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

  1. Gil Levkowitz1,
  2. Hadassa Waterman1,5,
  3. Eli Zamir2,5,
  4. Zvi Kam2,
  5. Shlomo Oved1,
  6. Wallace Y. Langdon3,
  7. Laura Beguinot4,
  8. Benjamin Geiger2, and
  9. Yosef Yarden1,6
  1. 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.

Keywords

Footnotes

  • 5 These authors contributed equally to this work.

  • 6 Corresponding author.

  • E-MAIL liyarden{at}weizmann.weizmann.ac.il; FAX 972-8-9344116.

    • Received June 15, 1998.
    • Accepted October 6, 1998.
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