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Proc. Natl. Acad. Sci. USA, published April 18, 2019 | https://doi.org/10.1073/pnas.1821370116 Hippo signaling is intrinsically regulated during cell cycle progression by APC/CCdh1

Wantae Kim^a,b,c, Yong Suk Cho^d, Xiaohui Wang^a, Ogyi Park^e, Xueyan Ma^f, Hanjun Kim^a, Wenjian Gan^g, Eek-hoon Jho^h, Boksik Chaⁱ, Yun-ji Jeung^b, Lei Zhang^f, Bin Gao^e, Wenyi Wei^g, Jin Jiang^d, Kyung-Sook Chung^b,1, and Yingzi Yang^a,1

^a Department of Developmental Biology, Harvard Stem Cell Institute, Harvard School of Dental Medicine, Boston, MA 02215; ^bBiomedical Translational Research Center, Korea Research Institute of Bioscience and Biotechnology, 34141 Daejeon, Republic of Korea; ^c Department of Biochemistry, Chungnam National University, 34134 Daejeon, Republic of Korea; ^d Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390; ^e Section on Liver Biology, National Institute on Alcohol Abuse and Alcoholism, National Institute of Health, Bethesda, MD 20892;^f Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 200031 Shanghai, China; ^gDepartment of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215; ^h Department of Life Science, University of Seoul, 02504 Seoul, South Korea; andⁱ Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104

¹To whom correspondence may be addressed.

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.

LATS1/2, YAP/TAZ, Hippo signaling, mitotic cell cycle, APC/CCdh1

논문정보

형식Research article
게재일2019년 04월 (BRIC 등록일 2019-04-24)
연구진국내(교신)+국외 연구진
분야 생명과학 > 세포생물학

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