Lysosomal targeting of E-cadherin: a unique mechanism for the down-regulation of cell-cell adhesion during epithelial to mesenchymal transitions
Lysosomal targeting of E-cadherin: a unique mechanism for the down-regulation of cell-cell adhesion during epithelial to mesenchymal transitions
复制标题
DOI：
10.1128/mcb.25.1.389-402.2005
复制
发表时间：
2005-01-01
影响因子：
5.3
通讯作者：
D'Souza-Schorey, C
中科院分区：
文献类型：
--
作者：
Palacios, F;Tushir, JS;D'Souza-Schorey, C
上皮性肿瘤进展和某些正常发育过程的一个显著特征是失去上皮表型和获得可移动的或间充质表型。这种上皮细胞向间充质细胞的转变伴随着E-钙粘附素功能的丧失，无论是转录机制还是转录后机制。在这里，我们证明了，当v-Src表达时，E-钙粘素内化，然后穿梭到溶酶体，而不是循环回到侧膜。因此，虽然E-钙粘素内化有助于粘连连接的溶解，但它随后与溶酶体的交通是确保细胞不会改变其细胞-细胞接触并保持运动的一种手段。我们还表明，E-钙粘附素的泛素标记对于其对溶酶体的分类是必不可少的。E-钙粘蛋白的溶酶体靶向性是通过肝细胞生长因子调节的酪氨酸激酶底物(HRS)和v-Src诱导的Rab5和Rab7 GTP酶的激活而介导的。我们的研究表明，在Src诱导的上皮向间充质转化过程中，E-钙粘附素的溶酶体靶向是耗尽细胞内E-钙粘附素的重要转录后机制。
A hallmark characteristic of epithelial tumor progression as well as some processes of normal development is the loss of the epithelial phenotype and acquisition of a motile or mesenchymal phenotype. Such epithelial to mesenchymal transitions are accompanied by the loss of E-cadherin function by either transcriptional or posttranscriptional mechanisms. Here we demonstrate that, upon v-Src expression, a potent trigger of epithelial to mesenchymal transitions, E-cadherin is internalized and then shuttled to the lysosome instead of being recycled back to the lateral membrane. Thus, while E-cadherin internalization facilitates the dissolution of adherens junctions, its subsequent traffic to the lysosome serves as a means to ensure that cells do not reform their cell-cell contacts and remain motile. We also show that ubiquitin tagging of E-cadherin is essential for its sorting to the lysosome. The lysosomal targeting of E-cadherin is mediated by hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) and v-Src-induced activation of the Rab5 and Rab7 GTPases. Our studies reveal that the lysosomal targeting of E-cadherin is an important posttranscriptional mechanism to deplete cellular E-cadherin during Src-induced epithelial to mesenchymal transitions.