Molecular mechanisms of the mammalian Hippo signaling pathway
Molecular mechanisms of the mammalian Hippo signaling pathway
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DOI：
10.16288/j.yczz.17-094
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发表时间：
2017-07-01
期刊：
影响因子：
--
通讯作者：
Zhao, Bin
中科院分区：
文献类型：
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作者：
Ji, Xinyan;Zhong, Guoxuan;Zhao, Bin
Hippo通路在多细胞生物中控制器官大小方面发挥着进化上保守的基本作用。重要的是，来自患者样本和小鼠模型研究的证据清楚地表明，Hippo信号通路的失调在许多不同类型的人类癌症的发生和发展中起着至关重要的作用。Hippo信号通路受各种刺激调节，例如机械应力、G蛋白偶联受体信号传导和细胞能量状态。当被激活时，Hippo激酶级联磷酸化并抑制转录共激活因子雅普（Yes相关蛋白）及其辅因子TAZ（具有PDZ结合基序的转录共激活因子），导致其细胞质保留和降解。当Hippo信号通路失活时，去磷酸化的雅普/TAZ易位到细胞核中，通过与TEAD（TEA domain）家族和其他转录因子结合激活基因转录。基因表达的这种变化促进细胞增殖和干细胞/祖细胞自我更新，但抑制细胞凋亡，从而协调地促进器官大小的增加、组织再生和肿瘤发生。本文综述了哺乳动物Hippo信号通路的分子机制，重点介绍了Hippo激酶级联及其上游信号、雅普对Hippo信号通路的调控以及雅普调控基因转录的机制。
The Hippo pathway plays an evolutionarily conserved fundamental role in controlling organ size in multicellular organisms. Importantly, evidence from studies of patient samples and mouse models clearly indicates that deregulation of the Hippo signaling pathway plays a crucial role in the initiation and progression of many different types of human cancers. The Hippo signaling pathway is regulated by various stimuli, such as mechanical stress, G-protein coupled receptor signaling, and cellular energy status. When activated, the Hippo kinase cascade phosphorylates and inhibits the transcription co-activator YAP (Yes-associated protein), and its paralog TAZ (transcriptional coactivator with PDZ-binding motif), resulting in their cytoplasmic retention and degradation. When the Hippo signaling pathway is inactive, dephosphorylated YAP/TAZ translocate into the nucleus and activate gene transcription through binding to TEAD (TEA domain) family and other transcription factors. Such changes in gene expression promote cell proliferation and stem cell/progenitor cell self-renewal but inhibit apoptosis, thereby coordinately promote increase in organ size, tissue regeneration, and tumorigenesis. In this review, we summarize the molecular mechanisms of the mammalian Hippo signaling pathway with special emphasis on the Hippo kinase cascade and its upstream signals, the Hippo signaling pathway regulation.of YAP and the mechanisms of YAP in regulation of gene transcription.