Summary

Function

Catalyzes the addition of N-acetylglucosamine in beta 1-6 linkage to the alpha-linked mannose of biantennary N-linked oligosaccharides. It is one of the most important enzymes involved in the regulation of the biosynthesis of glycoprotein oligosaccharides.

Disease relevance of MGAT5

• Our results indicate that inhibitors of MGAT5 might be useful in the treatment of malignancies by targeting their dependency on focal adhesion signaling for growth and metastasis [1].
• Amounts of MGAT5 glycan products are commonly increased in malignancies, and correlate with disease progression [1].
• Transformation of baby hamster kidney fibroblasts by the Rous sarcoma virus causes a significant increase in the GlcNAcbeta(1, 6)Man-branched oligosaccharides by elevating the activity and mRNA transcript levels encoding N-acetylglucosaminyltransferase V (GlcNAc-T V) [2].
• Mammary tumor growth and metastases induced by the polyomavirus middle T oncogene was considerably less in Mgat5-/- mice than in transgenic littermates expressing Mgat5 [1].
• Dysregulation of Mgat5 in humans may increase susceptibility to autoimmune diseases, such as multiple sclerosis [3].

High impact information on MGAT5

• Here we demonstrate that a deficiency in beta1,6 N-acetylglucosaminyltransferase V (Mgat5), an enzyme in the N-glycosylation pathway, lowers T-cell activation thresholds by directly enhancing TCR clustering [3].
• Mgat5-deficient mice showed kidney autoimmune disease, enhanced delayed-type hypersensitivity, and increased susceptibility to experimental autoimmune encephalomyelitis [3].
• Negative regulation of T-cell activation and autoimmunity by Mgat5 N-glycosylation [3].
• These data indicate that a galectin-glycoprotein lattice strengthened by Mgat5-modified glycans restricts TCR recruitment to the site of antigen presentation [3].
• Mgat5 initiates GlcNAc beta1,6 branching on N-glycans, thereby increasing N-acetyllactosamine, the ligand for galectins, which are proteins known to modulate T-cell proliferation and apoptosis [3].

Biological context of MGAT5

• Elevated activity and mRNA levels could be inhibited by blocking cell proliferation with herbimycin A, demonstrating that Src kinase activity can regulate GlcNAc-T V expression [2].
• This stimulation by src could be antagonized by co-transfection with a dominant-negative mutant of the Raf kinase, suggesting the involvement of Ets transcription factors in the regulation of GlcNAc-T V gene expression [2].
• Furthermore, Mgat5 glycan products stimulated membrane ruffling and phosphatidylinositol 3 kinase-protein kinase B activation, fueling a positive feedback loop that amplified oncogene signaling and tumor growth in vivo [1].
• We describe a new phenotype of wide occurrence in human cancer: expression of coarse vesicles rich in beta1,6-branched oligosaccharides. beta1,6-branching, catalyzed by GNT-V, is associated with metastasis and predicts poor survival in primary human breast and colon carcinomas [4].
• Promoter/reporter experiments showed that her-2/neu stimulates transcription from the human GlcNAc-T V promoter and that the her-2/neu response element was located about 400 bp 5' of the transcription initiation site and includes three Ets transcription factor binding sequences [5].

Anatomical context of MGAT5

• By contrast, a lectin-resistant BHK cell line selected for its ability to grow in high levels of L-phytohemagglutinin, LP3.3, is characterized by a specific decrease in its GlcNAc-T V activity [6].
• When extracts of Lec8 CHO cells were used as acceptors, GlcNAc-T V preferentially transferred to LAMPs, and only low level transfer was observed to other cell-derived glycoproteins, thus demonstrating specificity of GlcNAc-T V toward native glycoprotein acceptors [7].
• Mv1Lu type II alveolar cells transfected with Golgi beta1,6 N-acetylglucosaminyltransferase V (Mgat5), enhancing the polylactosamine content of complex-type N-glycans, exhibit stable expression of MLBs whose formation requires lysosomal proteolysis within dense autophagic vacuoles [8].
• GlcNAc beta 1-2(4,6-di-O-methyl-)Man alpha 1-6Glc beta-pnp was found to be an inhibitor of GlcNAc-T V from hamster kidney, hen oviduct microsomes and acute and chronic myeloid leukaemia leukocytes [9].

Associations of MGAT5 with chemical compounds

• These results demonstrate that the mechanism of glycoprotein-specific branching by GlcNAc-T V is determined primarily by its accessibility to available bi/triantennary oligosaccharides on glycoproteins and not by its recognition of peptide determinants or conformation-specific determinants [7].
• The formation of tri- and tetraantennary complex-type N-linked oligosaccharides in animal glycoproteins is partly regulated by UDP-N-acetylglucosamine:beta-6-D-mannoside beta-1,6-N-acetylglucosaminyltransferase (EC 2.4.1.155) (GlcNAc-T V), which generates 2,6-branched mannose [7].
• In Mv1Lu cells treated with the NPC-mimicking drug U18666A, cholesterol-rich MLBs accumulate independently of both Mgat5 expression and lysosomal proteolysis [8].
• The enzymatic mechanisms of the above changes were revealed in further study to involve the decrease of N-acetylglucosaminyl-transferase V and core alpha-1,6-fucosyltransferase by retinoic acid [10].
• Four analogs of trisaccharide 3 where OH-3" and OH-6" were replaced, independently, by NH2 and NHAc groups, were prepared by multi-step chemical synthesis and kinetically evaluated as substrates for GlcNAc T-V from hamster kidney [11].

Other interactions of MGAT5

• These results suggest that the growth-associated alteration in the oligosaccharides of transferrin is due, at least in part, to the regulation of GlcNAc-T V activity [12].
• Identification of target proteins of N-acetylglucosaminyl transferase V in human colon cancer and implications of protein tyrosine phosphatase kappa in enhanced cancer cell migration [13].
• Identification of target proteins of N-acetylglucosaminyl-transferase V and fucosyltransferase 8 in human gastric tissues by glycomic approach [14].

References