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 O. Liu, Long Yu

Research output: Contribution to journalArticlepeer-review

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

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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