Regulation of Hippo pathway transcription factor TEAD by p38 MAPK-induced cytoplasmic translocation.
Kimberly C LinToshiro MoroishiZhipeng MengHan-Sol JeongSteven W PlouffeYoshitaka SekidoJiahuai HanHyun Woo ParkKun-Liang GuanPublished in: Nature cell biology (2017)
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.
Keyphrases
- transcription factor
- dna binding
- stress induced
- signaling pathway
- gene expression
- papillary thyroid
- oxidative stress
- squamous cell
- dna methylation
- protein kinase
- cell proliferation
- squamous cell carcinoma
- genome wide identification
- young adults
- nuclear factor
- big data
- machine learning
- heat stress
- electronic health record
- deep learning
- human health