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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38 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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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., Han, J., Park, H. W., & 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