c-Cbl/Sli-1 regulates endocytic sorting and ubiquitination of the epidermal growth factor receptor
- Gil Levkowitz1,
- Hadassa Waterman1,5,
- Eli Zamir2,5,
- Zvi Kam2,
- Shlomo Oved1,
- Wallace Y. Langdon3,
- Laura Beguinot4,
- Benjamin Geiger2, and
- Yosef Yarden1,6
- Departments of 1Biological Regulation and 2Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel; 3Department of Pathology, The University of Western Australia, Queen Elizabeth II Medical Center, Nedlands, Western Australia 6907, Australia; 4Molecular Oncology Unit, DIBIT, and Instituto di Neuroscienze e Biommagini del CNR, H.S. Raffaele, Milan 20132, Italy
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.