N-Acetylglucosaminyltransferase III Antagonizes the Effect of N-Acetylglucosaminyltransferase V on α3β1 Integrin-mediated Cell Migration

Zhao, Yanyang; Nakagawa, Takatoshi; Itoh, Seiga; Inamori, Kei-ichiro; Isaji, Tomoya; Kariya, Yoshinobu; Kondo, Akihiro; Miyoshi, Eiji; Miyazaki, Kaoru; Kawasaki, Nana; Taniguchi, Naoyuki; Gu, Jianguo

doi:10.1074/jbc.m607274200

Cited by 134 publications

(117 citation statements)

References 44 publications

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“…These results suggest that decreases in N-acetylglucosamine in N-glycans increase cell surface expression of ␣5␤1 integrin (25). The 1,6-GlcNAc-branched N-glycans on the ␣3 subunit of integrin was reduced by ␤1,4-Nacetylglucosaminyltransferase-III, and this leads to reduced migration (47). Moreover it was discovered that N-glycans of the ␤-propeller domain of the integrin ␣5 subunit is essential for ␣5␤1 heterodimerization.…”

Section: Discussionmentioning

confidence: 94%

Core3 O-Glycan Synthase Suppresses Tumor Formation and Metastasis of Prostate Carcinoma PC3 and LNCaP Cells through Down-regulation of α2β1 Integrin Complex

Lee

Hatakeyama

et al. 2009

Journal of Biological Chemistry

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Cancer cells often express surface carbohydrates different from normal cells (1). One such change is expression of sialyl Lewis X and Lewis B blood group antigens in cancer cells (2, 3). These structural elements are seen as capping oligosaccharides attached to the underlying glycan backbone where they likely function as ligands for cell adhesion molecules.The structure of underlying glycans also changes during malignant transformation and differentiation. In particular, there are several reports that an increase in the ␤1,6-N-acetylglucosaminyl branch in N-glycans synthesized by ␤1,6-Nacetylglucosaminyltransferase-V is associated with oncogenic transformation (4 -7). Similar structural changes are seen in mucin-type O-glycans, which have N-acetylgalactosamine at the reducing end linked to polypeptide threonine or serine residues. Addition of different carbohydrate residues to N-acetylgalactosamine confers a variety of backbone structures on mucin-type O-glycans; the most abundant of those are classified as core1, core2, core3, and core4 O-glycans (8) (Fig.

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Section: Discussionmentioning

confidence: 94%

Core3 O-Glycan Synthase Suppresses Tumor Formation and Metastasis of Prostate Carcinoma PC3 and LNCaP Cells through Down-regulation of α2β1 Integrin Complex

Lee

Hatakeyama

et al. 2009

Journal of Biological Chemistry

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“…The affinity of the binding of integrin α5β1 to FN was significantly reduced as a result of the introduction of a bisecting GlcNAc to the α5 subunit. The opposing effects of GnT-III and GnT-V have been observed for the same target protein, integrin α3β1 [21]. GnT-V stimulated α3β1 integrin-mediated cell migration, while overexpression of GnT-III inhibited GnT-V-induced cell migration.…”

Section: N-glycans Regulate Integrin Functionsmentioning

confidence: 90%

Potential roles of N-glycosylation in cell adhesion

Isaji

et al. 2012

Glycoconj J

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127

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The functional units of cell adhesion are typically multiprotein complexes made up of three general classes of proteins; the adhesion receptors, the cell-extracellular matrix (ECM) proteins, and the cytoplasmic plaque/peripheral membrane proteins. The cell adhesion receptors are usually transmembrane glycoproteins (for example E-cadherin and integrin) that mediate binding at the extracellular surface and determine the specificity of cell-cell and cell-ECM recognition. E-cadherin-mediated cell-cell adhesion can be both temporally and spatially regulated during development, and represents a key step in the acquisition of the invasive phenotype for many tumors. On the other hand, integrin-mediated cell-ECM interactions play important roles in cytoskeleton organization and in the transduction of intracellular signals to regulate various processes such as proliferation, differentiation and cell migration. ECM proteins are typically large glycoproteins, including the collagens, fibronectins, laminins, and proteoglycans that assemble into fibrils or other complex macromolecular arrays. The most of these adhesive proteins are glycosylated. Here, we focus mainly on the modification of N-glycans of integrins and laminin-332, and a mutual regulation between cell adhesion and bisected N-glycan expression, to address the important roles of N-glycans in cell adhesion.

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“…All cell lines above, as well as human hepatoma HepG2 cells, were maintained in high glucose DMEM with 2 mM L-glutamine and 10% FBS, for CHO-K1 cells also with nonessential amino acids. Two other previously established MKN-45 cell lines transfected with GnT-III-expressing or mock vectors were cultured at 37°C in RPMI 1640 medium with 10% FBS (9). Pro-5 cells were gifts from Dr. Kitazume Shinobu (RIKEN) and cultured in ␣-MEM with 10% FBS.…”

Section: Methodsmentioning

confidence: 99%

Expression of N-Acetylglucosaminyltransferase III Suppresses α2,3-Sialylation, and Its Distinctive Functions in Cell Migration Are Attributed to α2,6-Sialylation Levels

Isaji

et al. 2016

Journal of Biological Chemistry

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N-Acetylglucosaminyltransferase III (GnT-III), which catalyzes the addition of the bisecting GlcNAc branch on N-glycans, is usually described as a metastasis suppressor. Overexpression of GnT-III inhibited migration in multiple types of tumor cells. However, these results seem controversial to the clinical observations for the increased expression of GnT-III in human hepatomas, glioma, and ovarian cancers. Here, we present evidence that these inconsistencies are mainly attributed to the different expression pattern of cell sialylation. In detail, we show that overexpression of GnT-III significantly inhibits ␣2,3-sialylation but not ␣2,6-sialylation. The migratory ability of cells without or with a low level of ␣2,6-sialylation is consistently suppressed after GnT-III overexpression. In contrast, the effects of GnT-III overexpression are variable in tumor cells that are highly ␣2,6-sialylated. Overexpression of GnT-III promotes the cell migration in glioma cells U-251 and hepatoma cells HepG2, although it has little influence in human breast cancer cell MDA-MB-231 and gastric cancer cell MKN-45. Interestingly, up-regulation of ␣2,6-sialylation by overexpressing ␤-galactoside ␣2,6-sialyltranferase 1 in the ␣2,6-hyposialylated HeLa-S3 cells abolishes the anti-migratory effects of GnT-III. Conversely, depletion of ␣2,6-sialylation by knock-out of ␤-galactoside ␣2,6-sialyltranferase 1 in ␣2,6-hypersialylated HepG2 cells endows GnT-III with the anti-migratory ability. Taken together, our data clearly demonstrate that high expression of ␣2,6-sialylation on the cell surface could affect the anti-migratory role of GnT-III, which provides an insight into the mechanistic roles of GnT-III in tumor metastasis.Alterations in N-linked glycosylation have been observed in various malignant diseases such as cancer. Certain glycan structures resulting from the dysregulated glycosyltransferases and glycosidases are well known tumor markers and closely associated with the malignant progression (1). As examples, the ␣1,6-fucosylated ␣-fetoprotein catalyzed by ␣1,6-fucosyltransferase has been developed as a biomarker for primary hepatoma by Abelev (2). An increase in ␤1,6-GlcNAc branching of N-glycans as a consequence of enhanced expression of N-acetylglucosaminyltransferase V (GnT-V) 2 is convincingly correlated with the increased frequency of tumor metastasis (3-6). N-Acetylglucosaminyltransferase III (GnT-III) is one more important glycosyltransferase that has been receiving much attention for its involvement in the biology of tumor (7,8). It catalyzes the transfer of N-acetylglucosamine (GlcNAc) in a ␤1,4 linkage to mannose on N-glycans forming a bisecting GlcNAc structure. This step plays critical roles in determining the structure of N-glycans because introduction of the bisecting GlcNAc residue could preclude further processing and elongation of N-glycans, such as the formation of ␤1,6-GlcNAc branching structures (9). Considering also that overexpression of GnT-III inhibited the metastasis of multiple types of carcinomas (10, 1...

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N-Acetylglucosaminyltransferase III Antagonizes the Effect of N-Acetylglucosaminyltransferase V on α3β1 Integrin-mediated Cell Migration

Cited by 134 publications

References 44 publications

Core3 O-Glycan Synthase Suppresses Tumor Formation and Metastasis of Prostate Carcinoma PC3 and LNCaP Cells through Down-regulation of α2β1 Integrin Complex

Core3 O-Glycan Synthase Suppresses Tumor Formation and Metastasis of Prostate Carcinoma PC3 and LNCaP Cells through Down-regulation of α2β1 Integrin Complex

Potential roles of N-glycosylation in cell adhesion

Expression of N-Acetylglucosaminyltransferase III Suppresses α2,3-Sialylation, and Its Distinctive Functions in Cell Migration Are Attributed to α2,6-Sialylation Levels

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