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

Jasminka Omerovic^*,1, Laura Santangelo^*,1, 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^*, and Maurizio Alimandi^*,,2

^* Department of Experimental Medicine and Pathology, University "La Sapienza," Rome, Italy;

Department of Biology, University of Rome Tor Vergata, Rome, Italy;

Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Rome, Italy;

Neuromed Institute, Pozzilli, Isernia, Italy;

^|| Azienda Ospedaliera Sant'Andrea, Rome, Italy;

^¶ Istituto Dermatologico Santa Maria e San Gallicano, IRCCS, Rome, Italy; and

Centro Ricerca Sperimentale, Istituto Regina Elena, Rome, Italy

²Correspondence: Department of Experimental Medicine and Pathology, University "La Sapienza," Viale Regina Elena 324 00161, Rome, Italy. E-mail: maurizio.alimandi{at}uniroma1.it

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, J., Santangelo, L., Puggioni, E. M-R., Marrocco, J., Dall'Armi, C., Palumbo, C., Belleudi, F., Di Marcotullio, L., Frati, L., Torrisi, M-R., Cesareni, G., Gulino, A., Alimandi, M. The E3 ligase Aip4/Itch ubiquitinates and targets ErbB-4 for degradation.

Key Words: negative regulators • ubiquitin ligase • nuclear translocation

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