Ji Xin-yan, Zhong Guoxuan, Zhao Bin
Life Sciences Institute and the Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou 310058, China.
1. Life Sciences Institute and the Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou 310058, China; 2. Institute of Aging Research, Hangzhou Normal University, Hangzhou 311121, China.
Yi Chuan. 2017 Jul 20;39(7):546-567. doi: 10.16288/j.yczz.17-094.
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.
河马通路在多细胞生物的器官大小控制中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，河马信号通路的失调在许多不同类型人类癌症的发生和发展中起着关键作用。河马信号通路受多种刺激调节，如机械应力、G蛋白偶联受体信号传导和细胞能量状态。激活时，河马激酶级联磷酸化并抑制转录共激活因子YAP（Yes相关蛋白）及其旁系同源物TAZ（具有PDZ结合基序的转录共激活因子），导致它们在细胞质中滞留并降解。当河马信号通路失活时，去磷酸化的YAP/TAZ易位进入细胞核，并通过与TEAD（TEA结构域）家族和其他转录因子结合来激活基因转录。这种基因表达的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，从而协同促进器官大小增加、组织再生和肿瘤发生。在本综述中，我们总结了哺乳动物河马信号通路的分子机制，特别强调了河马激酶级联及其上游信号、河马信号通路对YAP的调节以及YAP调节基因转录的机制。
