Polarized trafficking of E-cadherin in epithelial cells.

细胞粘附蛋白E-cadherin在身体的所有上皮组织中表达，在发育和成人中建立和维持极化细胞单层具有重要功能。e -钙粘蛋白也是一种重要的肿瘤抑制因子，其正常功能保证细胞甚至早期肿瘤不会转移；相反，e -钙粘蛋白在恶性肿瘤中总是丢失或功能失调。早期的研究表明，e -钙粘蛋白不断地移动或运输，进出上皮细胞表面。这种贩运具有双重作用，首先是将新制造的e -钙粘蛋白运送到其发挥作用的表面，其次是调节其粘附功能。我们在这个项目中的研究主要集中在控制e -钙粘蛋白向细胞表面传递的分子和细胞内区室。e -钙粘蛋白必须经过分类才能被运送到细胞的正确一侧。我们已经在e -钙粘蛋白中发现了分选信号，现在我们将鉴定完成这种分选的同源适配蛋白。新的成像技术使我们能够研究活细胞内的蛋白质运输。最近的研究表明，e -钙粘蛋白在到达细胞表面的过程中通过一个循环的核内体隔室。这一意想不到的途径，以及回收内体的结构和作用，现在将在活细胞中进行详细的研究。最后，我们将比较E-cadherin与密切相关的N-cadherin蛋白的分类和运输，以确定它们的运输是否存在内在差异，这可以解释它们在肿瘤细胞中的相反作用，其中N-cadherin取代E-cadherin并允许转移行为。这些研究将为了解e -钙粘蛋白的粘附和肿瘤抑制作用提供重要信息。此外，我们的发现将为我们理解细胞极性和蛋白质分选提供基础信息。

The cell adhesion protein E-cadherin is expressed in all epithelial tissues of the body where it has essential functions during development and in the adult in establishing and maintaining polarized cell monolayers. E-cadherin is also a vital tumour suppressor, its normal function guarantees that cells or even early tumours cannot metastasise; in contrast E-cadherin is always lost or malfunctions in malignant tumours. Earlier studies showed that E-cadherin is constantly moved, or trafficked, to and from the surface of epithelial cells. This trafficking has dual roles, firstly in delivering newly-made E-cadherin to the surface where it functions and secondly, in regulating its adhesive function. Our research in this project is focussed on the molecules and intracellular compartments that control the delivery of E-cadherin to the cell surface. E-cadherin must be sorted in order to be delivered to the correct side of the cell. Having previously discovered the sorting signal in E-cadherin, we will now identify the cognate adaptor protein(s) that accomplish this sorting. New imaging techniques allow us to study protein trafficking inside live cells. Such studies have recently revealed that E-cadherin passes through a recycling endosome compartment on its way to the cell surface. This unexpected route, and the structure and role of the recycling endosome will now be studied in detail in live cells. Finally we will compare the sorting and trafficking of E-cadherin with the closely-related N-cadherin protein, to determine whether there are inherent differences in their trafficking that could explain their opposite roles in tumour cells, where N-cadherin is substituted for E-cadherin and allows metastatic behaviour. These studies will provide important information for understanding the adhesive and tumour suppressive roles of E-cadherin. In addition our findings will generate information fundamental to our understanding of cell polarity and protein sorting.