A protein interaction map for cell-cell adhesion regulators identifies DUSP23 as a novel phosphatase for β-catenin.
A protein interaction map for cell-cell adhesion regulators identifies DUSP23 as a novel phosphatase for β-catenin.
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DOI：
10.1038/srep27114
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发表时间：
2016-06-03
影响因子：
4.6
通讯作者：
Brugge JS
中科院分区：
文献类型：
--
作者：
Gallegos LL;Ng MR;Sowa ME;Selfors LM;White A;Zervantonakis IK;Singh P;Dhakal S;Harper JW;Brugge JS
细胞间粘附是上皮细胞形态发生和维持状态的关键。我们以前确定了27个候选细胞-细胞粘附调节蛋白（CCARP），其下调在集体迁移过程中破坏上皮细胞-细胞粘附。使用蛋白质相互作用映射策略，我们发现18 CCARP连接到粘附连接或桥粒的核心组件。我们进一步绘制了CCARP和其他已知的细胞-细胞粘附蛋白之间的联系，包括最近发现E-钙粘蛋白粘附新成分的筛选结果。对一种与多种细胞-细胞粘附蛋白（磷酸酶DUSP 23）连接的新型CCARP的机制研究表明，它促进β-连环蛋白在Tyr 142处的去磷酸化，并增强α-和β-连环蛋白之间的相互作用。DUSP 23敲低特异性地减少了与E-钙粘蛋白的粘附，而不改变与纤连蛋白基质蛋白的粘附。此外，DUSP 23敲低产生“拉链样”细胞-细胞粘附，导致极化信号传递的缺陷，并减少集体迁移过程中的协调。因此，这项研究确定了调节细胞-细胞相互作用的蛋白质之间的多种新的连接，并为DUSP 23通过促进β-连环蛋白的去磷酸化在调节E-钙粘蛋白粘附连接中的先前未被认识的作用提供了证据。
Cell-cell adhesion is central to morphogenesis and maintenance of epithelial cell state. We previously identified 27 candidate cell-cell adhesion regulatory proteins (CCARPs) whose down-regulation disrupts epithelial cell-cell adhesion during collective migration. Using a protein interaction mapping strategy, we found that 18 CCARPs link to core components of adherens junctions or desmosomes. We further mapped linkages between the CCARPs and other known cell-cell adhesion proteins, including hits from recent screens uncovering novel components of E-cadherin adhesions. Mechanistic studies of one novel CCARP which links to multiple cell-cell adhesion proteins, the phosphatase DUSP23, revealed that it promotes dephosphorylation of β-catenin at Tyr 142 and enhances the interaction between α- and β-catenin. DUSP23 knockdown specifically diminished adhesion to E-cadherin without altering adhesion to fibronectin matrix proteins. Furthermore, DUSP23 knockdown produced “zipper-like” cell-cell adhesions, caused defects in transmission of polarization cues, and reduced coordination during collective migration. Thus, this study identifies multiple novel connections between proteins that regulate cell-cell interactions and provides evidence for a previously unrecognized role for DUSP23 in regulating E-cadherin adherens junctions through promoting the dephosphorylation of β-catenin.