@article{12d92efa084345cfa94a8fe72b34fb5a,
title = "Hippo signaling is intrinsically regulated during cell cycle progression by APC/CCdh1 ",
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/CCdh1 represents a previously unappreciated and evolutionarily conserved layer of Hippo signaling regulation.",
keywords = "APC/CCdh1, Hippo signaling, LATS1/2, Mitotic cell cycle, YAP/TAZ",
author = "Wantae Kim and Cho, {Yong Suk} and Xiaohui Wang and Ogyi Park and Xueyan Ma and Hanjun Kim and Wenjian Gan and Jho, {Eek hoon} and Boksik Cha and Jeung, {Yun ji} and Lei Zhang and Bin Gao and Wenyi Wei and Jin Jiang and Chung, {Kyung Sook} and Yingzi Yang",
note = "Funding Information: We thank members of the Y.Y. laboratory for stimulating discussion; S. Wincovitch (NIH/National Human Genome Research Institute) for pictures of proximity-ligation assay; S. Anderson (NIH/National Human Genome Research Institute) for flow cytometry; J. Lukas (Institute of Cancer Biology, Denmark) for reagents; and Radhika Khetani and Michael Steinbaugh of the Harvard Chan Bioinformatics Core from the Harvard T. H. Chan School of Public Health for assistance with the Gene Expression Omnibus submission. The assistance of Radhika Khetani and Michael Steinbaugh was supported by funding from Harvard Catalyst j The Harvard Clinical and Translational Science Center (NIH Award UL1 RR 025758 and financial contributions from participating institutions). This study is supported by National Human Genome Research Institute intramural research grants, and NIH Grant AA025725, R01CA222571 (to Y.Y. and X.W.); NIH Grant GM118063 and Welch Foundation Grant I-1603 (to J.J.); NIH Grant 1GM089763 (to W.W.); a National Institute of Alcohol Abuse and Alcoholism intramural research grant (to B.G.); National Research Foundation of Korea Grant NRF-2016R1A5A1010764 (to E.-h.J.); the Basic Research Program through the National Research Foundation Grant NRF-2018R1C1B6002749 (to W.K.); and the Korea Research Institute of Bioscience and Biotechnology Initiative of the Korea Research Council of Fundamental Science and Technology (K.-S.C.). Funding Information: ACKNOWLEDGMENTS. We thank members of the Y.Y. laboratory for stimulating discussion; S. Wincovitch (NIH/National Human Genome Research Institute) for pictures of proximity-ligation assay; S. Anderson (NIH/National Human Genome Research Institute) for flow cytometry; J. Lukas (Institute of Cancer Biology, Denmark) for reagents; and Radhika Khetani and Michael Steinbaugh of the Harvard Chan Bioinformatics Core from the Harvard T. H. Chan School of Public Health for assistance with the Gene Expression Omnibus submission. The assistance of Radhika Khetani and Michael Steinbaugh was supported by funding from Harvard Catalyst | The Harvard Clinical and Translational Science Center (NIH Award UL1 RR 025758 and financial contributions from participating institutions). This study is supported by National Human Genome Research Institute intramural research grants, and NIH Grant AA025725, R01CA222571 (to Y.Y. and X.W.); NIH Grant GM118063 and Welch Foundation Grant I-1603 (to J.J.); NIH Grant 1GM089763 (to W.W.); a National Institute of Alcohol Abuse and Alcoholism intramural research grant (to B.G.); National Research Foundation of Korea Grant NRF-2016R1A5A1010764 (to E.-h.J.); the Basic Research Program through the National Research Foundation Grant NRF-2018R1C1B6002749 (to W.K.); and the Korea Research Institute of Bioscience and Biotechnology Initiative of the Korea Research Council of Fundamental Science and Technology (K.-S.C.). Publisher Copyright: {\textcopyright} 2019 National Academy of Sciences. All rights reserved.",
year = "2019",
month = may,
day = "7",
doi = "10.1073/pnas.1821370116",
language = "English (US)",
volume = "116",
pages = "9423--9432",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "19",
}