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.
Bibliographical noteFunding 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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All Science Journal Classification (ASJC) codes
- Cell Biology