Abstract LB-17: WW domain-mediated interaction with Wbp2 is important for the oncogenic property of TAZ

Cancer and Developmental Cell Biology Division, Institute of Molecular and Cell Biology, Singapore.
Oncogene (Impact Factor: 8.46). 10/2010; 30(5):600-10. DOI: 10.1038/onc.2010.438
Source: PubMed


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 have complex regulatory roles as exemplified by recent reports showing that they can positively or negatively influence YAP activity in a cell and context-specific manner. 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.

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Available from: Kelly Hogue, Nov 25, 2015
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    • "The ability to induce anchorage-independent cell growth is a hallmark of oncogenes; this includes YAP, which has been shown to promote anchorage-independent growth of both MCF10A and NIH-3T3 cells [10], [11], [12], [36]. To investigate the functional role of the YAP C-terminus, we first sought to determine whether it is required for YAP to induce anchorage-independent growth. "
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    ABSTRACT: The Salvador-Warts-Hippo (SWH) pathway is an important regulator of tissue growth that is frequently subverted in human cancer. The key oncoprotein of the SWH pathway is the transcriptional co-activator, Yes-associated protein (YAP). YAP promotes tissue growth and transformation of cultured cells by interacting with transcriptional regulatory proteins via its WW domains, or, in the case of the TEAD1-4 transcription factors, an N-terminal binding domain. YAP possesses a putative transactivation domain in its C-terminus that is necessary to stimulate transcription factors in vitro, but its requirement for YAP function has not been investigated in detail. Interestingly, whilst the WW domains and TEAD-binding domain are highly conserved in the Drosophila melanogaster YAP orthologue, Yorkie, the majority of the C-terminal region of YAP is not present in Yorkie. To investigate this apparent conundrum, we assessed the functional roles of the YAP and Yorkie C-termini. We found that these regions were not required for Yorkie's ability to drive tissue growth in vivo, or YAP's ability to promote anchorage-independent growth or resistance to contact inhibition. However, the YAP transactivation domain was required for YAP's ability to induce cell migration and invasion. Moreover, a role for the YAP transactivation domain in cell transformation was uncovered when the YAP WW domains were mutated together with the transactivation domain. This shows that YAP can promote cell transformation in a flexible manner, presumably by contacting transcriptional regulatory proteins either via its WW domains or its transactivation domain.
    Preview · Article · Feb 2012 · PLoS ONE
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    • "However, an alternative possibility is that mop mutations might down-regulate Diap1 expression through an alternative process unrelated to Hpo signaling. Wbp2 (WW domain binding protein- 2) was first identified in mammals as a Yap-interacting protein (Chen et al., 1997), and recent studies have indicated that it can contribute to transcriptional activation by Yap and Taz (Dhananjayan et al., 2006; Chan et al., 2011), although the mechanism by which it does this is unknown. Studies of Drosophila wbp2 show that it acts as an enhancer of Yki's transcriptional activity, but the phenotypes observed are quite mild compared with loss of yki (Zhang et al., 2011). "
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    ABSTRACT: The Hippo signaling pathway emerged from studies of Drosophila tumor suppressor genes, and is now appreciated as a major growth control pathway in vertebrates as well as arthropods. As a recently discovered pathway, key components of the pathway are continually being identified, and new insights into how the pathway is regulated and deployed are arising at a rapid pace. Over the past year and a half, significant advances have been made in our understanding of upstream regulatory inputs into Hippo signaling, key negative regulators of Hippo pathway activity have been identified, and important roles for the pathway in regeneration have been described. This review describes these and other advances, focusing on recent progress in our understanding of Hippo signaling that has come from continued studies in Drosophila.
    Preview · Article · Jan 2012 · Developmental Dynamics
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    • "In addition to the regulatory control of TAZ in cell differentiation , it has been recently reported that TAZ promotes cell proliferation and epithelial-to-mesenchymal transition, and thus aggravates breast cancer and lung cancer (Lei et al., 2008; Chan et al., 2011; Lai et al., 2011; Zhou et al., 2011). Disruption of the TEAD-TAZ transcription complex or silencing of TEAD gene expression abolished TAZ-mediated tumour cell growth, suggesting an oncogenic potential of TAZ through TEAD activation in the Hippo pathway (Chan et al., 2008; 2009; Zhang et al., 2009). "
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    ABSTRACT: The transcriptional co-activator with PDZ-binding motif (TAZ) is characterized as a transcriptional modulator of mesenchymal stem cell differentiation into osteoblasts and adipocytes. Moreover, increased TAZ activity in the nucleus enhances osteoblast differentiation and suppresses adipocyte development by interacting with runt-related transcription factor 2 (RUNX2) and PPARγ, respectively. Therefore, it would be of interest to identify low MW compounds that modulate nuclear TAZ activity. High-throughput screening was performed using a library of low MW compounds in order to identify TAZ modulators that enhance nuclear TAZ localization. The effects and molecular mechanisms of a TAZ modulator have been characterized in osteoblast and adipocyte differentiation. We identified 2-butyl-5-methyl-6-(pyridine-3-yl)-3-[2'-(1H-tetrazole-5-yl)-biphenyl-4-ylmethyl]-3H-imidazo[4,5-b]pyridine] (TM-25659) as a TAZ modulator. TM-25659 enhanced nuclear TAZ localization in a dose-dependent manner and attenuated PPARγ-mediated adipocyte differentiation by facilitating PPARγ suppression activity of TAZ. In addition, TAZ-induced RUNX2 activity activation was further increased in osteoblasts, causing increased osteoblast differentiation. Accordingly, TM-25659 suppressed bone loss in vivo and decreased weight gain in an obesity model. After oral administration, TM-25659 had a favourable pharmacokinetic profile. TM-25659 stimulated nuclear TAZ localization and thus caused TAZ to suppress PPARγ-dependent adipogenesis and enhance RUNX2-induced osteoblast differentiation in vitro and in vivo. Our data suggest that TM-25659 could be beneficial in the control of obesity and bone loss.
    Full-text · Article · Sep 2011 · British Journal of Pharmacology
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