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Nat. Commun., Published: 12 June 2018, 9, Article number: 2301 | https://doi.org/10.1038/s41467-018-04757-w
Dishevelled has a YAP nuclear export function in a tumor suppressor context-dependent manner
Yoonmi Lee1,2, Nam Hee Kim2, Eunae Sandra Cho1, Ji Hye Yang1, Yong Hoon Cha3, Hee Eun Kang1, Jun Seop Yun1, Sue Bean Cho2, Seon-Hyeong Lee4, Petra Paclikova5, Tomasz W. Radaszkiewicz5, Vitezslav Bryja 5, Chi Gu Kang1, Young Soo Yuk1, So Young Cha1, Soo-Youl Kim4, Hyun Sil Kim2,* & Jong In Yook 1,*
1Department of Oral Pathology, Yonsei University College of Dentistry, Seoul 03722, Korea. 2 Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul 03722, Korea. 3Department of Oral and Maxillofacial Surgery, Yonsei University College of Dentistry, Seoul 03722, Korea. 4 Cancer Cell and Molecular Biology Branch, National Cancer Center, Ilsan 10408, Korea. 5 Institute of Experimental Biology, Faculty of Science, Masaryk University, Brno 62500, Czech Republic.
These authors contributed equally: Yoonmi Lee, Nam Hee Kim
1Department of Oral Pathology, Yonsei University College of Dentistry, Seoul 03722, Korea. 2 Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul 03722, Korea. 3Department of Oral and Maxillofacial Surgery, Yonsei University College of Dentistry, Seoul 03722, Korea. 4 Cancer Cell and Molecular Biology Branch, National Cancer Center, Ilsan 10408, Korea. 5 Institute of Experimental Biology, Faculty of Science, Masaryk University, Brno 62500, Czech Republic.
These authors contributed equally: Yoonmi Lee, Nam Hee Kim
*Correspondence to Hyun Sil Kim or Jong In Yook
Abstract
Phosphorylation-dependent YAP translocation is a well-known intracellular mechanism of the Hippo pathway; however, the molecular effectors governing YAP cytoplasmic translocation remains undefined. Recent findings indicate that oncogenic YAP paradoxically suppresses Wnt activity. Here, we show that Wnt scaffolding protein Dishevelled (DVL) is responsible for cytosolic translocation of phosphorylated YAP. Mutational inactivation of the nuclear export signal embedded in DVL leads to nuclear YAP retention, with an increase in TEAD transcriptional activity. DVL is also required for YAP subcellular localization induced by E-cadherin, α-catenin, or AMPK activation. Importantly, the nuclear-cytoplasmic trafficking is dependent on the p53-Lats2 or LKB1-AMPK tumor suppressor axes, which determine YAP phosphorylation status. In vivo and clinical data support that the loss of p53 or LKB1 relieves DVL-linked reciprocal inhibition between the Wnt and nuclear YAP activity. Our observations provide mechanistic insights into controlled proliferation coupled with epithelial polarity during development and human cancer.
논문정보
- Research article
- 2018년 06월 (BRIC 등록일 2018-06-26)
- 국내(교신)+국외 연구진
- 의약학 > 분자세포의학
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