Tumor-inhibitory antibodies to HER-2/ErbB-2 may act by recruiting c-Cbl and enhancing ubiquitination of HER-2

Cancer Res. 2000 Jul 1;60(13):3384-8.


Overexpression of HER-2/ErbB-2, a homologue of the epidermal growth factor receptor, is associated with poor prognosis, and an ErbB-2-specific antibody is therapeutic when administered to patients with metastatic breast cancer. To understand the mechanism underlying immunotherapy, we concentrated on antibody- and epidermal growth factor-induced degradation of ErbB-2. We show that enhanced degradation is preceded by poly-ubiquitination of ErbB-2. This process necessitates recruitment of the c-Cbl ubiquitin ligase to tyrosine 1112 of ErbB-2. Consequently, mutagenesis of this site retards antibody-induced degradation. Thus, the therapeutic potential of certain antibodies may be due to their ability to direct ErbB-2 to a c-Cbl-regulated proteolytic pathway.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Animals
  • Antibodies, Monoclonal / pharmacology*
  • CHO Cells
  • Cell Line
  • Consensus Sequence
  • Cricetinae
  • Humans
  • Mice
  • Mice, Nude
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Oncogene Protein v-cbl
  • Protein Processing, Post-Translational
  • Receptor, ErbB-2 / chemistry
  • Receptor, ErbB-2 / immunology*
  • Receptor, ErbB-2 / metabolism
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / immunology
  • Recombinant Proteins / metabolism
  • Retroviridae Proteins, Oncogenic / metabolism*
  • Stomach Neoplasms / drug therapy
  • Stomach Neoplasms / immunology
  • Stomach Neoplasms / pathology
  • Transfection
  • Transplantation, Heterologous
  • Tumor Cells, Cultured
  • Ubiquitins / metabolism*


  • Antibodies, Monoclonal
  • Oncogene Protein v-cbl
  • Recombinant Proteins
  • Retroviridae Proteins, Oncogenic
  • Ubiquitins
  • Receptor, ErbB-2