YAP1 Recruits c-Abl to Protect Angiomotin-Like 1 From Nedd4-mediated Degradation

PLoS One. 2012;7(4):e35735. doi: 10.1371/journal.pone.0035735. Epub 2012 Apr 27.

Abstract

Background: Tissue development and organ growth require constant remodeling of cell-cell contacts formed between epithelial cells. The Hippo signaling cascade curtails organ growth by excluding the transcriptional co-activator Yes Associated Protein 1 (YAP1) from the nucleus. Angiomotin family members recruit YAP1 to tight junctions [1], but whether YAP1 plays a specific role outside of the nucleus is currently unknown.

Methodology/principal findings: The present study demonstrates that the E3 ubiquitin ligase Nedd4.2 targets Angiomotin-like 1 (AMOTL1), a family member that promotes the formation of epithelial tight junctions, for ubiquitin-dependent degradation. Unexpectedly, YAP1 antagonizes the function of Nedd4.2, and protects AMOTL1 against Nedd4.2-mediated degradation. YAP1 recruits c-Abl, a tyrosine kinase that binds and phosphorylates Nedd4.2 on tyrosine residues, thereby modifying its ubiquitin-ligase activity.

Conclusions/significance: Our results uncover a novel function for cytoplasmic YAP1. YAP1 recruits c-Abl to protect AMOTL1 against Nedd4.2-mediated degradation. Thus, YAP1, excluded from the nucleus, contributes to the maintenance of tight junctions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Amino Acid Sequence
  • Animals
  • Cell Line
  • Dogs
  • Endosomal Sorting Complexes Required for Transport / genetics
  • Endosomal Sorting Complexes Required for Transport / metabolism*
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism*
  • Gene Expression
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Molecular Sequence Data
  • Nedd4 Ubiquitin Protein Ligases
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Phosphorylation
  • Proteasome Endopeptidase Complex / genetics
  • Proteasome Endopeptidase Complex / metabolism*
  • Proteolysis
  • Proto-Oncogene Proteins c-abl / genetics
  • Proto-Oncogene Proteins c-abl / metabolism*
  • RNA, Small Interfering
  • Signal Transduction / genetics
  • Tight Junctions / metabolism
  • Transcription Factors
  • Transfection
  • Ubiquitin / metabolism
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination

Substances

  • AMOTL1 protein, human
  • Adaptor Proteins, Signal Transducing
  • Endosomal Sorting Complexes Required for Transport
  • Membrane Proteins
  • Phosphoproteins
  • RNA, Small Interfering
  • Transcription Factors
  • Ubiquitin
  • YAP1 (Yes-associated) protein, human
  • Nedd4 Ubiquitin Protein Ligases
  • Nedd4 protein, human
  • Nedd4L protein, human
  • Ubiquitin-Protein Ligases
  • Proto-Oncogene Proteins c-abl
  • Proteasome Endopeptidase Complex