Prometastatic effect of N-acetylglucosaminyltransferase V is due to modification and stabilization of active matriptase by adding β1-6 GlcNAc branching
Prometastatic effect of N-acetylglucosaminyltransferase V is due to modification and stabilization of active matriptase by adding β1-6 GlcNAc branching
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DOI：
10.1074/jbc.m200673200
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发表时间：
2002-05-10
影响因子：
4.8
通讯作者：
Taniguchi, N
中科院分区：
文献类型：
--
作者：
Ihara, S;Miyoshi, E;Taniguchi, N
糖蛋白的寡糖部分在发育、癌变和恶性转化过程中发生结构改变。众所周知，β 1 -6 GlcNAc分支是UDP-GlcNAc α-甘露糖苷β 1 -6-N-乙酰葡糖胺基转移酶（GnT-V）的产物，与此类改变导致的恶性转化相关。然而，β 1 -6 GlcNAc分支与转移相关的机制仍不清楚，因为GnT-V糖基化的特异性糖蛋白的鉴定及其生物学功能尚未研究。我们在此报告，matriptase，激活尿激酶型纤溶酶原激活剂和肝细胞生长因子，是GnT-V的靶蛋白。GnT-V在胃癌细胞中的过表达导致严重的腹膜播散在无胸腺小鼠，这可以归因于matriptase的表达增加。这种增加是由于间质蛋白酶对降解的获得性抗性，因为它被GnT-V糖基化以及活性形式的相应增加。这些结果表明，这一过程是恶性转化的关键因素，它是寡糖修饰的直接结果。
Oligosaccharide moieties of glycoproteins are structurally altered during development, carcinogenesis, and malignant transformations. It is well known that beta1-6 GlcNAc branching, a product of UDP-GlcNAc alpha-mannoside beta1-6-N-acetylglucosaminyltransferase (GnT-V), is associated with malignant transformation as the results of such alterations. However, the mechanism by which beta1-6 GlcNAc branching is linked to metastasis remains unclear, because the identification of specific glycoprotein(s) that are glycosylated by GnT-V and its biological function have not been examined. We herein report that matriptase, which activates both urokinase-type plasminogen activator and hepatocyte growth factor, is a target protein for GnT-V. The overexpression of GnT-V in gastric cancer cells leads to severe peritoneal dissemination in athymic mice, which can be attributed to the increased expression of matriptase. This increase was due to the acquired resistance of matriptase to degradation, since it is glycosylated by GnT-V and a corresponding increase in the active form. These results indicate that this process is a key element in malignant transformation, its the direct result of oligosaccharide modification.