Study of a novel regulatory mechanism by which the aPKC/PAR system regulates the late phase of epithelical cell polarization

aPKC/PAR系统调控上皮细胞极化晚期的新型调控机制研究

• 批准号: 18570183
• 负责人: SUZUKI Atsushi
• 金额: $ 2.63万
• 依托单位: Yokohama City 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
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18570183/
• 关键词: aPKC; PAR-1; epithelial cells; polarity; basal laminina; dvstroglycan; cancer; muscular dystrophy

The PAR-aPKC system plays crucial roles in establishing the apicobasal polarity of epithelial cells. On the other hand, the importance of extracellular matrix (ECM) components, especially laminin, in determining the orientation of the epithelial polarity axis has recently been established. However, molecular links between the PAR-aPKC system and ECM are still missing. In this work, we revealed that one component of the PAR-aPKC system, PAR-lb kinase, regulates extracellular laminin organization by controlling the localization and function of the laminin receptor complex, i.e. the utrophin-dystroglycan (DG) complex. PAR-lb exerts this function, at least in part, by directly phosphorylating Ser-814 of DG. Through this regulatory pathway, PAR-lb plays indispensable roles in ECM-directed apical pole orientation in epithelial cells. The present results reveal a novel inside-out pathway, .by which the intrinsic PAR-aPKC system regulates the extrinsic polarity cue essential for integrating the polarity axes of individual cells in epithelial tissues. Since PAR-lb knockdown induces DG hypoglycosylation, the present results also imply an unexpected link between cell polarity proteins and congenital muscular dystrophies caused by defects in known or putative glycosyltransferases.

PAR-aPKC 系统在建立上皮细胞的顶端基底极性方面起着至关重要的作用。另一方面，细胞外基质（ECM）成分，尤其是层粘连蛋白，在确定上皮极性轴方向方面的重要性最近已经确定。然而，PAR-aPKC 系统和 ECM 之间的分子联系仍然缺失。在这项工作中，我们揭示了 PAR-aPKC 系统的一个组成部分，PAR-lb 激酶，通过控制层粘连蛋白受体复合物（即肌营养不良蛋白-肌营养不良聚糖 (DG) 复合物）的定位和功能来调节细胞外层粘连蛋白组织。 PAR-1b至少部分地通过直接磷酸化DG的Ser-814来发挥该功能。通过该调节途径，PAR-1b在上皮细胞中ECM引导的顶极方向中发挥着不可或缺的作用。目前的结果揭示了一种新的由内而外的途径，通过该途径，内在的 PAR-aPKC 系统调节外在的极性线索，这对于整合上皮组织中单个细胞的极性轴至关重要。由于PAR-1b敲低诱导DG低糖基化，因此目前的结果还暗示细胞极性蛋白与由已知或推定的糖基转移酶缺陷引起的先天性肌营养不良症之间存在意想不到的联系。

项目成果

Polarity protein PAR- lb regulates extracellular laminin organization through regulation of the utrophin-dystroglycan complex.

极性蛋白PAR-1b通过调节肌营养不良蛋白-肌营养不良聚糖复合物来调节细胞外层粘连蛋白组织。

• 发表时间: 2007
• 作者: Suzuki;A.;et. al.
• 通讯作者: et. al.

PAR-1bによるDystroglycan 複合体制御機構の解析

PAR-1b对肌营养不良聚糖复合物的调控机制分析

• 发表时间: 2006
• 作者: 山下 和成;ら
• 通讯作者: ら

Junctional development of epithelial cells is divided into distinct phases in which aPKC and Rho/ROCK/NMY2 are differentially involved.

上皮细胞的连接发育分为不同的阶段，其中 aPKC 和 Rho/ROCK/NMY2 的参与不同。

• 发表时间: 2006
• 作者: Kishikawa;M.;et. al.
• 通讯作者: et. al.

The PAR=aPKC system : lesson in polarity

PAR=aPKC 系统：极性的教训

• 发表时间: 2006
• 期刊: J.Cell Sci. 119
• 作者: Suzuki A;Ohno S
• 通讯作者: Ohno S

PAR-3はaPKC/PAR-6複合体形成を通じ上皮細胞のアピカルドメインの形成に働く

PAR-3 通过 aPKC/PAR-6 复合物的形成在上皮细胞顶端结构域的形成中发挥作用

• 发表时间: 2006
• 作者: 堀越 洋輔;ら
• 通讯作者: ら