Functional roles of N-glycans in cell signaling and cell adhesion in cancer

Abstract

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.

Figure 1

Glycosylation reactions catalyzed by the actions of glycosyltransferase GnT‐III, GnT‐V, and Fut8, and their biological functions.

Figure 2

Increased expression of GnT‐V in epithelial cells results in a loss of contact inhibition and increased cell motility. Overexpression of GnT‐III resulted in resistance of E‐cadherin to proteolysis, and the E‐cadherin remained on the cell–cell borders. Conversely, GnT‐III can be up‐regulated through cell–cell interactions; therefore, signals responsible for the maintenance of the cell differentiation phenotype may be neutralized.

Figure 3

Lack of core fucosylation of EGFR leads to the suppression of EGF signaling and cell growth. EGF binding to the high‐affinity type of EGFR is significantly reduced in Fut8^−/– cells, and that leads to dysfunction of EGF signaling and cell growth.