Department of Molecular Medicine, University of Padua School of Medicine, viale Colombo 3, 35126 Padua, Italy.
Center for Genome Research, Department of Biomedical Sciences, University of Modena and Reggio Emilia, via Giuseppe Campi 287, 41100 Modena, Italy.
Cell. 2014 Jul 3;158(1):157-70. doi: 10.1016/j.cell.2014.06.013. Epub 2014 Jun 26.
The Hippo transducers YAP/TAZ have been shown to play positive, as well as negative, roles in Wnt signaling, but the underlying mechanisms remain unclear. Here, we provide biochemical, functional, and genetic evidence that YAP and TAZ are integral components of the β-catenin destruction complex that serves as cytoplasmic sink for YAP/TAZ. In Wnt-ON cells, YAP/TAZ are physically dislodged from the destruction complex, allowing their nuclear accumulation and activation of Wnt/YAP/TAZ-dependent biological effects. YAP/TAZ are required for intestinal crypt overgrowth induced by APC deficiency and for crypt regeneration ex vivo. In Wnt-OFF cells, YAP/TAZ are essential for β-TrCP recruitment to the complex and β-catenin inactivation. In Wnt-ON cells, release of YAP/TAZ from the complex is instrumental for Wnt/β-catenin signaling. In line, the β-catenin-dependent maintenance of ES cells in an undifferentiated state is sustained by loss of YAP/TAZ. This work reveals an unprecedented signaling framework relevant for organ size control, regeneration, and tumor suppression.
Hippo 转导物 YAP/TAZ 已被证明在 Wnt 信号中发挥积极作用，也发挥消极作用，但潜在机制仍不清楚。在这里，我们提供生化、功能和遗传证据表明，YAP 和 TAZ 是 β-连环蛋白破坏复合物的组成部分，该复合物充当 YAP/TAZ 的细胞质汇。在 Wnt-ON 细胞中，YAP/TAZ 从破坏复合物中被物理分离，允许它们的核积累和激活 Wnt/YAP/TAZ 依赖性生物学效应。YAP/TAZ 是 APC 缺陷诱导的肠隐窝过度生长和体外隐窝再生所必需的。在 Wnt-OFF 细胞中，YAP/TAZ 是β-TrCP 招募到复合物和β-连环蛋白失活所必需的。在 Wnt-ON 细胞中，从复合物中释放 YAP/TAZ 对 Wnt/β-连环蛋白信号传导至关重要。与此一致的是，YAP/TAZ 的缺失维持了 ES 细胞在未分化状态下的β-连环蛋白依赖性。这项工作揭示了一个前所未有的信号框架，与器官大小控制、再生和肿瘤抑制有关。
