AMOT (angiomotin) is a membrane-associated protein that is expressed in ECs (endothelial cells) and controls migration, TJ (tight junction) formation, cell polarity and angiogenesis. Recent studies have revealed that AMOT and two AMOT-like proteins, AMOTL1 and AMOTL2, play critical roles in the Hippo pathway by regulating the subcellular localization of the co-activators YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif). However, it has been unclear how AMOT is regulated. In the present study, we report that AMOT undergoes proteasomal degradation. We identify three members of Nedd4 (neural-precursor-cell-expressed developmentally down-regulated)-like ubiquitin E3 ligases, Nedd4, Nedd4-2 and Itch, as the ubiquitin E3 ligases for the long isoform of AMOT, AMOT/p130. We demonstrate that Nedd4, Nedd4-2 and Itch mediate poly-ubiquitination of AMOT/p130 in vivo. Overexpression of Nedd4, Nedd4-2 or Itch leads to AMOT/p130 proteasomal degradation. Knockdown of Nedd4, Nedd4-2 and Itch causes an accumulation of steady-state level of AMOT/p130. We also show that three L/P-PXY motifs of AMOT/p130 and the WW domains of Nedd4 mediate their interaction. Furthermore, Nedd4-like ubiquitin E3 ligases might compete with YAP for the binding to AMOT/p130, and subsequently targeting AMOT/p130 for ubiquitin-dependent degradation. Together, these observations reveal a novel post-translational regulatory mechanism of AMOT/p130.
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Research Article|
May 11 2012
The Nedd4-like ubiquitin E3 ligases target angiomotin/p130 to ubiquitin-dependent degradation
Chenji Wang;
Chenji Wang
1
*State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, 220 Handan Road, Shanghai 200433, P.R. China
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Jian An;
Jian An
1
*State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, 220 Handan Road, Shanghai 200433, P.R. China
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Pingzhao Zhang;
Pingzhao Zhang
*State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, 220 Handan Road, Shanghai 200433, P.R. China
†Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, P.R. China
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Chen Xu;
Chen Xu
*State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, 220 Handan Road, Shanghai 200433, P.R. China
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Kun Gao;
Kun Gao
*State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, 220 Handan Road, Shanghai 200433, P.R. China
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Di Wu;
Di Wu
*State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, 220 Handan Road, Shanghai 200433, P.R. China
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Dejie Wang;
Dejie Wang
*State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, 220 Handan Road, Shanghai 200433, P.R. China
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Hongxiu Yu;
Hongxiu Yu
†Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, P.R. China
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Jun O. Liu;
Jun O. Liu
‡Departments of Pharmacology and Molecular Sciences and Oncology, The Johns Hopkins School of Medicine, Baltimore, MD 21205, U.S.A.
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Long Yu
Long Yu
2
*State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, 220 Handan Road, Shanghai 200433, P.R. China
†Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, P.R. China
2To whom correspondence should be addressed (email longyu@fudan.edu.cn).
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Publisher: Portland Press Ltd
Received:
November 16 2011
Revision Received:
February 06 2012
Accepted:
March 02 2012
Accepted Manuscript online:
March 02 2012
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem J (2012) 444 (2): 279–289.
Article history
Received:
November 16 2011
Revision Received:
February 06 2012
Accepted:
March 02 2012
Accepted Manuscript online:
March 02 2012
Citation
Chenji Wang, Jian An, Pingzhao Zhang, Chen Xu, Kun Gao, Di Wu, Dejie Wang, Hongxiu Yu, Jun O. Liu, Long Yu; The Nedd4-like ubiquitin E3 ligases target angiomotin/p130 to ubiquitin-dependent degradation. Biochem J 1 June 2012; 444 (2): 279–289. doi: https://doi.org/10.1042/BJ20111983
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