N-glycan, a fundamental and versatile protein modification in mammals, plays critical roles in various physiological and pathological events including cancer progression. The formation of N-glycan ...branches catalyzed by specific N-acetylglucosaminyltransferases GnT-III, GnT-IVs, GnT-V, GnT-IX (Vb) and a fucosyltransferase, Fut8, provides functionally diverse N-glycosylated proteins. Aberrations of these branches are often found in cancer cells and are profoundly involved in cancer growth, invasion and metastasis. In this review, we focus on the GlcNAc and fucose branches of N-glycans and describe how their expression is dysregulated in cancer by genetic and nongenetic mechanisms including epigenetics and nucleotide sugar metabolisms. We also survey the roles that these N-glycans play in cancer progression and therapeutics. Finally, we discuss possible applications of our knowledge on basic glycobiology to the development of medicine and biomarkers for cancer therapy.
The endoplasmic reticulum (ER) is equipped with multiple quality control systems (QCS) that are necessary for shaping the glycoproteome of eukaryotic cells. These systems facilitate the productive ...folding of glycoproteins, eliminate defective products, and function as effectors to evoke cellular signaling in response to various cellular stresses. These ER functions largely depend on glycans, which contain sugar‐based codes that, when needed, function to recruit carbohydrate‐binding proteins that determine the fate of glycoproteins. To ensure their functionality, the biosynthesis of such glycans is therefore strictly monitored by a system that selectively degrades structurally defective glycans before adding them to proteins. This system, which is referred to as the glycan QCS, serves as a mechanism to reduce the risk of abnormal glycosylation under conditions where glycan biosynthesis is genetically or metabolically stalled. On the other hand, glycan QCS increases the risk of global hypoglycosylation by limiting glycan availability, which can lead to protein misfolding and the activation of unfolded protein response to maintaining cell viability or to initiate cell death programs. This review summarizes the current state of our knowledge of the mechanisms underlying glycan QCS in mammals and its physiological and pathological roles in embryogenesis, tumor progression, and congenital disorders associated with abnormal glycosylation.
The biosynthesis of asparagine‐linked glycans is strictly monitored by a system that selectively degrades structurally defective glycans before adding them to proteins in the endoplasmic reticulum. This novel cellular system, which is referred to as the glycan quality control system (QCS), has a dual role in maintaining and disrupting ER homeostasis. We here discuss how these two opposite functions of the glycan QCS can be cell context‐dependent and determined by genetic and environmental factors.
The glycosylation of cell surface receptors has been shown to regulate each step of signal transduction, including receptor trafficking to the cell surface, ligand binding, dimerization, ...phosphorylation, and endocytosis. In this review we focus on the role of glycosyltransferases that are involved in the modification of N-glycans, such as the effect of branching and elongation in signaling by various cell surface receptors. In addition, the role of those enzymes in the EMT/MET programs, as related to differentiation and cancer development, progress and therapy resistance is discussed.
Oligosaccharyltransferase (OST) is a multi-span membrane protein complex that catalyzes the addition of glycans to selected Asn residues within nascent polypeptides in the lumen of the endoplasmic ...reticulum. This process, termed N-glycosylation, is a fundamental post-translational protein modification that is involved in the quality control, trafficking of proteins, signal transduction, and cell-to-cell communication. Given these crucial roles, N-glycosylation is essential for homeostasis at the systemic and cellular levels, and a deficiency in genes that encode for OST subunits often results in the development of complex genetic disorders. A growing body of evidence has also demonstrated that the expression of OST subunits is cell context-dependent and is frequently altered in malignant cells, thus contributing to tumor cell survival and proliferation. Importantly, a recently developed inhibitor of OST has revealed this enzyme as a potential target for the treatment of incurable drug-resistant tumors. This review summarizes our current knowledge regarding the functions of OST in the light of health and tumor progression, and discusses perspectives on the clinical relevance of inhibiting OST as a tumor treatment.
Glycosylation is the most ubiquitous post-translational modification in eukaryotes.
-glycan is attached to nascent glycoproteins and is processed and matured by various glycosidases and ...glycosyltransferases during protein transport. Genetic and biochemical studies have demonstrated that alternations of the
-glycan structure play crucial roles in various physiological and pathological events including progression of cancer, diabetes, and Alzheimer's disease. In particular, the formation of
-glycan branches regulates the functions of target glycoprotein, which are catalyzed by specific
-acetylglucosaminyltransferases (GnTs) such as GnT-III, GnT-IVs, GnT-V, and GnT-IX, and a fucosyltransferase, FUT8s. Although the 3D structures of all enzymes have not been solved to date, recent progress in structural analysis of these glycosyltransferases has provided insights into substrate recognition and catalytic reaction mechanisms. In this review, we discuss the biological significance and structure-function relationships of these enzymes.
Glycosylation is one of the most common post‐translational modification reactions and nearly half of all known proteins in eukaryotes are glycosylated. In fact, changes in oligosaccharide structures ...are associated with many physiological and pathological events, including cell growth, migration, differentiation, tumor invasion, host–pathogen interactions, cell trafficking, and transmembrane signaling. Emerging roles of glycan functions have been highly attractive to scientists in various fields of life science as they open a field, “Functional Glycomics”, that is a comprehensive study of the glycan structures in relation to functions. In particular, the N‐glycans of signaling molecules including receptors or adhesion molecules are considered to be involved in cellular functions. This review will focus on the roles of glycosyltransferases involved in the biosynthesis of N‐glycan branching and identification of cell surface receptors as their target proteins. We also suggest that the modulation of N‐glycans of those receptors alters their important functions such as cell signaling and cell adhesion which are implicated in cancer invasion and metastasis. (Cancer Sci 2008; 99: 1304–1310)
This Special Issue on “Advances in Glycation: from food to human health and disease” was planned after the XXV International Symposium on Glycoconjugates (Glyco25) in Milan in order to ask special ...attention of importance of glycation to glycoscience community. In addition, we also celebrate the 30th anniversary of JMARS (Japan Maillard Reaction Society), and dedicated to one of the pioneers of this field, Professor Vincent Monnier, MD. He contributed enormously to studies on glycation related to aging and diseases to date and also he contributed to establish IMARS (International Maillard Reaction Society) as well as JMARS.
Disease-associated glycans on cell surface proteins Takahashi, Motoko; Kizuka, Yasuhiko; Ohtsubo, Kazuaki ...
Molecular aspects of medicine,
October 2016, 2016-Oct, 2016-10-00, 20161001, Volume:
51
Journal Article
Peer reviewed
Most of membrane molecules including cell surface receptors and secreted proteins including ligands are glycoproteins and glycolipids. Therefore, identifying the functional significance of glycans is ...crucial for developing an understanding of cell signaling and subsequent physiological and pathological cellular events. In particular, the function of N-glycans associated with cell surface receptors has been extensively studied since they are directly involved in controlling cellular functions. In this review, we focus on the roles of glycosyltransferases that are involved in the modification of N-glycans and their target proteins such as epidermal growth factor receptor (EGFR), ErbB3, transforming growth factor β (TGF-β) receptor, T-cell receptors (TCR), β-site APP cleaving enzyme (BACE1), glucose transporter 2 (GLUT2), E-cadherin, and α5β1 integrin in relation to diseases and epithelial–mesenchymal transition (EMT) process. Above of those proteins are subjected to being modified by several glycosyltransferases such as N-acetylglucosaminyltransferase III (GnT-III), N-acetylglucosaminyltransferase IV (GnT-IV), N-acetylglucosaminyltransferase V (GnT-V), α2,6 sialyltransferase 1 (ST6GAL1), and α1,6 fucosyltransferase (Fut8), which are typical N-glycan branching enzymes and play pivotal roles in regulating the function of cell surface receptors in pathological cell signaling.
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