期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：6
页码：1785-1790
DOI：10.1073/pnas.1420850112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceThe control of organ growth involves cell-cell communication that is mediated by signal transduction pathways. The Hippo signaling pathway has emerged as an essential regulator of organ size in Drosophila and mammals, and defects in Hippo signaling drive cancer progression. An important unresolved question in the growth control field is, How is the Hippo pathway regulated? Recent reports show that adherens junctions and cell polarity complexes regulate the Hippo pathway, but controversy exists about the mechanisms involved. Here we report that in Drosophila and in mammalian cells, adherens junctions and basolateral polarity complexes regulate the Hippo pathway independently of each other. These results thus deepen our knowledge of this important growth control and tumor suppressor pathway. 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 -catenin (-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 -cat and scrib induced both cell-autonomous and non-cell-autonomous Yki activity. In mammalian cells, knockdown of E-cad or -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.
