YAP/TAZ Incorporation in the β-Catenin Destruction Complex Orchestrates the Wnt Response

• Published in: Cell 2014-07, Vol.158 (1), p.157-170
• Main Authors: Azzolin, Luca, Panciera, Tito, Soligo, Sandra, Enzo, Elena, Bicciato, Silvio, Dupont, Sirio, Bresolin, Silvia, Frasson, Chiara, Basso, Giuseppe, Guzzardo, Vincenza, Fassina, Ambrogio, Cordenonsi, Michelangelo, Piccolo, Stefano
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Animals; beta Catenin - metabolism; Cell Cycle Proteins; Cell Line; Embryonic Stem Cells - metabolism; HEK293 Cells; Humans; Mice; Models, Biological; Phosphoproteins - metabolism; Transcription Factors - metabolism; Wnt Proteins - metabolism
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2014.06.013

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. [Display omitted] •In Wnt OFF, YAP/TAZ are sequestered in the β-catenin destruction complex•YAP/TAZ are essential for βTrCP recruitment to the complex and β-catenin inactivation•In Wnt ON, YAP/TAZ are released from the complex and accumulate in the nucleus•YAP/TAZ are required for crypt overgrowth induced by APC loss and regeneration The Hippo and Wnt signaling cascades—central to development and physiology and playing a major role in multiple diseases—actually represent two aspects of a single integrative signaling pathway.