hide
Free keywords:
Biological Transport; Cell Compartmentation; Down-Regulation; *Endocytosis; Endosomes; Ligands; Models, Biological; Mutation; Oncogene Protein v-cbl; Protein Processing, Post-Translational; Protein-Tyrosine Kinases/metabolism; Proto-Oncogene Proteins/genetics/*metabolism; Proto-Oncogene Proteins c-cbl; Receptor, Epidermal Growth Factor/genetics/*metabolism; Receptor, erbB-3; Retroviridae Proteins, Oncogenic/*metabolism; Signal Transduction; *Ubiquitin-Protein Ligases; Ubiquitins/*metabolism
Abstract:
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 that ligand-induced degradation of internalized ErbB-1, but not ErbB-3, is mediated by transient mobilization of a minor fraction of c-Cbl into ErbB-1-containing endosomes. This recruitment depends on the receptor's tyrosine kinase activity and an intact carboxy-terminal region. The alternative fate is recycling of internalized ErbBs to the cell surface. Cbl-mediated receptor sorting involves covalent attachment of ubiquitin molecules, and subsequent 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 controlling the fate, and, hence, signaling potency, of growth factor receptors.
