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 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.
Levkowitz
G
G
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
Waterman
H
H
Zamir
E
E
Kam
Z
Z
Oved
S
S
Langdon
W Y
WY
Beguinot
L
L
Geiger
B
B
Yarden
Y
Y
D001692:Biological Transport; D002451:Cell Compartmentation; D015536:Down-Regulation; D004705:Endocytosis; D011992:Endosomes; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D008954:Models, Biological; D009154:Mutation; D050722:Oncogene Protein v-cbl; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D050721:Proto-Oncogene Proteins c-cbl; D020893:Receptor, ErbB-3; D015682:Retroviridae Proteins, Oncogenic / Q000378:metabolism*; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases; D014452:Ubiquitins / Q000378:metabolism*
D008024:Ligands; D050722:Oncogene Protein v-cbl; D011518:Proto-Oncogene Proteins; D015682:Retroviridae Proteins, Oncogenic; D014452:Ubiquitins; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D020893:Receptor, ErbB-3