APA
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Kim, W., Cho, Y., Wang, X. L., Park, O., Ma, X., Kim, H., … Yang, Y. (2019). Hippo signaling is intrinsically regulated during cell cycle progression by APC/CCdh1. Proceedings of the National Academy of Sciences of the United States of America.
Chicago/Turabian
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Kim, Wantae, Y. Cho, Xiaohui L. Wang, Ogyi Park, Xueyan Ma, Hanjun Kim, W. Gan, et al. “Hippo Signaling Is Intrinsically Regulated during Cell Cycle Progression by APC/CCdh1.” Proceedings of the National Academy of Sciences of the United States of America (2019).
MLA
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Kim, Wantae, et al. “Hippo Signaling Is Intrinsically Regulated during Cell Cycle Progression by APC/CCdh1.” Proceedings of the National Academy of Sciences of the United States of America, 2019.
BibTeX Click to copy
@article{wantae2019a,
title = {Hippo signaling is intrinsically regulated during cell cycle progression by APC/CCdh1},
year = {2019},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
author = {Kim, Wantae and Cho, Y. and Wang, Xiaohui L. and Park, Ogyi and Ma, Xueyan and Kim, Hanjun and Gan, W. and Jho, E. and Cha, B. and Jeung, Yunsuk and Zhang, Lei and Gao, B. and Wei, Wenyi and Jiang, Jin and Chung, K. and Yang, Yingzi}
}
Significance The Hippo signaling pathway is evolutionarily conserved in the animal kingdom and plays essential roles in regulating tissue growth during development and regeneration. We have identified APC/CCdh1, a core component of cell cycle control machinery, as an evolutionarily conserved and previously unknown regulator of large tumor suppressor (LATS) kinases, which critically inhibit the YAP/TAZ transcription factors in transducing Hippo signaling. Our results suggest a model that APC/CCdh1 destabilizes LATS1/2 kinases in G1 phase of the cell cycle, leading to increased YAP/TAZ activities that promote G1/S transition by upregulating downstream gene expression, including E2F1. Our findings have important implications for a link between cell proliferation and LATS-regulated YAP/TAZ activities. 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.
