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Title: The PDZ-binding motif of Yes-associated protein is required for its co-activation of TEAD-mediated CTGF transcription and oncogenic cell transforming activity

Abstract

Highlights: •Loss of the PDZ-binding motif inhibits constitutively active YAP (5SA)-induced oncogenic cell transformation. •The PDZ-binding motif of YAP promotes its nuclear localization in cultured cells and mouse liver. •Loss of the PDZ-binding motif inhibits YAP (5SA)-induced CTGF transcription in cultured cells and mouse liver. -- Abstract: 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’s 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 weremore » 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’s co-activation of TEAD-mediated CTGF transcription.« less

Authors:
; ; ; ; ;
Publication Date:
OSTI Identifier:
22242282
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 443; Journal Issue: 3; Other Information: Copyright (c) 2013 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; CELL CULTURES; CELL PROLIFERATION; CONNECTIVE TISSUE; GROWTH FACTORS; LIVER; MICE; ONCOGENIC TRANSFORMATIONS; PHOSPHORYLATION; TRANSCRIPTION

Citation Formats

Shimomura, Tadanori, Miyamura, Norio, Hata, Shoji, Miura, Ryota, Hirayama, Jun, E-mail: hirayama.dbio@mri.tmd.ac.jp, and Nishina, Hiroshi, E-mail: nishina.dbio@mri.tmd.ac.jp. The PDZ-binding motif of Yes-associated protein is required for its co-activation of TEAD-mediated CTGF transcription and oncogenic cell transforming activity. United States: N. p., 2014. Web. doi:10.1016/J.BBRC.2013.12.100.
Shimomura, Tadanori, Miyamura, Norio, Hata, Shoji, Miura, Ryota, Hirayama, Jun, E-mail: hirayama.dbio@mri.tmd.ac.jp, & Nishina, Hiroshi, E-mail: nishina.dbio@mri.tmd.ac.jp. The PDZ-binding motif of Yes-associated protein is required for its co-activation of TEAD-mediated CTGF transcription and oncogenic cell transforming activity. United States. doi:10.1016/J.BBRC.2013.12.100.
Shimomura, Tadanori, Miyamura, Norio, Hata, Shoji, Miura, Ryota, Hirayama, Jun, E-mail: hirayama.dbio@mri.tmd.ac.jp, and Nishina, Hiroshi, E-mail: nishina.dbio@mri.tmd.ac.jp. Fri . "The PDZ-binding motif of Yes-associated protein is required for its co-activation of TEAD-mediated CTGF transcription and oncogenic cell transforming activity". United States. doi:10.1016/J.BBRC.2013.12.100.
@article{osti_22242282,
title = {The PDZ-binding motif of Yes-associated protein is required for its co-activation of TEAD-mediated CTGF transcription and oncogenic cell transforming activity},
author = {Shimomura, Tadanori and Miyamura, Norio and Hata, Shoji and Miura, Ryota and Hirayama, Jun, E-mail: hirayama.dbio@mri.tmd.ac.jp and Nishina, Hiroshi, E-mail: nishina.dbio@mri.tmd.ac.jp},
abstractNote = {Highlights: •Loss of the PDZ-binding motif inhibits constitutively active YAP (5SA)-induced oncogenic cell transformation. •The PDZ-binding motif of YAP promotes its nuclear localization in cultured cells and mouse liver. •Loss of the PDZ-binding motif inhibits YAP (5SA)-induced CTGF transcription in cultured cells and mouse liver. -- Abstract: 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’s 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’s co-activation of TEAD-mediated CTGF transcription.},
doi = {10.1016/J.BBRC.2013.12.100},
journal = {Biochemical and Biophysical Research Communications},
number = 3,
volume = 443,
place = {United States},
year = {Fri Jan 17 00:00:00 EST 2014},
month = {Fri Jan 17 00:00:00 EST 2014}
}
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