ADAM10 mediates E-cadherin shedding and regulates epithelial cell-cell adhesion, migration, and, β-catenin translocation
ADAM10 mediates E-cadherin shedding and regulates epithelial cell-cell adhesion, migration, and, β-catenin translocation
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DOI：
10.1073/pnas.0500918102
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发表时间：
2005-06-28
影响因子：
11.1
通讯作者：
Saftig, P
中科院分区：
文献类型：
--
作者：
Maretzky, T;Reiss, K;Saftig, P
E-钙粘蛋白控制广泛的细胞行为，包括细胞-细胞粘附、分化和组织发育。我们在这里表明，E-钙粘蛋白是专门切割的ADAM（解整合素和金属蛋白酶）10在其胞外域。对ADAM 10缺陷型成纤维细胞、抑制剂研究和RNA干扰介导的ADAM 10下调的分析表明，ADAM 10不仅负责组成性脱落，而且还负责成纤维细胞和角质形成细胞中该粘附分子的调节性脱落。ADAM 10介导的E-cadherin脱落影响上皮细胞-细胞粘附以及细胞迁移。此外，由ADAM 10脱落的E-钙粘蛋白调节β-连环蛋白亚细胞定位和下游信号传导。上皮细胞中ADAM 10的过表达增加了β-连环蛋白下游基因cyclin D1的表达，并呈剂量依赖性地增强了细胞增殖。在ADAM 10缺陷的小鼠胚胎中，C-末端E-钙粘蛋白片段不产生，全长蛋白积累，突出了ADAM 10在E-钙粘蛋白脱落中的体内相关性。我们的数据强烈表明，这种蛋白酶构成了一个主要的调节元件的多种功能的E-钙粘蛋白在生理以及病理条件下。
E-cadherin controls a wide array of cellular behaviors, including cell-cell adhesion, differentiation, and tissue development. We show here that E-cadherin is cleaved specifically by ADAM (a disintegrin and metalloprotease) 10 in its ectodomain. Analysis of ADAM 10-deficient fibroblasts, inhibitor studies, and RNA interference-mediated down-regulation of ADAM10 demonstrated that ADAM10 is responsible not only for the constitutive shedding but also for the regulated shedding of this adhesion molecule in fibroblasts and keratinocytes. ADAM10-mediated E-cadherin shedding affects epithelial cell-cell adhesion as well as cell migration. Furthermore, the shedding of E-cadherin by ADAM10 modulates the beta-catenin subcellular localization and downstream signaling. ADAM10 overexpression in epithelial cells increased the expression of the beta-catenin downstream gene cyclin D1 dose-dependently and enhanced cell proliferation. In ADAM10-deficient mouse embryos, the C-terminal E-cadherin fragment is not generated, and the full-length protein accumulates, highlighting the in vivo relevance for ADAM10 in E-cadherin shedding. Our data strongly suggest that this protease constitutes a major regulatory element for the multiple functions of E-cadherin under physiological as well as pathological conditions.