Tumor-inhibitory antibodies to HER-2/ErbB-2 may act by recruiting c-Cbl and enhancing ubiquitination of HER-2.
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.
Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
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Klapper
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Waterman
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Sela
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Yarden
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D016466:CHO Cells; D002460:Cell Line; D016384:Consensus Sequence; D006224:Cricetinae; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D050722:Oncogene Protein v-cbl; D011499:Protein Processing, Post-Translational; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D015682:Retroviridae Proteins, Oncogenic / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D014162:Transfection; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014452:Ubiquitins / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D050722:Oncogene Protein v-cbl; D018719:Erb-b2 Receptor Tyrosine Kinases; D011994:Recombinant Proteins; D015682:Retroviridae Proteins, Oncogenic; D014452:Ubiquitins