title: The E3 ligase Aip4/Itch ubiquitinates and targets ErbB-4 for degradation.
abstract: 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.
authors.affiliation: Department of Experimental Medicine and Pathology, University La Sapienza, Viale Regina Elena 324 00161, Rome, Italy.
authors.forename: Jasminka
authors.initials: J
authors.lastname: Omerovic
authors.forename: Laura
authors.initials: L
authors.lastname: Santangelo
authors.forename: Eleonora Maria-Rosaria
authors.initials: EM
authors.lastname: Puggioni
authors.forename: Jordan
authors.initials: J
authors.lastname: Marrocco
authors.forename: Claudia
authors.initials: C
authors.lastname: Dall'Armi
authors.forename: Camilla
authors.initials: C
authors.lastname: Palumbo
authors.forename: Francesca
authors.initials: F
authors.lastname: Belleudi
authors.forename: Lucia
authors.initials: L
authors.lastname: Di Marcotullio
authors.forename: Luigi
authors.initials: L
authors.lastname: Frati
authors.forename: Maria-Rosaria
authors.initials: MR
authors.lastname: Torrisi
authors.forename: Gianni
authors.initials: G
authors.lastname: Cesareni
authors.forename: Alberto
authors.initials: A
authors.lastname: Gulino
authors.forename: Maurizio
authors.initials: M
authors.lastname: Alimandi
mesh_terms: D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D011992:Endosomes; D066246:ErbB Receptors / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D015723:Gene Library; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D007668:Kidney / Q000378:metabolism; D019151:Peptide Library; D025941:Protein Interaction Mapping; D021381:Protein Transport; D066247:Receptor, ErbB-4; D012097:Repressor Proteins / Q000378:metabolism*; D013347:Subcellular Fractions; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D019151:Peptide Library; D012097:Repressor Proteins; D025801:Ubiquitin; C432966:ITCH protein, human; D044767:Ubiquitin-Protein Ligases; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D066247:Receptor, ErbB-4