Abstract
Glycosylation is a very frequent and functionally important post-translational protein modification that undergoes profound changes in cancer. Growth and death factor receptors and plasma membrane glycoproteins, which upon activation by extracellular ligands trigger a signal transduction cascade, are targets of several molecular anti-cancer drugs. In this review, we provide a thorough picture of the mechanisms bywhich glycosylation affects the activity of growth and death factor receptors in normal and pathological conditions. Glycosylation affects receptor activity through three non-mutually exclusive basic mechanisms: (1) by directly regulating intracellular transport, ligand binding, oligomerization and signaling of receptors; (2) through the binding of receptor carbohydrate structures to galectins, forming a lattice thatregulates receptor turnover on the plasma membrane; and (3) by receptor interaction with gangliosides inside membrane microdomains. Some carbohydrate chains, for example core fucose and β1,6-branching, exert a stimulatory effect on all receptors, while other structures exert opposite effects on different receptors or in different cellular contexts. In light of the crucial role played by glycosylation in the regulation of receptor activity, the development of next-generation drugs targeting glyco-epitopes of growth factor receptors should be considered a therapeutically interesting goal.
Highlights
Cells receive the order to proliferate, survive, or die usually from the outside, in the form of small proteins that bind to specific receptors on their surface
The β1,6-branched glycans and their biosynthetic enzyme MGAT5 play a very important role in enhancing EGFR activity. These mechanisms include the activation of p21-activated kinase 1, which leads to resistance to anoikis [34], the inhibition of the protein tyrosine phosphatase kappa (RPTPκ) [35], and radioresistance [39], all related to the EGFR signaling pathway [38]
The role of O-glycosylation on Fibroblast growth factor receptors (FGFRs) signaling is shown by the effects of inhibition of GALNT3, which increases FGF23 cleavage [153] and by galactosylation of O-glycans of FGFR2 due to overexpression of C1GALT1 (Table 1), which results in the activation of the receptor and exacerbation of the malignant phenotype of CRC cells [70]
Summary
Cells receive the order to proliferate, survive, or die usually from the outside, in the form of small proteins that bind to specific receptors on their surface. Binding of these ligands, which include growth factors, cytokines, hormones, and death-inducing molecules, to their receptors triggers intracellular signaling cascades, which lead to gene transcription. Most of these receptors are classical tyrosine kinase receptors (RTKs). Notch receptors, which exhibit a very peculiar kind of glycosylation, have been the topic of recent reviews [4,5,6] and are not discussed here
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