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