Regulation of Hippo pathway transcription factor TEAD by p38 MAPK-induced cytoplasmic translocation

Kimberly C. Lin; Toshiro Moroishi; Zhipeng Meng; Han Sol Jeong; Steven W. Plouffe; Yoshitaka Sekido; Jiahuai Han; Hyun Woo Park; Kun Liang Guan

doi:10.1038/ncb3581

Regulation of Hippo pathway transcription factor TEAD by p38 MAPK-induced cytoplasmic translocation

Kimberly C. Lin, Toshiro Moroishi, Zhipeng Meng, Han Sol Jeong, Steven W. Plouffe, Yoshitaka Sekido, Jiahuai Han, Hyun Woo Park, Kun Liang Guan

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Abstract

The Hippo pathway controls organ size and tissue homeostasis, with deregulation leading to cancer. The core Hippo components in mammals are composed of the upstream serine/threonine kinases Mst1/2, MAPK4Ks and Lats1/2. Inactivation of these upstream kinases leads to dephosphorylation, stabilization, nuclear translocation and thus activation of the major functional transducers of the Hippo pathway, YAP and its paralogue TAZ. YAP/TAZ are transcription co-activators that regulate gene expression primarily through interaction with the TEA domain DNA-binding family of transcription factors (TEAD). The current paradigm for regulation of this pathway centres on phosphorylation-dependent nucleocytoplasmic shuttling of YAP/TAZ through a complex network of upstream components. However, unlike other transcription factors, such as SMAD, NF-κB, NFAT and STAT, the regulation of TEAD nucleocytoplasmic shuttling has been largely overlooked. In the present study, we show that environmental stress promotes TEAD cytoplasmic translocation via p38 MAPK in a Hippo-independent manner. Importantly, stress-induced TEAD inhibition predominates YAP-activating signals and selectively suppresses YAP-driven cancer cell growth. Our data reveal a mechanism governing TEAD nucleocytoplasmic shuttling and show that TEAD localization is a critical determinant of Hippo signalling output.

Original language	English
Pages (from-to)	996-1002
Number of pages	7
Journal	Nature Cell Biology
Volume	19
Issue number	8
DOIs	https://doi.org/10.1038/ncb3581
Publication status	Published - 2017 Aug 1

Bibliographical note

Funding Information:
This work was supported by grants from the National Institutes of Health (CA196878, DE15964 and GM51586) to K.-L.G., the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (2014R1A5A2009936) to H.-S.J. and by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI17C1560), and the National Research Foundation of Korea (NRF) grant funded by the Korea government (MOE) (2017R1D1A1B03034797) and (MSIP) (2017R1A4A1015328) to H.W.P. K.C.L. and S.W.P. were supported in part by the University of California, San Diego (UCSD) Graduate Training Program in Cellular and Molecular Pharmacology (T32 GM007752).

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© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

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Cell Biology

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title = "Regulation of Hippo pathway transcription factor TEAD by p38 MAPK-induced cytoplasmic translocation",

abstract = "The Hippo pathway controls organ size and tissue homeostasis, with deregulation leading to cancer. The core Hippo components in mammals are composed of the upstream serine/threonine kinases Mst1/2, MAPK4Ks and Lats1/2. Inactivation of these upstream kinases leads to dephosphorylation, stabilization, nuclear translocation and thus activation of the major functional transducers of the Hippo pathway, YAP and its paralogue TAZ. YAP/TAZ are transcription co-activators that regulate gene expression primarily through interaction with the TEA domain DNA-binding family of transcription factors (TEAD). The current paradigm for regulation of this pathway centres on phosphorylation-dependent nucleocytoplasmic shuttling of YAP/TAZ through a complex network of upstream components. However, unlike other transcription factors, such as SMAD, NF-κB, NFAT and STAT, the regulation of TEAD nucleocytoplasmic shuttling has been largely overlooked. In the present study, we show that environmental stress promotes TEAD cytoplasmic translocation via p38 MAPK in a Hippo-independent manner. Importantly, stress-induced TEAD inhibition predominates YAP-activating signals and selectively suppresses YAP-driven cancer cell growth. Our data reveal a mechanism governing TEAD nucleocytoplasmic shuttling and show that TEAD localization is a critical determinant of Hippo signalling output.",

author = "Lin, {Kimberly C.} and Toshiro Moroishi and Zhipeng Meng and Jeong, {Han Sol} and Plouffe, {Steven W.} and Yoshitaka Sekido and Jiahuai Han and Park, {Hyun Woo} and Guan, {Kun Liang}",

note = "Funding Information: This work was supported by grants from the National Institutes of Health (CA196878, DE15964 and GM51586) to K.-L.G., the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (2014R1A5A2009936) to H.-S.J. and by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI17C1560), and the National Research Foundation of Korea (NRF) grant funded by the Korea government (MOE) (2017R1D1A1B03034797) and (MSIP) (2017R1A4A1015328) to H.W.P. K.C.L. and S.W.P. were supported in part by the University of California, San Diego (UCSD) Graduate Training Program in Cellular and Molecular Pharmacology (T32 GM007752). Publisher Copyright: {\textcopyright} 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.",

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AU - Lin, Kimberly C.

AU - Moroishi, Toshiro

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AU - Jeong, Han Sol

AU - Plouffe, Steven W.

AU - Sekido, Yoshitaka

AU - Han, Jiahuai

AU - Park, Hyun Woo

AU - Guan, Kun Liang

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PY - 2017/8/1

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N2 - The Hippo pathway controls organ size and tissue homeostasis, with deregulation leading to cancer. The core Hippo components in mammals are composed of the upstream serine/threonine kinases Mst1/2, MAPK4Ks and Lats1/2. Inactivation of these upstream kinases leads to dephosphorylation, stabilization, nuclear translocation and thus activation of the major functional transducers of the Hippo pathway, YAP and its paralogue TAZ. YAP/TAZ are transcription co-activators that regulate gene expression primarily through interaction with the TEA domain DNA-binding family of transcription factors (TEAD). The current paradigm for regulation of this pathway centres on phosphorylation-dependent nucleocytoplasmic shuttling of YAP/TAZ through a complex network of upstream components. However, unlike other transcription factors, such as SMAD, NF-κB, NFAT and STAT, the regulation of TEAD nucleocytoplasmic shuttling has been largely overlooked. In the present study, we show that environmental stress promotes TEAD cytoplasmic translocation via p38 MAPK in a Hippo-independent manner. Importantly, stress-induced TEAD inhibition predominates YAP-activating signals and selectively suppresses YAP-driven cancer cell growth. Our data reveal a mechanism governing TEAD nucleocytoplasmic shuttling and show that TEAD localization is a critical determinant of Hippo signalling output.

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Regulation of Hippo pathway transcription factor TEAD by p38 MAPK-induced cytoplasmic translocation

Abstract

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