Dishevelled has a YAP nuclear export function in a tumor suppressor context-dependent manner

Yoonmi Lee; Nam Hee Kim; Eunae Sandra Cho; Ji Hye Yang; Yong Hoon Cha; Hee Eun Kang; Jun Seop Yun; Sue Bean Cho; Seon Hyeong Lee; Petra Paclikova; Tomasz W. Radaszkiewicz; Vitezslav Bryja; Chi Gu Kang; Young Soo Yuk; So Young Cha; Soo Youl Kim; Hyun Sil Kim; Jong In Yook

doi:10.1038/s41467-018-04757-w

Dishevelled has a YAP nuclear export function in a tumor suppressor context-dependent manner

Yoonmi Lee, Nam Hee Kim, Eunae Sandra Cho, Ji Hye Yang, Yong Hoon Cha, Hee Eun Kang, Jun Seop Yun, Sue Bean Cho, Seon Hyeong Lee, Petra Paclikova, Tomasz W. Radaszkiewicz, Vitezslav Bryja, Chi Gu Kang, Young Soo Yuk, So Young Cha, Soo Youl Kim, Hyun Sil Kim, Jong In Yook

Department of Oral Pathology

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Article number	2301
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-04757-w
Publication status	Published - 2018 Dec 1

Bibliographical note

Funding 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.

Publisher Copyright:
© 2018 The Author(s).

All Science Journal Classification (ASJC) codes

Physics and Astronomy(all)
Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)

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Lee, Y., Kim, N. H., Cho, E. S., Yang, J. H., Cha, Y. H., Kang, H. E., Yun, J. S., Cho, S. B., Lee, S. H., Paclikova, P., Radaszkiewicz, T. W., Bryja, V., Kang, C. G., Yuk, Y. S., Cha, S. Y., Kim, S. Y., Kim, H. S., & Yook, J. I. (2018). Dishevelled has a YAP nuclear export function in a tumor suppressor context-dependent manner. Nature communications, 9(1), Article 2301. https://doi.org/10.1038/s41467-018-04757-w

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title = "Dishevelled has a YAP nuclear export function in a tumor suppressor context-dependent manner",

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.",

author = "Yoonmi Lee and Kim, {Nam Hee} and Cho, {Eunae Sandra} and Yang, {Ji Hye} and Cha, {Yong Hoon} and Kang, {Hee Eun} and Yun, {Jun Seop} and Cho, {Sue Bean} and Lee, {Seon Hyeong} and Petra Paclikova and Radaszkiewicz, {Tomasz W.} and Vitezslav Bryja and Kang, {Chi Gu} and Yuk, {Young Soo} and Cha, {So Young} and Kim, {Soo Youl} and Kim, {Hyun Sil} and Yook, {Jong In}",

note = "Funding 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 Pacl{\'i}kov{\'a} is a Brno Ph.D. Talent Scholarship Holder, funded by the Brno City Municipality. Publisher Copyright: {\textcopyright} 2018 The Author(s).",

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T1 - Dishevelled has a YAP nuclear export function in a tumor suppressor context-dependent manner

AU - Lee, Yoonmi

AU - Kim, Nam Hee

AU - Cho, Eunae Sandra

AU - Yang, Ji Hye

AU - Cha, Yong Hoon

AU - Kang, Hee Eun

AU - Yun, Jun Seop

AU - Cho, Sue Bean

AU - Lee, Seon Hyeong

AU - Paclikova, Petra

AU - Radaszkiewicz, Tomasz W.

AU - Bryja, Vitezslav

AU - Kang, Chi Gu

AU - Yuk, Young Soo

AU - Cha, So Young

AU - Kim, Soo Youl

AU - Kim, Hyun Sil

AU - Yook, Jong In

N1 - Funding 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. Publisher Copyright: © 2018 The Author(s).

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N2 - 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.

AB - 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.

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Dishevelled has a YAP nuclear export function in a tumor suppressor context-dependent manner

Abstract

Bibliographical note

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UN SDGs

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