Recycling of E-cadherin: implications for dynamic cell adhesion

e -钙粘蛋白是体内介导细胞间粘附的主要蛋白之一。在胚胎发育过程中，e -钙粘蛋白对于建立正常的机体模式和许多上皮器官的细胞结构至关重要。终其一生，e -钙粘蛋白维持上皮屏障，如消化道内壁。E-cadherin已被明确认定为肿瘤抑制分子：E-cadherin正常功能的丧失导致肿瘤转移和肿瘤侵袭。因此，了解e -钙粘蛋白在细胞中的生理功能和调控是必要的。e -钙粘蛋白通常在细胞表面表达，与邻近细胞粘附。最近，我们发现细胞可以内化和循环这种表面e -钙粘蛋白：即使在成熟上皮中，一部分e -钙粘蛋白分子似乎也在细胞内外不断运动。这一机制很可能参与了胃肠道等器官细胞间黏附接触的动态重塑以及伤口愈合过程。这种循环机制的破坏也可能潜在地促进肿瘤的发生。在这项资助中，我们建议通过研究介导e -钙粘蛋白回收的分子和细胞机制来建立这一发现。我们将描述e -钙粘蛋白被运输的细胞途径。由于这些信号通路可能在癌症和炎症中受到干扰，因此将对调节循环的信号通路进行分析。其他与e -钙粘蛋白相互作用的分子将被研究，以确定它们是否也会进行循环。来自这些研究的信息将对理解e -钙粘蛋白在健康器官和常见癌症中的作用具有广泛的意义。

E-cadherin is one of the major proteins responsible for mediating cell-to-cell adhesion in the body. During embryonic development E-cadherin is essential for establishing the normal body pattern and the cellular architecture of many epithelial organs. Throughout life E-cadherin serves to maintain epithelial barriers, such as the lining of the digestive tract. E-cadherin has been clearly identified as a tumour suppressor molecule: loss of normal E-cadherin function leads to tumour metastasis and cancer invasion. It is therefore essential to understand the physiological function and regulation of E-cadherin in cells. E-cadherin is normally expressed on the surface of cells for adhesion to neighbouring cells. Recently, we found that cells can internalise and recycle this surface E-cadherin: even in mature epithelia, a proportion of the E-cadherin molecules appear to undergo constant movement in and out of the cell. It is likely that this mechanism participates in the dynamic remodelling of adhesive contacts between cells in organs such as the gastrointestinal tract and during wound healing. Corruption of this recycling mechanism could also potentially contribute to tumorigenesis. In this grant we propose to build upon this discovery by investigating molecular and cellular mechanisms that mediate E-cadherin recycling. We will characterize the cellular pathways by which E-cadherin is trafficked. The signaling pathways that regulate recycling will be analysed, since these may be perturbed in cancer and inflammation. Other molecules that interact with E-cadherin will be studied to determine whether they too recycle. The information from these studies will have broad implications for understanding the role of E-cadherin in healthy organs and in common cancers.