Casein kinase 1 is a novel negative regulator of E-cadherin-based cell-cell contacts
Casein kinase 1 is a novel negative regulator of E-cadherin-based cell-cell contacts
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DOI：
10.1128/mcb.01590-06
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发表时间：
2007-05-01
影响因子：
5.3
通讯作者：
Fujita, Yasuyuki
中科院分区：
文献类型：
--
作者：
Dupre-Crochet, Sophie;Figueroa, Angelica;Fujita, Yasuyuki
钙粘蛋白是形成紧密和紧密的细胞-细胞接触的最重要的膜蛋白。基于钙粘蛋白的细胞-细胞粘附在各种生理和病理过程中动态建立和/或破坏。然而，调控细胞-细胞接触的分子机制尚不完全清楚。在本文中，我们报道了酪蛋白激酶1 （CK1）在细胞-细胞接触调节中的新功能作用。首先，我们观察到IC261，一种CK1的特异性抑制剂，稳定了钙粘蛋白为基础的细胞-细胞接触，而CK1的过表达破坏了它们。在体外和细胞培养系统中，CKI与e -钙粘蛋白共定位并磷酸化e -钙粘蛋白的细胞质结构域。我们发现E-cadherin的主要CK1磷酸化位点是丝氨酸846，这是经典钙粘蛋白之间的一个高度保守的残基。组成性磷酸化的E-cadherin （S846D）不能在细胞间接触处定位，并且粘附活性降低。此外，磷酸化的E-cadherin （S846D）与0-catenin的相互作用较弱，并且比野生型E-cadherin更有效地内化。这些数据表明CK1是钙粘蛋白为基础的细胞-细胞接触的一种新的负调节因子。
Cadherins are the most crucial membrane proteins for the formation of tight and compact cell-cell contacts. Cadherin-based cell-cell adhesions are dynamically established and/or disrupted during various physiological and pathological processes. However, the molecular mechanisms that regulate cell-cell contacts are not fully understood. In this paper, we report a novel functional role of casein kinase 1 (CK1) in the regulation of cell-cell contacts. Firstly, we observed that IC261, a specific inhibitor of CK1, stabilizes cadherin-based cell-cell contacts, whereas the overexpression of CK1 disrupts them. CKI colocalizes with E-cadherin and phosphorylates the cytoplasmic domain of E-cadherin in vitro and in a cell culture system. We show that the major CK1 phosphorylation site of E-cadherin is serine 846, a highly conserved residue between classical cadherins. Constitutively phosphorylated E-cadherin (S846D) is unable to localize at cell-cell contacts and has decreased adhesive activity. Furthermore, phosphorylated E-cadherin (S846D) has weaker interactions with 0-catenin and is internalized more efficiently than wild-type E-cadherin. These data indicate that CK1 is a novel negative regulator of cadherin-based cell-cell contacts.