Molecular mechanisms of the mammalian Hippo signaling pathway.

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.Hippo信号通路是近年来发现的在多细胞生物器官大小调控方面发挥重要作用的信号通路。病人样品分析和小鼠模型研究表明,Hippo信号通路的失调在多种癌症发生发展的不同阶段起着关键作用。Hippo信号通路能感知机械环境、G蛋白耦联受体信号和细胞能量水平等多种外界刺激,并通过蛋白激酶链的激活直接磷酸化转录辅激活因子YAP(Yes-associated protein)及其同源蛋白TAZ(transcriptional coactivator with PDZ-binding motif),从而导致它们的胞质滞留和降解。非磷酸化形式的YAP/TAZ进入细胞核内通过结合TEAD家族及其他转录因子激活靶基因的转录表达,从而促进细胞增殖、促进干细胞及祖细胞的自我更新、抑制细胞凋亡。在这些细胞生物学过程的协同作用下,Hippo信号通路调控器官大小、组织再生及肿瘤的发生发展。本文概述了哺乳动物Hippo信号通路的分子机制,重点介绍了Hippo信号通路的激酶链及其上游信号、Hippo信号通路调控其关键效应分子YAP的机制以及YAP调控基因转录发挥功能的分子机制。