Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Nature cell biology, 2017-08, Vol.19 (8), p.996-1002

Ort / Verlag

England

Erscheinungsjahr

2017

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.