAM/MUC18 Expression and Cancer Metastasis

Polysialic Acid and Mucin Type O-Glycans on the Neural Cell Adhesion Molecule Differentially Regulate Myoblast Fusion

Receptor Tyrosine Phosphatase β (RPTPβ) Activity and Signaling Are Attenuated by Glycosylation and Subsequent Cell Surface Galectin-1 Binding

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