YAP/TAZ Incorporation in the β-Catenin Destruction Complex Orchestrates the Wnt Response
YAP/TAZ Incorporation in the β-Catenin Destruction Complex Orchestrates the Wnt Response
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DOI：
10.1016/j.cell.2014.06.013
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发表时间：
2014-07-03
期刊：
影响因子：
64.5
通讯作者：
Piccolo, Stefano
中科院分区：
文献类型：
--
作者：
Azzolin, Luca;Panciera, Tito;Piccolo, Stefano
河马信号转导系统YAP/TAZ在Wnt信号中既有积极的作用，也有消极的作用，但其潜在的机制尚不清楚。在这里，我们提供了生化、功能和遗传学证据，证明YAP和TAZ是作为YAP/TAZ细胞质汇的β-连环蛋白破坏复合体的组成部分。在Wnt-on细胞中，YAP/TAZ从物理上从破坏复合体中移位，允许它们的核积累和激活依赖于WNT/YAP/TAZ的生物效应。YAP/TAZ是APC缺乏所致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募集到复合体和b-连环蛋白失活所必需的。在Wnt-on细胞中，YAP/TAZ从复合体中的释放有助于Wnt/β-连环蛋白的信号传递。因此，依赖于β连环蛋白的ES细胞在未分化状态的维持是通过YAP/TAZ的丢失来维持的。这项工作揭示了一个前所未有的与器官大小控制、再生和肿瘤抑制相关的信号框架。
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 beta-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 beta-TrCP recruitment to the complex and b-catenin inactivation. In Wnt-ON cells, release of YAP/TAZ from the complex is instrumental for Wnt/beta-catenin signaling. In line, the beta-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.