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 antibod y is therapeutic when administered to patients with metastatic breast cance r. To understand the mechanism underlying immunotherapy, we concentrated on antibody- and epidermal growth factor-induced degradation of ErbB-2, We sh ow that enhanced degradation is preceded by poly-ubiquitination of ErbB-2, This process necessitates recruitment of the c-Cbl ubiquitin ligase to tyro sine 1112 of ErbB-2. Consequently, mutagenesis of this site retards antibod y-induced degradation, Thus, the therapeutic potential of certain antibodie s mag be due to their ability to direct ErbB-2 to a c-Cbl-regulated proteol ytic pathway.