The metalloprotease meprinbeta processes E-cadherin and weakens intercellular adhesion.
The metalloprotease meprinbeta processes E-cadherin and weakens intercellular adhesion.
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金属蛋白酶MEPRINBETA会处理E-钙粘蛋白并削弱细胞间粘附。
DOI：
10.1371/journal.pone.0002153
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发表时间：
2008-05-14
期刊：
影响因子：
3.7
通讯作者：
Lottaz, Daniel
中科院分区：
文献类型：
--
作者：
Huguenin, Maya;Mueller, Eliane J.;Trachsel-Roesmann, Sandra;Oneda, Beatrice;Ambort, Daniel;Sterchi, Erwin E.;Lottaz, Daniel
Meprin （EC 3.4.24.18）是一种类似astastin的金属蛋白酶，在肠和肾小管上皮中表达，与癌症有关，但机制联系尚不清楚。我们使用MDCK和Caco-2细胞稳定转染meprinα和/或meprinβ，建立肾和肠上皮细胞在生理水平上表达该蛋白酶的模型。在两种模型中，E-cadherin被切割，产生细胞相关的97 kda E-cadherin片段，该片段在meprin酶原激活时增强，在meprin抑制剂存在时减弱。裂解位点位于靠近质膜的胞外区域。纯化组分的体外实验表明，97-kDa片段是meprinβ特异性产生的，而不是ADAM-10或MMP-7。伴随着e -钙粘蛋白的分裂和e -钙粘蛋白细胞质尾部的降解，斑块蛋白β-连环蛋白和血小板红蛋白被细胞内蛋白酶加工，而α-连环蛋白不直接与e -钙粘蛋白结合，保持完整。使用共聚焦显微镜，我们观察到meprinβ和E-cadherin在融合前或融合早期不完全极化细胞的侧膜上部分共定位。表达meprinβ的细胞表现出细胞间接触强度降低，形成多细胞聚集体的倾向显著降低。通过在细胞背景下鉴定E-cadherin作为meprinβ的底物，本研究揭示了该蛋白酶在上皮细胞中的新的生物学作用。我们的研究结果表明，meprinβ在通过切割e -钙粘蛋白来控制粘附性方面起着至关重要的作用，并可能影响广泛的生物学过程，包括上皮屏障功能和癌症进展。
Meprin (EC 3.4.24.18), an astacin-like metalloprotease, is expressed in the epithelium of the intestine and kidney tubules and has been related to cancer, but the mechanistic links are unknown. We used MDCK and Caco-2 cells stably transfected with meprinα and or meprinβ to establish models of renal and intestinal epithelial cells expressing this protease at physiological levels. In both models E-cadherin was cleaved, producing a cell-associated 97-kDa E-cadherin fragment, which was enhanced upon activation of the meprin zymogen and reduced in the presence of a meprin inhibitor. The cleavage site was localized in the extracellular domain adjacent to the plasma membrane. In vitro assays with purified components showed that the 97-kDa fragment was specifically generated by meprinβ, but not by ADAM-10 or MMP-7. Concomitantly with E-cadherin cleavage and degradation of the E-cadherin cytoplasmic tail, the plaque proteins β-catenin and plakoglobin were processed by an intracellular protease, whereas α-catenin, which does not bind directly to E-cadherin, remained intact. Using confocal microscopy, we observed a partial colocalization of meprinβ and E-cadherin at lateral membranes of incompletely polarized cells at preconfluent or early confluent stages. Meprinβ-expressing cells displayed a reduced strength of cell-cell contacts and a significantly lower tendency to form multicellular aggregates. By identifying E-cadherin as a substrate for meprinβ in a cellular context, this study reveals a novel biological role of this protease in epithelial cells. Our results suggest a crucial role for meprinβ in the control of adhesiveness via cleavage of E-cadherin with potential implications in a wide range of biological processes including epithelial barrier function and cancer progression.
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影响因子：
21.3
作者：
Batlle, E;Sancho, E;de Herreros, AG
通讯作者：
de Herreros, AG
影响因子：
4.8
作者：
Bertenshaw, GP;Turk, BE;Bond, JS
通讯作者：
Bond, JS
影响因子：
4.8
作者：
Calautti, E;Li, J;Goetinck, PF
通讯作者：
Goetinck, PF
DOI：
10.1083/jcb.107.4.1575
发表时间：
1988-10
期刊：
The Journal of cell biology
影响因子：
--
作者：
Gumbiner B;Stevenson B;Grimaldi A
通讯作者：
Grimaldi A
影响因子：
3.7
作者：
Becker, C;Kruse, MN;Stöcker, W
通讯作者：
Stöcker, W