@article {93,
	title = {Ligand-induced ubiquitination of the epidermal growth factor receptor involves the interaction of the c-Cbl RING finger and UbcH7.},
	journal = {The Journal of biological chemistry},
	volume = {274},
	year = {1999},
	month = {1999 Oct 29},
	pages = {31707-12},
	abstract = {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.},
	keywords = {Cysteine 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},
	issn = {0021-9258},
	author = {Yokouchi, M and Kondo, T and Houghton, A and Bartkiewicz, M and Horne, W C and Zhang, H and Yoshimura, A and Baron, R}
}
