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

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.

Pubmed ID: 10531381

Authors

  • Yokouchi M
  • Kondo T
  • Houghton A
  • Bartkiewicz M
  • Horne WC
  • Zhang H
  • Yoshimura A
  • Baron R

Journal

The Journal of biological chemistry

Publication Data

October 29, 1999

Associated Grants

  • Agency: NIAMS NIH HHS, Id: AR-42927

Mesh Terms

  • 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