权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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，例如平分 GlcNAc、β1、6 GlcNAc 和核心岩藻糖（α1、6 岩藻糖），分别是 GnT-III、GnT-V 和 Fut8 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：1）α3β1整合素可以被GnT-III或GnT-V修饰，并且GnT-III抑制GnT-V刺激的α3β1整合素介导的细胞迁移。 GnT-III 对 α3 亚基修饰的优先性可能解释了 GnT-III 对 GnT V 诱导的细胞迁移的抑制。这些结果首次证明 GnT-III 和 GnT-V 竞争性修饰相同的靶标糖蛋白，并且酶之间的这种竞争可以正向或负向调节靶蛋白的生物学功能。 2)，使用 Fut8^<+/+> 和 Fut8^</-/-> 胚胎成纤维细胞研究了核心岩藻糖基化在 α3β1 整合素介导的事件中的作用。 Fut8^</-/-> 细胞中α3β1 整合素介导的迁移减少。重新引入 Fut8 有可能逆转此类损伤，这表明核心岩藻糖基化对于功能性 α3β1 整合素至关重要。 3)、整合素具有多个潜在的N-糖基化位点，只有位于某些基序上的N-聚糖调节整合素构象和生物学功能。例如，只有位于 α5 整合素任一 β 螺旋桨上的 N-聚糖有助于整合素功能的调节。