Lau Ken S, Dennis James W
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
Glycobiology. 2008 Oct;18(10):750-60. doi: 10.1093/glycob/cwn071. Epub 2008 Aug 13.
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.
高尔基体中间区域的N-聚糖分支产生用于形成晶格的凝集素（如半乳糖凝集素）的配体，这些凝集素调节包括表皮生长因子（EGF）和转化生长因子-β（TGF-β）受体在内的糖蛋白的表面水平。此外，糖蛋白的功能类别在N-聚糖多样性（N-聚糖/肽的数量）方面存在差异，这是糖蛋白的一个遗传编码特征，它与代谢通量（UDP-GlcNAc）和N-聚糖分支相互作用，以差异性地调节表面水平。肿瘤发生会增加β1,6-N-乙酰葡糖胺基转移酶V（由Mgat5编码）的表达，其高亲和力的半乳糖凝集素配体促进生长受体的表面保留，且对UDP-GlcNAc的依赖性降低。Mgat5（-/-）肿瘤细胞在体内的转移能力较低，在体外对细胞因子的反应较弱，但会发生支持肿瘤细胞增殖的继发性变化。这些变化包括Caveolin-1的缺失，Caveolin-1是EGF信号的负调节因子，以及活性氧的增加，活性氧是磷酸酪氨酸磷酸酶的抑制剂。这些研究表明了一种癌症治疗的系统方法，即通过代谢和N-聚糖分支来靶向受体的表面分布，以诱导生长停滞。
