c-Cbl/Sli-1 regulates endocytic sorting and ubiquitination of the epidermal growth factor receptor

Ligand-induced down-regulation of two growth factor receptors, EGF receptor (ErbB-1) and ErbB-3, correlates with differential ability to recruit c-Cbl , whose invertebrate orthologs are negative regulators of ErbB. We report t hat ligand-induced degradation of internalized ErbB-1, but not ErbB-3, is m ediated by transient mobilization of a minor fraction of c-Cbl into ErbB-1- containing endosomes. This recruitment depends on the receptor's tyrosine k inase activity and an intact carboxy-terminal region. The alternative fate is recycling of internalized ErbBs to the cell surface. Cbl-mediated recept or sorting involves covalent attachment of ubiquitin molecules, and subsequ ent lysosomal and proteasomal degradation. The oncogenic viral form of Cbl inhibits down-regulation by shunting endocytosed receptors to the recycling pathway. These results reveal an endosomal sorting machinery capable of co ntrolling the fate, and, hence, signaling potency, of growth factor recepto rs.