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.
journal_name
Proc Natl Acad Sci U S Aauthors
Kim W,Cho YS,Wang X,Park O,Ma X,Kim H,Gan W,Jho EH,Cha B,Jeung YJ,Zhang L,Gao B,Wei W,Jiang J,Chung KS,Yang Ydoi
10.1073/pnas.1821370116subject
Has Abstractpub_date
2019-05-07 00:00:00pages
9423-9432issue
19eissn
0027-8424issn
1091-6490pii
1821370116journal_volume
116pub_type
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