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

• Published in: Cancer research (Chicago, Ill.) Vol. 60; no. 13; pp. 3384 - 3388
• Main Authors: KLAPPER, L. N, WATERMAN, H, SELA, M, YARDEN, Y
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.07.2000
• Subjects: Amino Acid Sequence; Amino Acid Substitution; Animals; Antibodies, Monoclonal - pharmacology; Antineoplastic agents; Biological and medical sciences; c-Cbl gene; Cell Line; CHO Cells; Consensus Sequence; Cricetinae; ErbB-2 gene; HER-2 gene; Humans; Immunotherapy; Medical sciences; Mice; Mice, Nude; Molecular Sequence Data; Mutagenesis, Site-Directed; Oncogene Protein v-cbl; Pharmacology. Drug treatments; 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; ubiquitin; Ubiquitins - metabolism; Antineoplastic agent; Human; Stomach; Carbon-nitrogen ligases; Enzyme; Rodentia; Monoclonal antibody; Malignant tumor; In vitro; In vivo; Vertebrata; Mammalia; Epidermal growth factor; Treatment; Mouse; Ligases; Animal; Immunotherapy; Digestive diseases; Mechanism of action; Tumor cell; Ubiquitin-protein ligase; Gastric disease; Biological receptor
• ISSN: 0008-5472; 1538-7445

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.