Department of Developmental Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
Dev Cell. 2012 Feb 14;22(2):255-67. doi: 10.1016/j.devcel.2011.12.011. Epub 2012 Jan 25.
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.
Hippo（Hpo）信号通路控制着从果蝇到哺乳动物等物种的组织生长和器官大小，并且在广泛的人类癌症中失调。该核心途径由 Hpo/Warts（Wts）激酶盒组成，该激酶盒磷酸化并使转录共激活因子 Yorkie（Yki）失活。在这里，我们报告说，棘皮动物（Ed），一种含有免疫球蛋白结构域的细胞粘附分子，作为 Hpo 途径的上游调节剂。Ed 的缺失会损害 Yki 的磷酸化，导致 Yki 活性升高，从而增加 Hpo 靶基因的表达并驱动组织过度生长。Ed 与 Hpo 结合伙伴 Salvador（Sav）在黏着连接处以物理方式相互作用并稳定其。Ed/Sav 相互作用是通过细胞-细胞接触促进的，并且需要 Ed 细胞质结构域的二聚化。Sav 或二聚化的 Ed 细胞质结构域的过表达可抑制 Ed 缺失表型。我们提出，Ed 可能通过与 Sav 的结合和稳定，将细胞-细胞接触与 Hpo 信号联系起来，从而调节 Hpo 激酶活性。
