The cell adhesion molecule echinoid functions as a tumor suppressor and upstream regulator of the Hippo signaling pathway.
The cell adhesion molecule echinoid functions as a tumor suppressor and upstream regulator of the Hippo signaling pathway.
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DOI：
10.1016/j.devcel.2011.12.011
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发表时间：
2012-02-14
影响因子：
11.8
通讯作者：
Jiang, Jin
中科院分区：
文献类型：
--
作者：
Yue, Tao;Tian, Aiguo;Jiang, Jin
Hippo（Hpo）信号通路控制从果蝇到哺乳动物的物种中的组织生长和器官大小，并且在广泛的人类癌症中被解除管制。核心途径由Hpo/Warts（Wts）激酶盒组成，其磷酸化并灭活转录辅激活因子Yorkie（Yki）。在这里，我们报告，海胆（艾德），免疫球蛋白结构域的细胞粘附分子，作为HPO通路的上游调节器。艾德的损失损害Yki磷酸化，导致升高的Yki活性，其增加Hpo靶基因表达并驱动组织过度生长。艾德与粘附连接处的Hpo结合伴侣萨尔瓦多（Sav）发生物理相互作用并使其稳定。艾德/Sav相互作用通过细胞-细胞接触促进，并且需要艾德胞质结构域的二聚化。Sav或二聚艾德胞质结构域的过表达抑制了艾德表型的丢失。我们认为，艾德可能通过结合和稳定Sav，从而调节Hpo激酶活性，从而将细胞-细胞接触与Hpo信号传导联系起来。
The Hippo (Hpo) signaling pathway controls tissue growth and organ size in species ranging from Drosophila to mammals and is deregulated in a wide range of human cancers. The core pathway consists of the Hpo/Warts (Wts) kinase cassette that phosphorylates and inactivates the transcriptional coactivator Yorkie (Yki). Here, we report that Echinoid (Ed), an immunoglobulin domain-containing cell adhesion molecule, acts as an upstream regulator of the Hpo pathway. Loss of Ed compromises Yki phosphorylation, resulting in elevated Yki activity that increases Hpo target gene expression and drives tissue overgrowth. Ed physically interacts with and stabilizes the Hpo-binding partner Salvador (Sav) at adherens junctions. Ed/Sav interaction is promoted by cell-cell contact and requires dimerization of Ed cytoplasmic domain. Overexpression of Sav or dimerized Ed cytoplasmic domain suppressed loss-of-Ed phenotypes. We propose that Ed may link cell-cell contact to Hpo signaling through binding and stabilizing Sav, thus modulating the Hpo kinase activity.
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