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.

中文翻译：

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p38 MAPK诱导的细胞质易位对河马途径转录因子TEAD的调节。

河马途径控制着器官的大小和组织的动态平衡，调节失调会导致癌症。哺乳动物中河马的核心成分由上游丝氨酸/苏氨酸激酶Mst1 / 2，MAPK4Ks和Lats1 / 2组成。这些上游激酶的失活导致去磷酸化，稳定化，核易位，并因此激活了河马途径，YAP及其旁系TAZ的主要功能传感器。YAP / TAZ是转录共激活因子，主要通过与TEA域DNA结合转录因子家族（TEAD）相互作用来调节基因表达。用于调节该途径的当前范例集中在通过上游组分的复杂网络对YAP / TAZ的磷酸化依赖性核质穿梭。但是，与其他转录因子（例如SMAD，NF-κB，NFAT和STAT）不同，TEAD核质穿梭的调控已被大大忽略。在本研究中，我们表明环境胁迫以独立于河马的方式通过p38 MAPK促进TEAD胞质易位。重要的是，应激诱导的TEAD抑制作用占主导地位的YAP激活信号，并选择性地抑制YAP驱动的癌细胞生长。我们的数据揭示了控制TEAD核质穿梭的机制，并表明TEAD定位是河马信号输出的关键决定因素。应激诱导的TEAD抑制主要作用于YAP激活信号，并选择性抑制YAP驱动的癌细胞生长。我们的数据揭示了控制TEAD核质穿梭的机制，并表明TEAD定位是河马信号输出的关键决定因素。应激诱导的TEAD抑制主要作用于YAP激活信号，并选择性抑制YAP驱动的癌细胞生长。我们的数据揭示了控制TEAD核质穿梭的机制，并表明TEAD定位是河马信号输出的关键决定因素。