Maretzky Thorsten, Reiss Karina, Ludwig Andreas, Buchholz Julian, Scholz Felix, Proksch Erhardt, de Strooper Bart, Hartmann Dieter, Saftig Paul
Biochemical Institute and Department of Dermatology, Christian-Albrechts-University Kiel, D-24098 Kiel, Germany.
Proc Natl Acad Sci U S A. 2005 Jun 28;102(26):9182-7. doi: 10.1073/pnas.0500918102. Epub 2005 Jun 15.
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 ADAM10-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.
E-钙黏蛋白控制着一系列广泛的细胞行为，包括细胞间黏附、分化和组织发育。我们在此表明，E-钙黏蛋白在其胞外结构域被ADAM（一种解整合素和金属蛋白酶）10特异性切割。对ADAM10缺陷型成纤维细胞的分析、抑制剂研究以及RNA干扰介导的ADAM10下调表明，ADAM10不仅负责这种黏附分子在成纤维细胞和角质形成细胞中的组成性脱落，还负责其调节性脱落。ADAM10介导的E-钙黏蛋白脱落影响上皮细胞间黏附以及细胞迁移。此外，ADAM10介导的E-钙黏蛋白脱落调节β-连环蛋白的亚细胞定位和下游信号传导。上皮细胞中ADAM10的过表达剂量依赖性地增加了β-连环蛋白下游基因细胞周期蛋白D1的表达，并增强了细胞增殖。在ADAM10缺陷型小鼠胚胎中，未产生E-钙黏蛋白的C末端片段，全长蛋白积累，突出了ADAM10在E-钙黏蛋白脱落在体内的相关性。我们的数据强烈表明，这种蛋白酶构成了生理和病理条件下E-钙黏蛋白多种功能的主要调节元件。
