MST4 kinase suppresses gastric tumorigenesis by limiting YAP activation via a non-canonical pathway.
MST4 kinase suppresses gastric tumorigenesis by limiting YAP activation via a non-canonical pathway.
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MST4 激酶通过非经典途径限制 YAP 激活来抑制胃肿瘤发生
DOI：
10.1084/jem.20191817
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发表时间：
2020-06-01
期刊：
影响因子：
--
通讯作者：
Zhou Z
中科院分区：
文献类型：
--
作者：
An L;Nie P;Chen M;Tang Y;Zhang H;Guan J;Cao Z;Hou C;Wang W;Zhao Y;Xu H;Jiao S;Zhou Z
An等鉴定了一种新的MST 4介导的雅普失活信号通路，并证明MST 4-雅普轴是抑制体内胃肿瘤发生所必需的。雅普的过度活化通常与肿瘤发生相关，并且新出现的证据提示雅普的多层Hippo非依赖性调节。在这项研究中，我们确定了一个新的MST 4-雅普轴，它作为一个非经典的Hippo信号通路，限制了应激诱导的雅普激活。MST 4激酶直接在Thr 83磷酸化雅普，阻断其与importin α的结合，从而导致雅普在胞质内滞留和失活。由于MST 4介导的雅普磷酸化Thr 83信号传导和经典的雅普磷酸化Ser 127信号传导之间的相互作用，Thr 83处的雅普磷酸化水平与Ser 127处的磷酸化水平相关。模拟MST 4介导的替代信号的T83 E突变抑制了野生型雅普及其模拟经典Hippo信号丧失的S127 A突变体的活性。小鼠中MST 4的消耗促进了胃肿瘤的发生，减少了Thr 83磷酸化和雅普的过度活化。此外，MST 4-雅普信号转导的缺失与人胃癌的不良预后相关。总的来说，我们的研究揭示了一个非经典的MST 4-雅普信号轴抑制胃肿瘤的发生。
An et al. identify a novel MST4-mediated YAP inactivation signaling pathway and demonstrate that the MST4–YAP axis is required to suppress gastric tumorigenesis in vivo. Hyperactivation of YAP has been commonly associated with tumorigenesis, and emerging evidence hints at multilayered Hippo-independent regulations of YAP. In this study, we identified a new MST4–YAP axis, which acts as a noncanonical Hippo signaling pathway that limits stress-induced YAP activation. MST4 kinase directly phosphorylated YAP at Thr83 to block its binding with importin α, therefore leading to YAP cytoplasmic retention and inactivation. Due to a consequential interplay between MST4-mediated YAP phospho-Thr83 signaling and the classical YAP phospho-Ser127 signaling, the phosphorylation level of YAP at Thr83 was correlated to that at Ser127. Mutation of T83E mimicking MST4-mediated alternative signaling restrained the activity of both wild-type YAP and its S127A mutant mimicking loss of classical Hippo signal. Depletion of MST4 in mice promoted gastric tumorigenesis with diminished Thr83 phosphorylation and hyperactivation of YAP. Moreover, loss of MST4–YAP signaling was associated with poor prognosis of human gastric cancer. Collectively, our study uncovered a noncanonical MST4–YAP signaling axis essential for suppressing gastric tumorigenesis.
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