Cbl-directed monoubiquitination of CIN85 is involved in regulation of ligand-induced degradation of EGF receptors

• DOI: 10.1073/pnas.192462299
• Publication Date: 2002-09-17T16:40:55Z
• Authors: Kaisa Haglund; Noriaki Shimokawa; Iwona Szymkiewicz; Ivan Dikic
• Keywords: Internalization

Addition of ubiquitin or chains to target proteins leads their mono- polyubiquitination, respectively. Whereas polyubiquitination targets for degradation, monoubiquitination is thought regulate receptor internalization and endosomal sorting. Cbl are major ligases that promote ligand-dependent degradation tyrosine kinases. They also recruit CIN85-endophilin in the complex with activated receptors, thus controlling endocytosis. Here we show adaptor protein CIN85 its homologue CMS monoubiquitinated by Cbl/Cbl-b after epidermal growth factor (EGF) stimulation. Monoubiquitination required direct interactions between Cbl, intact RING finger domain a acceptor site present carboxyl terminus CIN85. Cbl-b found polyubiquitinated EGF receptors during prolonged stimulation degraded together lysosome. Dominant interfering forms CIN85, which have been shown previously delay were impaired monoubiquitination. Thus, our data demonstrate can mediate cargo as well control sorting