Signaling mechanism of epithelial cell-cell attachment and cell polarity.

上皮细胞-细胞附着和细胞极性的信号传导机制。

基本信息

批准号：
12219215
负责人：
OHNO Shigeo
金额：
$ 172.29万
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 on Priority Areas
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12219215/
关键词：
aPKC ASIP PAR-3 PAR-6 Lg1 Asymmetric division cell polarity epithelia

项目摘要

Epithelial cells represent the fundamental cell type in metazoa, which constitute sheets covering surface and make boundary between the interior and exterior of the organism. They not only work as selective permeability barriers, but also play active physiological roles such as adsorption and secretion. Furthermore, they provide driving forces of dynamic morphogenesis for development through the considerable plasticity in their structural organization. Recent progress in understanding evolutionarily-conserved cell polarity-machinery has provided significant insight in the mechanism by which the epithelial apico-basal polarity is generated. The breakthrough was opened by genetic analysis in C.elegans, that found the presence of cell polarity proteins, PAR proteins (PAR-1 to PAR-6), which, are essential to establish anterior-posterior (A-P) polarity of the embryo. We found that, among these PAR proteins, PAR-3 and PAR-6 form a ternary complex with atypical PKC (aPKC) and works as core cassette in generating asymmetries in many different cell types of various species. In epithelia, the protein complex asymmetrically localize to apical membrane in Drosophila or TJ in cultured epithelial cells of mammals, and exert indispensable roles to develop epithelia-specific cell adhesion structures triggered by cell-cell contact. We also found that Lg1, another conserved polarity protein, is one of the downstream targets of aPKC/PAR-3/PAR-6 complex required to direct cell polarization of epithelial cells. We also demonstrate that, PAR-1b, plays a role on development of asymmetric membrane domains whereas it does not play a significant role on the formation of cell-cell junctions. aPKC excludes PAR-1b from the apical membrane in cooperation with 14-3-3, and thus antagonizes PAR-1b activity. Taken together, mammalian PAR-1b plays a role on the establishment and maintenance of epithelial cell polarity under the negative control of aPKC.

上皮细胞代表后生动物中的基本细胞类型，该细胞构成覆盖表面并在生物体内部和外部之间界限。它们不仅起到了选择性的渗透性障碍的作用，而且还起着积极的生理作用，例如吸附和分泌。此外，它们通过其结构组织的相当可塑性提供了动态形态发生的驱动力。理解进化保存的细胞极性机制的最新进展为产生上皮apico-basal极性的机制提供了重要的见解。突破是通过遗传分析在C.Elegans中打开的，C.Elegans发现了细胞极性蛋白，PAR蛋白（PAR-1至PAR-6）的存在，这对于建立胚胎的前后（A-P）极性至关重要。我们发现，在这些PAR蛋白中，PAR-3和PAR-6形成了具有非典型PKC（APKC）的三元复合物，并且在许多不同物种的许多不同细胞类型中生成不对称性。在上皮中，蛋白质复合物不对称地定位于哺乳动物培养的上皮细胞中的果蝇或TJ的顶膜，并发挥不可或缺的作用，以发展由细胞细胞接触触发的上皮细胞粘附结构。我们还发现，LG1是另一种保守的极性蛋白，是导向上皮细胞的细胞极化所需的APKC/PAR-3/PAR-6复合物的下游靶标之一。我们还证明，PAR-1B在不对称膜结构域的发展中发挥作用，而它在细胞 - 细胞连接的形成中并不重要。 APKC与14-3-3合作将PAR-1B排除在顶端膜中，从而拮抗PAR-1B活性。综上所述，哺乳动物PAR-1B在APKC的负面控制下对上皮细胞极性的建立和维持起着作用。