Hippo signaling is intrinsically regulated during cell cycle progression by APC/CCdh1

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Title
Hippo signaling is intrinsically regulated during cell cycle progression by APC/CCdh1
Author(s)
Wantae Kim; Y S Cho; X Wang; O Park; X Ma; H Kim; W Gan; E H Jho; B Cha; Yun-Ji Jeung; L Zhang; B Gao; W Wei; J Jiang; Kyung-Sook Chung; Y Yang
Bibliographic Citation
Proceedings of National Academy of Sciences of United States of America, vol. 116, no. 19, pp. 9423-9432
Publication Year
2019
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.
Keyword
APC/CCdh1Hippo signalingLATS1/2Mitotic cell cycleYAP/TAZ
ISSN
0027-8424
Publisher
Natl Acad Sciences
DOI
http://dx.doi.org/10.1073/pnas.1821370116
Type
Article
Appears in Collections:
Division of Research on National Challenges > 1. Journal Articles
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