Siew Wee Chan1, Chun Jye Lim1, Caixia Huang1, Yaan Fun Chong1, Herath Jayantha Gunaratne2, Kelly A. Hogue2, Walter P. Blackstock2, Kieran F. Harvey3,4, and Wanjin Hong1,5,6
Published in Oncogene, 25th October 2010. [Epub ahead of print]
1 - Cancer and Developmental Cell Biology Division, Institute of Molecular and Cell Biology, 61 Biopolis Drive, Singapore 138673, Singapore.
2 - Mass Spectrometry and Systems Biology Laboratory, Institute of Molecular and Cell Biology, 61 Biopolis Drive, Singapore 138673, Singapore.
3 - Cell Growth and Proliferation Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
4 - Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.
5 - Department of Biochemistry, National University of Singapore, Singapore.
6 - Corresponding author, e-mail: email@example.com.
The transcriptional co-activators YAP and TAZ are downstream targets inhibited by the Hippo tumor suppressor pathway. YAP and TAZ both possess WW domains which are important protein-protein interaction modules that mediate interaction with proline-rich motifs, most commonly PPXY. The WW domains of YAP play complex regulatory roles as exemplified by recent reports showing that they can positively or negatively influence YAP activity in a cell and context-specific fashion. In this study, we show that the WW domain of TAZ is important for it to transform both MCF10A and NIH3T3 cells and to activate transcription of ITGB2 but not CTGF, as introducing point mutations into the WW domain of TAZ (WWm) abolished its transforming and transcription-promoting ability. Using a proteomic approach we discovered potential regulatory proteins that interact with TAZ WW domain and identified Wbp2. The interaction of Wbp2 with TAZ is dependent on the WW domain of TAZ and the PPXY-containing C-terminal region of Wbp2. Knockdown of endogenous Wbp2 suppresses, whereas overexpression of Wbp2 enhances, TAZ-driven transformation. Forced interaction of WWm with Wbp2 by direct C-terminal fusion of full-length Wbp2 or its TAZ-interacting C-terminal domain restored the transforming and transcription-promoting ability of TAZ. These results suggest that the WW domain-mediated interaction with Wbp2 promotes the transforming ability of TAZ.