Cbl-mediated ubiquitinylation is required for lysosomal sorting of epidermal growth factor receptor but is dispensable for endocytosis

Lei Duan, Yuko Miura, Manjari Dimri, Biswanath Majumder, Ingrid L. Dodge, Alagarsamy L. Reddi, Amiya Ghosh, Norvin Fernandes, Pengcheng Zhou, Karen Mullane-Robinson, Navin Rao, Stephen Donoghue, Rick A. Rogers, David Bowtell, Mayumi Naramura, Hua Gu, Vimla Band, Hamid Band

Research output: Contribution to journalArticle

163 Scopus citations

Abstract

Ligand-induced down-regulation controls the signaling potency of the epidermal growth factor receptor (EGFR/ErbB1). Overexpression studies have identified Cbl-mediated ubiquitinylation of EGFR as a mechanism of ligand-induced EGFR down-regulation. However, the role of endogenous Cbl in EGFR down-regulation and the precise step in the endocytic pathway regulated by Cbl remain unclear. Using Cbl-/- mouse embryonic fibroblast cell lines, we demonstrate that endogenous Cbl is essential for ligand-induced ubiquitinylation and efficient degradation of EGFR. Further analyses using Chinese hamster ovary cells with a temperature-sensitive defect in ubiquitinylation confirm a crucial role of the ubiquitin machinery in Cbl-mediated EGFR degradation. However, internalization into early endosomes did not require Cbl function or an intact ubiquitin pathway. Confocal immunolocalization studies indicated that Cbl-dependent ubiquitinylation plays a critical role at the early endosome to late endosome/lysosome sorting step of EGFR down-regulation. These findings establish Cbl as the major endogenous ubiquitin ligase responsible for EGFR degradation, and show that the critical role of Cbl-mediated ubiquitinylation is at the level of endosomal sorting, rather than at the level of internalization.

Original languageEnglish (US)
Pages (from-to)28950-28960
Number of pages11
JournalJournal of Biological Chemistry
Volume278
Issue number31
DOIs
StatePublished - Aug 1 2003

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Duan, L., Miura, Y., Dimri, M., Majumder, B., Dodge, I. L., Reddi, A. L., Ghosh, A., Fernandes, N., Zhou, P., Mullane-Robinson, K., Rao, N., Donoghue, S., Rogers, R. A., Bowtell, D., Naramura, M., Gu, H., Band, V., & Band, H. (2003). Cbl-mediated ubiquitinylation is required for lysosomal sorting of epidermal growth factor receptor but is dispensable for endocytosis. Journal of Biological Chemistry, 278(31), 28950-28960. https://doi.org/10.1074/jbc.M304474200