title: YAP/TAZ incorporation in the β-catenin destruction complex orchestrates the Wnt response.
abstract: 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.
authors: Department of Molecular Medicine, University of Padua School of Medicine, viale Colombo 3, 35126 Padua, Italy.
authors: Luca
authors: L
authors: Azzolin
authors: Department of Molecular Medicine, University of Padua School of Medicine, viale Colombo 3, 35126 Padua, Italy.
authors: Tito
authors: T
authors: Panciera
authors: Department of Molecular Medicine, University of Padua School of Medicine, viale Colombo 3, 35126 Padua, Italy.
authors: Sandra
authors: S
authors: Soligo
authors: Department of Molecular Medicine, University of Padua School of Medicine, viale Colombo 3, 35126 Padua, Italy.
authors: Elena
authors: E
authors: Enzo
authors: Center for Genome Research, Department of Biomedical Sciences, University of Modena and Reggio Emilia, via Giuseppe Campi 287, 41100 Modena, Italy.
authors: Silvio
authors: S
authors: Bicciato
authors: Department of Molecular Medicine, University of Padua School of Medicine, viale Colombo 3, 35126 Padua, Italy.
authors: Sirio
authors: S
authors: Dupont
authors: Clinical and Experimental Hematology, Department of Paediatrics, University of Padua, via Giustiniani 3, 35128 Padua, Italy.
authors: Silvia
authors: S
authors: Bresolin
authors: Clinical and Experimental Hematology, Department of Paediatrics, University of Padua, via Giustiniani 3, 35128 Padua, Italy.
authors: Chiara
authors: C
authors: Frasson
authors: Clinical and Experimental Hematology, Department of Paediatrics, University of Padua, via Giustiniani 3, 35128 Padua, Italy.
authors: Giuseppe
authors: G
authors: Basso
authors: Department of Medicine, University of Padua School of Medicine, via Gabelli 61, 35126 Padua, Italy.
authors: Vincenza
authors: V
authors: Guzzardo
authors: Department of Medicine, University of Padua School of Medicine, via Gabelli 61, 35126 Padua, Italy.
authors: Ambrogio
authors: A
authors: Fassina
authors: Department of Molecular Medicine, University of Padua School of Medicine, viale Colombo 3, 35126 Padua, Italy. Electronic address: michelangelo.cordenonsi@unipd.it.
authors: Michelangelo
authors: M
authors: Cordenonsi
authors: Department of Molecular Medicine, University of Padua School of Medicine, viale Colombo 3, 35126 Padua, Italy. Electronic address: piccolo@bio.unipd.it.
authors: Stefano
authors: S
authors: Piccolo
mesh_terms: D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins; D002460:Cell Line; D053595:Embryonic Stem Cells / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008954:Models, Biological; D010750:Phosphoproteins / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*; D000091102:YAP-Signaling Proteins; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D010750:Phosphoproteins; D014157:Transcription Factors; D051153:Wnt Proteins; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D051176:beta Catenin; D000217:Acyltransferases; C486363:tafazzin protein, mouse