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

PAR-aPKC系统在上皮细胞顶基极性的建立中起着至关重要的作用。另一方面，细胞外基质（ECM）成分，特别是层粘连蛋白，在确定上皮极性轴方向方面的重要性最近已经确立。然而，PAR-aPKC系统与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的定位和功能来调节细胞外层粘连蛋白组织，即utrophin- dystrodyglycan （DG）复合物。PAR-lb至少部分通过直接磷酸化DG的Ser-814发挥这一功能。通过这一调控途径，PAR-lb在ecm引导的上皮细胞顶极取向中起着不可或缺的作用。目前的研究结果揭示了一种由内而外的新途径。内在PAR-aPKC系统调节外部极性，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-lb敲低诱导DG低糖基化，目前的结果也暗示了细胞极性蛋白与由已知或假定的糖基转移酶缺陷引起的先天性肌营养不良之间的意想不到的联系。

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.