The Nedd4-like ubiquitin E3 ligases target angiomotin/p130 to ubiquitin-dependent degradation

Chenji Wang, Jian An, Pingzhao Zhang, Chen Xu, Kun Gao, Di Wu, Dejie Wang, Hongxiu Yu, Jun Liu, Long Yu

Research output: Contribution to journalArticle

Abstract

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 AMOTlike 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 steadystate 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 posttranslational regulatory mechanism of AMOT/p130.

Original languageEnglish (US)
Pages (from-to)279-289
Number of pages11
JournalBiochemical Journal
Volume444
Issue number2
DOIs
StatePublished - Jun 1 2012

Fingerprint

Ubiquitin-Protein Ligases
Ubiquitin
Degradation
Cell Polarity
Proteins
Tight Junctions
Ubiquitination
Endothelial cells
Protein Binding
Cell Movement
Protein Isoforms
Membrane Proteins
Endothelial Cells

Keywords

  • Angiomotin (AMOT)
  • Degradation
  • Neural-precursor-cell-expressed developmentally down-regulated 4 (Nedd4)
  • Stability
  • Ubiquitination
  • Yes-associated protein (YAP)

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

The Nedd4-like ubiquitin E3 ligases target angiomotin/p130 to ubiquitin-dependent degradation. / Wang, Chenji; An, Jian; Zhang, Pingzhao; Xu, Chen; Gao, Kun; Wu, Di; Wang, Dejie; Yu, Hongxiu; Liu, Jun; Yu, Long.

In: Biochemical Journal, Vol. 444, No. 2, 01.06.2012, p. 279-289.

Research output: Contribution to journalArticle

Wang, C, An, J, Zhang, P, Xu, C, Gao, K, Wu, D, Wang, D, Yu, H, Liu, J & Yu, L 2012, 'The Nedd4-like ubiquitin E3 ligases target angiomotin/p130 to ubiquitin-dependent degradation', Biochemical Journal, vol. 444, no. 2, pp. 279-289. https://doi.org/10.1042/BJ20111983
Wang, Chenji ; An, Jian ; Zhang, Pingzhao ; Xu, Chen ; Gao, Kun ; Wu, Di ; Wang, Dejie ; Yu, Hongxiu ; Liu, Jun ; Yu, Long. / The Nedd4-like ubiquitin E3 ligases target angiomotin/p130 to ubiquitin-dependent degradation. In: Biochemical Journal. 2012 ; Vol. 444, No. 2. pp. 279-289.
@article{286575077a8048cf9c7db8eb20240852,
title = "The Nedd4-like ubiquitin E3 ligases target angiomotin/p130 to ubiquitin-dependent degradation",
abstract = "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 AMOTlike 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 steadystate 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 posttranslational regulatory mechanism of AMOT/p130.",
keywords = "Angiomotin (AMOT), Degradation, Neural-precursor-cell-expressed developmentally down-regulated 4 (Nedd4), Stability, Ubiquitination, Yes-associated protein (YAP)",
author = "Chenji Wang and Jian An and Pingzhao Zhang and Chen Xu and Kun Gao and Di Wu and Dejie Wang and Hongxiu Yu and Jun Liu and Long Yu",
year = "2012",
month = "6",
day = "1",
doi = "10.1042/BJ20111983",
language = "English (US)",
volume = "444",
pages = "279--289",
journal = "Biochemical Journal",
issn = "0264-6021",
publisher = "Portland Press Ltd.",
number = "2",

}

TY - JOUR

T1 - The Nedd4-like ubiquitin E3 ligases target angiomotin/p130 to ubiquitin-dependent degradation

AU - Wang, Chenji

AU - An, Jian

AU - Zhang, Pingzhao

AU - Xu, Chen

AU - Gao, Kun

AU - Wu, Di

AU - Wang, Dejie

AU - Yu, Hongxiu

AU - Liu, Jun

AU - Yu, Long

PY - 2012/6/1

Y1 - 2012/6/1

N2 - 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 AMOTlike 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 steadystate 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 posttranslational regulatory mechanism of AMOT/p130.

AB - 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 AMOTlike 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 steadystate 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 posttranslational regulatory mechanism of AMOT/p130.

KW - Angiomotin (AMOT)

KW - Degradation

KW - Neural-precursor-cell-expressed developmentally down-regulated 4 (Nedd4)

KW - Stability

KW - Ubiquitination

KW - Yes-associated protein (YAP)

UR - http://www.scopus.com/inward/record.url?scp=84860870373&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84860870373&partnerID=8YFLogxK

U2 - 10.1042/BJ20111983

DO - 10.1042/BJ20111983

M3 - Article

C2 - 22385262

AN - SCOPUS:84860870373

VL - 444

SP - 279

EP - 289

JO - Biochemical Journal

JF - Biochemical Journal

SN - 0264-6021

IS - 2

ER -