The E3 ligase Aip4/Itch ubiquitinates and targets ErbB-4 for degradation

Jasminka Omerovic, Laura Santangelo, Eleonora Maria Rosaria Puggioni, Jordan Marrocco, Claudia Dall'Armi, Camilla Palumbo, Francesca Belleudi, Lucia Di Marcotullio, Luigi Frati, Maria Rosaria Torrisi, Gianni Cesareni, Alberto Gulino, Maurizio Alimandi

Research output: Contribution to journalArticlepeer-review


The ErbB-4 receptors are unique in the EGFR/ErbB family for the ability to associate with WW domain-containing proteins. To identify new ligands of the cytoplasmic tail of ErbB-4, we panned a brain cDNA phage library with ErbB-4 peptides containing sequence motifs corresponding to putative docking sites for class-I WW domains. This approach led to identification of AIP4/Itch, a member of the Nedd4-like family of E3 ubiquitin protein ligases, as a protein that specifically interacts with and ubiquitinates ErbB-4 in vivo. Interaction with the ErbB-4 receptors occurs via the WW domains of AIP4/Itch. Functional analyses demonstrate that AIP4/Itch is recruited to the ErbB-4 receptor to promote its polyubiquitination and degradation, thereby regulating stability of the receptor and access of receptor intracellular domains to the nuclear compartment. These findings expand our understanding of the mechanisms contributing to the integrity of the ErbB signaling network and mechanistically link the cellular ubiquitination pathway of AIP4/Itch to the ErbB-4 receptor.

Original languageEnglish
Pages (from-to)2849-2862
Number of pages14
JournalFASEB Journal
Issue number11
Publication statusPublished - Sep 2007


  • Negative regulators
  • Nuclear translocation
  • Ubiquitin ligase

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology


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