Adaptive Regulation at the Cell Surface by N‐Glycosylation

The association of receptors and solute transporters with components of the endocytic machinery regulates their surface levels, and thereby cellular sensitivity to cytokines, ligands and nutrients in the extracellular environment. Most transmembrane receptors and solute transporters are glycoproteins, and the Asn (N)‐linked oligosaccharides (N‐glycans) can bind animal lectins, forming multivalent lattices or microdomains that regulate glycoprotein mobility in the plane of membrane. The N‐glycan number (sequence‐encoded NXS/T) and context‐dependent Golgi N‐glycan branching cooperate to regulate glycoprotein affinities for the galectin family of lectins. Galectin‐3 binding reduces EGF receptor trafficking into clathrin‐coated pits and caveolae lipid rafts, decreases ligand‐independent receptor activation and promotes α5β1 integrin remodelling in focal adhesions. N‐glycan branching in the medial Golgi increases glycan affinity for galectins, and the Golgi pathway is sensitive to uridine diphosphate‐N‐acetylglucosamine (UDP‐GlcNAc) supply, in turn hexosamine pathway metabolites (fructose‐6‐P, glutamine and acetyl‐CoA). Thus, lattice avidity and cellular responsiveness to extracellular cues are regulated in an adaptive manner by metabolism and Golgi modification to glycoproteins. Computational modelling of the hexosamine/Golgi/lattice has provided new insight on cell surface adaptation in cancer and autoimmune disease.

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