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

Research output: Contribution to journalArticle

31 Citations (Scopus)

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 languageEnglish
Pages (from-to)996-1002
Number of pages7
JournalNature Cell Biology
Volume19
Issue number8
DOIs
Publication statusPublished - 2017 Aug 1

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p38 Mitogen-Activated Protein Kinases
Transcription Factors
Organ Size
Protein-Serine-Threonine Kinases
Transducers
Mammals
Neoplasms
Homeostasis
Phosphotransferases
Phosphorylation
Gene Expression
DNA
Growth

All Science Journal Classification (ASJC) codes

  • Cell Biology

Cite this

Lin, K. C., Moroishi, T., Meng, Z., Jeong, H. S., Plouffe, S. W., Sekido, Y., ... Guan, K. L. (2017). Regulation of Hippo pathway transcription factor TEAD by p38 MAPK-induced cytoplasmic translocation. Nature Cell Biology, 19(8), 996-1002. https://doi.org/10.1038/ncb3581
Lin, Kimberly C. ; Moroishi, Toshiro ; Meng, Zhipeng ; Jeong, Han Sol ; Plouffe, Steven W. ; Sekido, Yoshitaka ; Han, Jiahuai ; Park, Hyun Woo ; Guan, Kun Liang. / Regulation of Hippo pathway transcription factor TEAD by p38 MAPK-induced cytoplasmic translocation. In: Nature Cell Biology. 2017 ; Vol. 19, No. 8. pp. 996-1002.
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Lin, KC, Moroishi, T, Meng, Z, Jeong, HS, Plouffe, SW, Sekido, Y, Han, J, Park, HW & Guan, KL 2017, 'Regulation of Hippo pathway transcription factor TEAD by p38 MAPK-induced cytoplasmic translocation', Nature Cell Biology, vol. 19, no. 8, pp. 996-1002. https://doi.org/10.1038/ncb3581

Regulation of Hippo pathway transcription factor TEAD by p38 MAPK-induced cytoplasmic translocation. / Lin, Kimberly C.; Moroishi, Toshiro; Meng, Zhipeng; Jeong, Han Sol; Plouffe, Steven W.; Sekido, Yoshitaka; Han, Jiahuai; Park, Hyun Woo; Guan, Kun Liang.

In: Nature Cell Biology, Vol. 19, No. 8, 01.08.2017, p. 996-1002.

Research output: Contribution to journalArticle

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AU - Guan, Kun Liang

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