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Functional analysis of effects of N-glycans on membrane recnpthrs and their associations

N-聚糖对膜受体及其关联的影响的功能分析

基本信息

批准号：
18570177
负责人：
GU Jianguo
金额：
$ 2.55万
依托单位：
Tohoku Pharmaceutical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

Glycosylation is involved in a variety of physiological and pathological events, including cell growth, migration, differentiation and tumor invasion. Branched N-glycans, such as bisecting GlcNAc, β1, 6 GlcNAc and core fucose (α1, 6 fucose), are enzymatic products of GnT-III, GnT-V and Fut8, respectively. These branched structures are highly associated with various biological functions of cell adhesion molecules, including cell adhesion and cancer metastasis. We have found Following: 1), α3β1 integrin could be modified by either GnT-III or GnT-V, and GnT-III inhibited GnT-V-stimulated α3β1 integrin-mediated cell migration. The priority of GnT-III for modification of the α3 subunit may explain inhibition of GnT V-induced cell migration by GnT-III. These results were the first to demonstrate that GnT-III and GnT-V competitively modify the same target glycoprotein and that this competition between enzymes either positively or negatively regulates the biological function of the target protein. 2), the role of core fucosylation in α3β1 integrin-mediated events has been studied using Fut8^<+/+> and Fut8^<-/-> embryonic fibroblasts. α3β1 integrin-mediated migration was reduced in Fut8^<-/-> cells. Reintroduction of Fut8 has the potential to reverse such impairments, suggesting that core fucosylation is essential for functional α3β1 integrin. 3), integrins have multiple potential N-glycosylation sites, only N-glycans located on certain motifs regulate integrin conformation and biological function. For example, only N-glycans located on either the β-propeller of α5 integrin contribute to the regulation of integrin function.

糖基化参与多种生理和病理事件，包括细胞生长、迁移、分化和肿瘤侵袭。支链N-聚糖，如二等分GlcNAc、β1，6 GlcNAc和核心岩藻糖（α1，6岩藻糖），分别是GnT-III、GnT-V和Fut 8的酶促产物。这些分支结构与细胞粘附分子的各种生物学功能高度相关，包括细胞粘附和癌症转移。我们发现：GnT-V和GnT-III均可修饰α3β1整合素，GnT-III可抑制GnT-V刺激的α3β1整合素介导的细胞迁移。GnT-III优先修饰α3亚基可以解释GnT-III抑制GnT V诱导的细胞迁移。这些结果首次证明GnT-III和GnT-V竞争性修饰相同的靶糖蛋白，并且酶之间的这种竞争正向或负向调节靶蛋白的生物学功能。2），已经使用Fut 8 ^<+/+>和Fut 8 ^<-/->胚胎成纤维细胞研究了核心岩藻糖基化在α3β1整联蛋白介导的事件中的作用。α3β1整合素介导的迁移在Fut 8 ^<-/->细胞中减少。Fut 8的重新引入有可能逆转这种损伤，表明核心岩藻糖基化对于功能性α3β1整联蛋白是必不可少的。3）整合素具有多个潜在的N-糖基化位点，只有位于特定基序上的N-聚糖才能调节整合素的构象和生物学功能。例如，仅位于α5整联蛋白的β-推进器上的N-聚糖有助于整联蛋白功能的调节。