Regulation of Hippo pathway transcription factor TEAD by p38 MAPK-induced cytoplasmic translocation.
Regulation of Hippo pathway transcription factor TEAD by p38 MAPK-induced cytoplasmic translocation.
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DOI：
10.1038/ncb3581
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发表时间：
2017-07-28
影响因子：
21.3
通讯作者：
Guan KL
中科院分区：
文献类型：
--
作者：
Lin KC;Moroishi T;Meng Z;Jeong HS;Plouffe SW;Sekido Y;Han J;Park HW;Guan KL
Hippo通路控制器官大小和组织稳态，失调导致癌症。哺乳动物中的核心Hippo组分由上游丝氨酸/苏氨酸激酶Mst 1/2、MAPK 4Ks和Lats 1/2组成。这些上游激酶的失活导致去磷酸化、稳定化、核转位，从而激活Hippo途径的主要功能性转导物雅普及其副产物TAZ。雅普/TAZ是主要通过与转录因子的TEA结构域DNA结合家族（TEAD）相互作用来调节基因表达的转录共激活因子。目前的模式，这一途径的调节中心磷酸化依赖的核质穿梭的雅普/TAZ通过一个复杂的网络上游组件。然而，与SMAD、NF-κB、NFAT和STAT等转录因子不同，TEAD核质穿梭的调控机制一直被人们所忽视。在本研究中，我们表明，环境压力促进TEAD细胞质易位通过p38 MAPK在海马非依赖性的方式。重要的是，应激诱导的TEAD抑制主导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TEAD核质穿梭的机制，并表明TEAD定位是海马信号输出的关键决定因素。
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.
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Hippo 通路在器官大小控制、组织稳态和癌症中的作用
影响因子：
64.5
作者：
Yu FX;Zhao B;Guan KL
通讯作者：
Guan KL
影响因子：
16.6
作者：
Meng Z;Moroishi T;Mottier-Pavie V;Plouffe SW;Hansen CG;Hong AW;Park HW;Mo JS;Lu W;Lu S;Flores F;Yu FX;Halder G;Guan KL
通讯作者：
Guan KL
DOI：
10.1083/jcb.201501025
发表时间：
2015-08-03
期刊：
The Journal of cell biology
影响因子：
--
作者：
Kim NG;Gumbiner BM
通讯作者：
Gumbiner BM
DOI：
10.1038/nrd4161
发表时间：
2014-01
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
通讯作者：
--
影响因子：
64.5
作者：
Yu FX;Zhao B;Panupinthu N;Jewell JL;Lian I;Wang LH;Zhao J;Yuan H;Tumaneng K;Li H;Fu XD;Mills GB;Guan KL
通讯作者：
Guan KL