The study investigates the role of c-Cbl in the endocytic sorting and ubiquitination of the epidermal growth factor receptor (EGF receptor, ErbB-1) and the Neu differentiation factor receptor (ErbB-3). The results show that c-Cbl transiently associates with ErbB-1-containing endosomes, leading to its degradation, while ErbB-3 is recycled to the cell surface. This association depends on the receptor's tyrosine kinase activity and an intact carboxy-terminal region. The oncogenic viral form of c-Cbl, v-Cbl, interferes with this process by directing receptors to the recycling pathway. The study also reveals that c-Cbl increases the ligand-induced ubiquitination of ErbB-1, which is necessary for its degradation. The findings suggest that c-Cbl plays a crucial role in controlling the fate and signaling potency of growth factor receptors by regulating their endosomal sorting and ubiquitination.The study investigates the role of c-Cbl in the endocytic sorting and ubiquitination of the epidermal growth factor receptor (EGF receptor, ErbB-1) and the Neu differentiation factor receptor (ErbB-3). The results show that c-Cbl transiently associates with ErbB-1-containing endosomes, leading to its degradation, while ErbB-3 is recycled to the cell surface. This association depends on the receptor's tyrosine kinase activity and an intact carboxy-terminal region. The oncogenic viral form of c-Cbl, v-Cbl, interferes with this process by directing receptors to the recycling pathway. The study also reveals that c-Cbl increases the ligand-induced ubiquitination of ErbB-1, which is necessary for its degradation. The findings suggest that c-Cbl plays a crucial role in controlling the fate and signaling potency of growth factor receptors by regulating their endosomal sorting and ubiquitination.