title: N-Glycans in cancer progression.
abstract: N-Glycan branching in the medial-Golgi generates ligands for lattice-forming lectins (e.g., galectins) that regulate surface levels of glycoproteins including epidermal growth factor (EGF) and transforming growth factor-beta (TGF-beta) receptors. Moreover, functional classes of glycoproteins differ in N-glycan multiplicities (number of N-glycans/peptide), a genetically encoded feature of glycoproteins that interacts with metabolic flux (UDP-GlcNAc) and N-glycan branching to differentially regulate surface levels. Oncogenesis increases beta1,6-N-acetylglucosaminyltransferase V (encoded by Mgat5) expression, and its high-affinity galectin ligands promote surface retention of growth receptors with a reduced dependence on UDP-GlcNAc. Mgat5(-/-) tumor cells are less metastatic in vivo and less responsive to cytokines in vitro, but undergo secondary changes that support tumor cell proliferation. These include loss of Caveolin-1, a negative regulator of EGF signaling, and increased reactive oxygen species, an inhibitor of phosphotyrosine phosphatases. These studies suggest a systems approach to cancer treatment where the surface distribution of receptors is targeted through metabolism and N-glycan branching to induce growth arrest.
authors.affiliation: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
authors.forename: Ken S
authors.initials: KS
authors.lastname: Lau
authors.forename: James W
authors.initials: JW
authors.lastname: Dennis
mesh_terms: D000818:Animals; D018450:Disease Progression; D006801:Humans; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D011134:Polysaccharides / Q000378:metabolism*; D011485:Protein Binding; D015398:Signal Transduction
chemical_list: D011134:Polysaccharides; D017351:N-Acetylglucosaminyltransferases