Polarized trafficking of E-cadherin in epithelial cells.

细胞黏附蛋白E-钙粘附素在人体的所有上皮组织中都有表达，在发育过程中具有重要的功能，在成人中也具有建立和维持极化细胞单层的功能。E-钙粘素也是一种重要的肿瘤抑制因子，它的正常功能保证了细胞甚至早期肿瘤不会转移；相比之下，在恶性肿瘤中，E-钙粘附素总是丢失或发生故障。早期的研究表明，E-钙粘素不断地移动或运输到上皮细胞表面或从上皮细胞表面转移出来。这种贩运具有双重作用，首先是将新制造的E-钙粘附素运送到其功能所在的表面，其次是调节其黏附功能。我们在这个项目中的研究集中在控制E-钙粘蛋白向细胞表面输送的分子和细胞内隔室。必须对E-钙粘附素进行分类，才能将其传递到细胞的正确一侧。之前在E-钙粘附素中发现了分选信号，现在我们将确定完成这种分选的同源适配蛋白(S)。新的成像技术使我们能够研究活细胞内的蛋白质运输。这类研究最近揭示，E-钙粘附素在到达细胞表面的过程中会通过一个循环的内体隔间。现在将在活细胞中详细研究这一意想不到的途径，以及循环内体的结构和作用。最后，我们将比较E-钙粘素的分类和运输与密切相关的N-钙粘素蛋白，以确定它们在运输过程中是否存在内在差异，这可以解释它们在肿瘤细胞中的相反作用，在肿瘤细胞中，N-钙粘附素取代E-钙粘附素并允许转移行为。这些研究将为理解E-钙粘附素的黏附和肿瘤抑制作用提供重要信息。此外，我们的发现将产生对我们理解细胞极性和蛋白质分类的基本信息。

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.