The PDZ-binding motif of Yes-associated protein is required for its co-activation of TEAD-mediated CTGF transcription and oncogenic cell transforming activity
详细信息 查看全文
- 作者：Tadanori Shimomura ; Norio Miyamura ; Shoji Hata ; Ryota Miura ; Jun Hirayama ; Hiroshi Nishina
- 关键词：YAP ; Yes-associated protein ; CTGF ; connective tissue growth factor ; TEAD ; TEA domain family member ; TAZ ; transcriptional co-activator with PDZ-binding motif
- 刊名：Biochemical and Biophysical Research Communications
- 出版年：17 January, 2014
- 年：2014
- 卷：443
- 期：3
- 页码：917-923
- 全文大小：921 K
文摘
YAP is a transcriptional co-activator that acts downstream of the Hippo signaling pathway and regulates multiple cellular processes, including proliferation. Hippo pathway-dependent phosphorylation of YAP negatively regulates its function. Conversely, attenuation of Hippo-mediated phosphorylation of YAP increases its ability to stimulate proliferation and eventually induces oncogenic transformation. The C-terminus of YAP contains a highly conserved PDZ-binding motif that regulates YAP鈥檚 functions in multiple ways. However, to date, the importance of the PDZ-binding motif to the oncogenic cell transforming activity of YAP has not been determined. In this study, we disrupted the PDZ-binding motif in the YAP (5SA) protein, in which the sites normally targeted by Hippo pathway-dependent phosphorylation are mutated. We found that loss of the PDZ-binding motif significantly inhibited the oncogenic transformation of cultured cells induced by YAP (5SA). In addition, the increased nuclear localization of YAP (5SA) and its enhanced activation of TEAD-dependent transcription of the cell proliferation gene CTGF were strongly reduced when the PDZ-binding motif was deleted. Similarly, in mouse liver, deletion of the PDZ-binding motif suppressed nuclear localization of YAP (5SA) and YAP (5SA)-induced CTGF expression. Taken together, our results indicate that the PDZ-binding motif of YAP is critical for YAP-mediated oncogenesis, and that this effect is mediated by YAP鈥檚 co-activation of TEAD-mediated CTGF transcription.