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

• Published in: Nature cell biology Vol. 19; no. 8; pp. 996 - 1002
• Main Authors: Lin, Kimberly C., Moroishi, Toshiro, Meng, Zhipeng, Jeong, Han-Sol, Plouffe, Steven W., Sekido, Yoshitaka, Han, Jiahuai, Park, Hyun Woo, Guan, Kun-Liang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2017; Nature Publishing Group
• Subjects: 13; 14/19; 38/70; 38/77; 631/136/83/2360; 631/67; 631/80/389/2023/2022; 631/80/86/2366; 82/51; 82/80; 96/106; 96/109; 96/95; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Biological transport; Cancer; Cancer Research; Cell Biology; Cell Line, Tumor; Cell Proliferation; Cell research; Cytoplasm - enzymology; Deactivation; Deoxyribonucleic acid; Dephosphorylation; Deregulation; Developmental Biology; DNA; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Environmental stress; Gene expression; Gene regulation; Genetic aspects; HEK293 Cells; Hippo Signaling Pathway; Homeostasis; Humans; Inactivation; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Kinases; letter; Life Sciences; Localization; MAP kinase; Mice, Nude; Molecular biology; Muscle Proteins - genetics; Muscle Proteins - metabolism; Neoplasms - enzymology; Neoplasms - genetics; Neoplasms - pathology; NF-AT protein; Nuclear transport; Osmotic Pressure; p38 mitogen-activated protein kinases; p38 Mitogen-Activated Protein Kinases - genetics; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphoproteins - genetics; Phosphoproteins - metabolism; Phosphorylation; Physiological aspects; Protein Binding; Protein Serine-Threonine Kinases - metabolism; Protein Transport; Serine; Signal Transduction; Signaling; Smad protein; Stem Cells; TEA Domain Transcription Factors; Threonine; Time Factors; Trans-Activators; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Transcriptional Coactivator with PDZ-Binding Motif Proteins; Transducers; Transfection; Translocation; YAP-Signaling Proteins; Yes-associated protein; United States
• DOI: 10.1038/ncb3581
• ISSN: 1465-7392; 1476-4679

Lin et al. find that stress-induced p38 MAPK activation leads to cytoplasmic relocation of the Hippo pathway nuclear transcription factor TEAD. TEAD relocation causes inhibition of YAP activity and suppresses YAP-driven cancer cell growth. 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 1 , 2 . YAP/TAZ are transcription co-activators that regulate gene expression primarily through interaction with the TEA domain DNA-binding family of transcription factors (TEAD) 3 . The current paradigm for regulation of this pathway centres on phosphorylation-dependent nucleocytoplasmic shuttling of YAP/TAZ through a complex network of upstream components 2 . 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.