title: Wnt Signaling Promotes Breast Cancer by Blocking ITCH-Mediated Degradation of YAP/TAZ Transcriptional Coactivator WBP2.
abstract: Cross-talk between the Hippo and Wnt pathways has been implicated recently in breast cancer development, but key intersections have yet to be fully defined. Here we report that WBP2, a transcription coactivator that binds the Hippo pathway transcription factor YAP/TAZ, contributes to Wnt signaling and breast cancer pathogenesis. Clinically, overexpression of WBP2 in breast cancer specimens correlated with malignant progression and poor patient survival. In breast cancer cells, nuclear entry and interaction of WBP2 with β-catenin was stimulated by Wnt3A, thereby activating TCF-mediated transcription and driving malignant invasive character. Mechanistic investigations showed WBP2 levels were controlled by the E3 ligase ITCH, which bound and target WBP2 for ubiquitin-dependent proteasomal degradation. Accordingly, ITCH silencing could elevate WBP2 levels. Wnt signaling upregulated WBP2 by disrupting ITCH-WBP2 interactions via EGFR-mediated tyrosine phosphorylation of WBP2 and TAZ/YAP competitive binding. Conversely, ITCH-mediated downregulation of WBP2 inhibited TCF/β-catenin transcription, in vitro transformation, and in vivo tumorigenesis. We identified somatic mutations in ITCH, which impaired its ability to degrade WBP2 and to block its function in cancer, even while retaining binding capacity to WBP2. Thus, the Wnt pathway appeared to engage WBP2 primarily by affecting its protein stability. Our findings show how WBP2/ITCH signaling functions to link the intricate Wnt and Hippo signaling networks in breast cancer. Cancer Res; 76(21); 6278-89. ©2016 AACR.
authors: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors: Shen Kiat
authors: SK
authors: Lim
authors: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors: Ssu Yi
authors: SY
authors: Lu
authors: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors: Shin-Ae
authors: SA
authors: Kang
authors: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors: Hock Jin
authors: HJ
authors: Tan
authors: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors: Zilin
authors: Z
authors: Li
authors: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors: Zhen Ning
authors: ZN
authors: Adrian Wee
authors: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors: Jye Swei
authors: JS
authors: Guan
authors: Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore.
authors: Vishnu Priyanka
authors: VP
authors: Reddy Chichili
authors: Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore.
authors: J
authors: J
authors: Sivaraman
authors: Department of Pathology, National University Hospital, Singapore.
authors: Thomas
authors: T
authors: Putti
authors: Department of Pathology, Singapore General Hospital, Singapore.
authors: Aye Aye
authors: AA
authors: Thike
authors: Department of Pathology, Singapore General Hospital, Singapore.
authors: Puay Hoon
authors: PH
authors: Tan
authors: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|Institute of Molecular and Cell Biology, Agency for Science Technology and Research, Singapore.|Mechanobiology Institute, National University of Singapore, Singapore.
authors: Marius
authors: M
authors: Sudol
authors: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore.
authors: David M
authors: DM
authors: Virshup
authors: Institute of Molecular and Cell Biology, Agency for Science Technology and Research, Singapore.
authors: Siew Wee
authors: SW
authors: Chan
authors: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|Institute of Molecular and Cell Biology, Agency for Science Technology and Research, Singapore.
authors: Wanjin
authors: W
authors: Hong
authors: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. bchlyp@nus.edu.sg.|National University Cancer Institute, Singapore.|NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore.
authors: Yoon Pin
authors: YP
authors: Lim
mesh_terms: D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000502:physiology; D005260:Female; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D012097:Repressor Proteins / Q000502:physiology*; D015534:Trans-Activators; D014157:Transcription Factors / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*; D060449:Wnt Signaling Pathway / Q000502:physiology*; D060509:Wnt3A Protein / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C106908:WBP2 protein, human; C555510:WNT3A protein, human; D060509:Wnt3A Protein; C456659:YY1AP1 protein, human; D000217:Acyltransferases; C108675:TAFAZZIN protein, human; C432966:ITCH protein, human; D044767:Ubiquitin-Protein Ligases; C512478:EGFR protein, human; D066246:ErbB Receptors; D046988:Proteasome Endopeptidase Complex