β1,6-branched N-glycans (β1,6-GlcNAc N-glycans)

β1,6-branched N-glycans are complex carbohydrate structures synthesized in the Golgi apparatus, primarily through the action of the enzyme N-acetylglucosaminyltransferase V (MGAT5 or GnT-V) [1.1.1, 1.1.4]. In many cancers, MGAT5 is overexpressed, leading to an increase in these branched glycans on the extracellular domains of key transmembrane receptors, including the Epidermal Growth Factor Receptor (EGFR), Transforming Growth Factor-beta Receptor (TGFBR), and various integrins [1.3.5, 1.5.2]. These glycans facilitate the formation of a galectin-glycan lattice by binding to galectins, such as Galectin-3, which cross-links and stabilizes the receptors on the cell surface [1.4.2, 1.5.4]. This stabilization prevents the receptors from being internalized via endocytosis, resulting in sustained oncogenic signaling that promotes cell proliferation, survival, and epithelial-mesenchymal transition (EMT) [1.3.3, 1.5.4]. Consequently, these glycans are critical drivers of tumor progression and metastasis across multiple solid malignancies [1.1.3, 1.5.1]. Therapeutic strategies targeting this pathway include small-molecule inhibitors of MGAT5 or alpha-mannosidase II, as well as agents that disrupt the galectin-glycan lattice to restore normal receptor turnover [1.4.1, 1.4.2].

Other names

β1,6-GlcNAc branched N-glycansGnT-V-modified N-glycansMGAT5-modified N-glycansTri-antennary N-glycansTetra-antennary N-glycansL-PHA-reactive glycans

Inhibition of N-acetylglucosaminyltransferase V (MGAT5) or alpha-mannosidase II to prevent glycan branching, or disruption of the galectin-glycan lattice to promote receptor endocytosis [1.4.2, 1.5.4].