The E3 ligase Aip4/Itch ubiquitinates and targets ErbB-4 for degradation.
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.
Omerovic
Jasminka
J
Department of Experimental Medicine and Pathology, University La Sapienza, Viale Regina Elena 324 00161, Rome, Italy.
Santangelo
Laura
L
Puggioni
Eleonora Maria-Rosaria
EM
Marrocco
Jordan
J
Dall'Armi
Claudia
C
Palumbo
Camilla
C
Belleudi
Francesca
F
Di Marcotullio
Lucia
L
Frati
Luigi
L
Torrisi
Maria-Rosaria
MR
Cesareni
Gianni
G
Gulino
Alberto
A
Alimandi
Maurizio
M
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*
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