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.
Bibliographical noteFunding Information:
We thank E. Tunkle for preparation of the manuscript and K.Y. Kim for statistical analysis. We thank professor H.W. Park at Yonsei University for generously providing the Last1/2−/− 293 A, Last1/2−/− MEF and AMPK-null MEF cells. We thank Yonsei Advanced Imaging Center in cooperation with Carl Zeiss Microscopy, Yonsei University College of Medicine, for technical assistance. This work was supported by grants from the National Research Foundation of Korea (NFR-2017R1A2B3002241, NRF-2016R1E1A1A01942724, NRF-2017R1C1B1012464, NRF-2018M3A9E2022820) funded by the Korean government (MSIP), a grant from the National Research Foundation of Korea (NRF-2014R1A6A3A04055110) and a grant from the Korea Health Industry Development Institute (KHIDI) funded by the Ministry for Health & Welfare Korea (HI17C2586). V.B. was supported by the Czech Science Foundation (GA17-16680S, GA18-17658S), by the Neuron Fund for Support of Science and Marie Curie ITN WntsApp (Grant no. 608180). Petra Paclíková is a Brno Ph.D. Talent Scholarship Holder, funded by the Brno City Municipality.
© 2018 The Author(s).
All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)