title: UDP-N-acetylglucosamine:alpha-6-D-mannoside beta1,6 N-acetylglucosaminyltransferase V (Mgat5) deficient mice.
abstract: Targeted gene mutations in mice that cause deficiencies in protein glycosylation have revealed functions for specific glycans structures in embryogenesis, immune cell regulation, fertility and cancer progression. UDP-N-acetylglucosamine:alpha-6-D-mannoside beta1,6 N-acetylglucosaminyltransferase V (GlcNAc-TV or Mgat5) produces N-glycan intermediates that are elongated with poly N-acetyllactosamine to create ligands for the galectin family of mammalian lectins. We generated Mgat5-deficient mice by gene targeting methods in embryonic stem cells, and observed a complex phenotype in adult mice including susceptibility to autoimmune disease, reduced cancer progression and a behavioral defect. We found that Mgat5-modified N-glycans on the T cell receptor (TCR) complex bind to galectin-3, sequestering TCR within a multivalent galectin-glycoprotein lattice that impedes antigen-dependent receptor clustering and signal transduction. Integrin receptor clustering and cell motility are also sensitive to changes in Mgat5-dependent N-glycosylation. These studies demonstrate that low affinity but high avidity interactions between N-glycans and galectins can regulate the distribution of cell surface receptors and their responsiveness to agonists.
authors.affiliation: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. Dennis@mshri.on.ca
authors.forename: James W
authors.initials: JW
authors.lastname: Dennis
authors.forename: Judy
authors.initials: J
authors.lastname: Pawling
authors.forename: Pam
authors.initials: P
authors.lastname: Cheung
authors.forename: Emily
authors.initials: E
authors.lastname: Partridge
authors.forename: Michael
authors.initials: M
authors.lastname: Demetriou
mesh_terms: D000818:Animals; D002455:Cell Division; D051379:Mice; D018345:Mice, Knockout; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000502:physiology*; D011134:Polysaccharides / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism
chemical_list: D011134:Polysaccharides; D011948:Receptors, Antigen, T-Cell; D017351:N-Acetylglucosaminyltransferases; C052254:alpha-1,6-mannosylglycoprotein beta 1,6-N-acetylglucosaminyltransferase