Yang Chih-Chao, Graves Hillary K, Moya Ivan M, Tao Chunyao, Hamaratoglu Fisun, Gladden Andrew B, Halder Georg
Departments of Biochemistry and Molecular Biology and Program in Genes and Development, The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030; Genetics, University of Texas MD Anderson Cancer Center, Houston, TX 77030;
Departments of Biochemistry and Molecular Biology and.
Proc Natl Acad Sci U S A. 2015 Feb 10;112(6):1785-90. doi: 10.1073/pnas.1420850112. Epub 2015 Jan 26.
Adherens junctions (AJs) and cell polarity complexes are key players in the establishment and maintenance of apical-basal cell polarity. Loss of AJs or basolateral polarity components promotes tumor formation and metastasis. Recent studies in vertebrate models show that loss of AJs or loss of the basolateral component Scribble (Scrib) cause deregulation of the Hippo tumor suppressor pathway and hyperactivation of its downstream effectors Yes-associated protein (YAP) and Transcriptional coactivator with PDZ-binding motif (TAZ). However, whether AJs and Scrib act through the same or independent mechanisms to regulate Hippo pathway activity is not known. Here, we dissect how disruption of AJs or loss of basolateral components affect the activity of the Drosophila YAP homolog Yorkie (Yki) during imaginal disc development. Surprisingly, disruption of AJs and loss of basolateral proteins produced very different effects on Yki activity. Yki activity was cell-autonomously decreased but non-cell-autonomously elevated in tissues where the AJ components E-cadherin (E-cad) or α-catenin (α-cat) were knocked down. In contrast, scrib knockdown caused a predominantly cell-autonomous activation of Yki. Moreover, disruption of AJs or basolateral proteins had different effects on cell polarity and tissue size. Simultaneous knockdown of α-cat and scrib induced both cell-autonomous and non-cell-autonomous Yki activity. In mammalian cells, knockdown of E-cad or α-cat caused nuclear accumulation and activation of YAP without overt effects on Scrib localization and vice versa. Therefore, our results indicate the existence of multiple, genetically separable inputs from AJs and cell polarity complexes into Yki/YAP regulation.
黏着连接（AJs）和细胞极性复合体是顶端-基底细胞极性建立和维持的关键参与者。AJs或基底外侧极性成分的缺失会促进肿瘤形成和转移。最近在脊椎动物模型中的研究表明，AJs的缺失或基底外侧成分Scribble（Scrib）的缺失会导致Hippo肿瘤抑制通路失调及其下游效应因子Yes相关蛋白（YAP）和含PDZ结合基序的转录共激活因子（TAZ）的过度激活。然而，AJs和Scrib是否通过相同或独立的机制调节Hippo通路活性尚不清楚。在这里，我们剖析了AJs的破坏或基底外侧成分的缺失如何在幼虫盘发育过程中影响果蝇YAP同源物Yorkie（Yki）的活性。令人惊讶的是，AJs的破坏和基底外侧蛋白的缺失对Yki活性产生了非常不同的影响。在AJ成分E-钙黏蛋白（E-cad）或α-连环蛋白（α-cat）被敲低的组织中，Yki活性在细胞自主水平上降低，但在非细胞自主水平上升高。相比之下，scrib敲低主要导致Yki的细胞自主激活。此外，AJs或基底外侧蛋白的破坏对细胞极性和组织大小有不同的影响。同时敲低α-cat和scrib会诱导细胞自主和非细胞自主的Yki活性。在哺乳动物细胞中，敲低E-cad或α-cat会导致YAP的核积累和激活，而对Scrib的定位没有明显影响，反之亦然。因此，我们的结果表明，存在多种从AJs和细胞极性复合体到Yki/YAP调节的遗传上可分离的输入。
