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Genes & development
Dec 01, 1998;12 (23): 3663-74.

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

G Levkowitz, H Waterman, E Zamir, Z Kam, S Oved, W Y Langdon, L Beguinot, B Geiger, Y Yarden
Author Information
  1. G Levkowitz: Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
PMID: 9851973 DOI: 10.1101/gad.12.23.3663

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.

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Grants

  1. R01 CA072981/NCI NIH HHS
  2. R37 CA072981/NCI NIH HHS
  3. CA72981/NCI NIH HHS

MeSH Term

Biological Transport
Cell Compartmentation
Down-Regulation
Endocytosis
Endosomes
ErbB Receptors
Ligands
Models, Biological
Mutation
Oncogene Protein v-cbl
Protein Processing, Post-Translational
Protein-Tyrosine Kinases
Proto-Oncogene Proteins
Proto-Oncogene Proteins c-cbl
Receptor, ErbB-3
Retroviridae Proteins, Oncogenic
Signal Transduction
Ubiquitin-Protein Ligases
Ubiquitins

Chemicals

Ligands
Oncogene Protein v-cbl
Proto-Oncogene Proteins
Retroviridae Proteins, Oncogenic
Ubiquitins
Proto-Oncogene Proteins c-cbl
Ubiquitin-Protein Ligases
ErbB Receptors
Protein-Tyrosine Kinases
Receptor, ErbB-3
Journal Article Research Support, U.S. Gov't, P.H.S.
Article has an altmetric score of 6

Word Cloud

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