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Ligand-induced ubiquitination of the epidermal growth factor receptor involves the interaction of the c-Cbl RING finger and UbcH7.

TitleLigand-induced ubiquitination of the epidermal growth factor receptor involves the interaction of the c-Cbl RING finger and UbcH7.
Publication TypeJournal Article
Year of Publication1999
AuthorsYokouchi M, Kondo T, Houghton A, Bartkiewicz M, Horne WC, Zhang H, Yoshimura A, Baron R
JournalThe Journal of biological chemistry
Date Published1999 Oct 29
KeywordsCysteine Endopeptidases, Cysteine Proteinase Inhibitors, Epidermal Growth Factor, Leupeptins, Ligands, Ligases, Models, Biological, Multienzyme Complexes, Phosphorylation, Proteasome Endopeptidase Complex, Protein Binding, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-cbl, Receptor, Epidermal Growth Factor, Recombinant Fusion Proteins, Two-Hybrid System Techniques, Tyrosine, Ubiquitin-Conjugating Enzymes, Ubiquitin-Protein Ligases, Ubiquitins, Zinc Fingers

c-Cbl plays a negative regulatory role in tyrosine kinase signaling by an as yet undefined mechanism. We demonstrate here, using the yeast two-hybrid system and an in vitro binding assay, that the c-Cbl RING finger domain interacts with UbcH7, a ubiquitin-conjugating enzyme (E2). UbcH7 interacted with the wild-type c-Cbl RING finger domain but not with a RING finger domain that lacks the amino acids that are deleted in 70Z-Cbl, an oncogenic mutant of c-Cbl. The in vitro interaction was enhanced by sequences on both the N- and C-terminal sides of the RING finger. In vivo and in vitro experiments revealed that c-Cbl and UbcH7 synergistically promote the ligand-induced ubiquitination of the epidermal growth factor receptor (EGFR). In contrast, 70Z-Cbl markedly reduced the ligand-induced, UbcH7-mediated ubiquitination of the EGFR. MG132, a proteasome inhibitor, significantly prolonged the ligand-induced phosphorylation of both the EGFR and c-Cbl. Thus, c-Cbl plays an essential role in the ligand-induced ubiquitination of the EGFR by a mechanism that involves an interaction of the RING finger domain with UbcH7. This mechanism participates in the down-regulation of tyrosine kinase receptors and loss of this function, as occurs in the naturally occurring 70Z-Cbl isoform, probably contributes to oncogenic transformation.

Alternate JournalJ. Biol. Chem.

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