Hippo signaling is intrinsically regulated during cell cycle progression by APC/C Cdh1
Year: 2019
Type: article
Abstract: The Hippo-YAP/TAZ signaling pathway plays a pivotal role in growth control during development and regeneration and its dysregulation is widely implicated in various cancers. To further understand the cellular and molecular mechanisms underlying Hippo signaling regulation, we have found that activities of core Hippo signaling components, large tumor suppressor (LATS) kinases and YAP/TAZ transcription factors, oscillate during mitotic cell cycle. We further identified that the anaphase-promoting complex/cyclosome (APC/C) Cdh1 E3 ubiquitin ligase complex, which plays a key role governing eukaryotic cell cycle progression, intrinsically regulates Hippo signaling activities. CDH1 recognizes LATS kinases to promote their degradation and, hence, YAP/TAZ regulation by LATS phosphorylation is under cell cycle control. As a result, YAP/TAZ activities peak in G1 phase. Furthermore, we show in Drosophila eye and wing development that Cdh1 is required in vivo to regulate the LATS homolog Warts with a conserved mechanism. Cdh1 reduction increased Warts levels, which resulted in reduction of the eye and wing sizes in a Yorkie dependent manner. Therefore, LATS degradation by APC/C Cdh1 represents a previously unappreciated and evolutionarily conserved layer of Hippo signaling regulation.
Institutions: Harvard University, Chungnam National University, Harvard Stem Cell Institute, Korea Research Institute of Bioscience and Biotechnology, The University of Texas Southwestern Medical Center, National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, Chinese Academy of Sciences, Center for Excellence in Molecular Cell Science, Beth Israel Deaconess Medical Center, University of Seoul, Oklahoma Medical Research Foundation
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: green
Awards: G1599927933, Mechanisms of Hippo signaling in Alcoholic liver disease, Harvard Clinical and Translational Science Center (UL1), Cellular and molecular mechanism of Hippo signaling in suppressing liver tumor formation, Interplay between Cdh1 and major regulatory pathways in human cancer, G6461892610, Cell signaling in development and regeneration
OpenAlex ID: W2940319923