Conjugation to Nedd8 instigates ubiquitylation and down-regulation of activated receptor tyrosine kinases.
When appended to the epidermal growth factor receptor (EGFR), ubiquitin serves as a sorting signal for lysosomal degradation. Here we demonstrate that the ubiquitin ligase of EGFR, namely c-Cbl, also mediates receptor modification with the ubiquitin-like molecule Nedd8. EGF stimulates receptor neddylation, which enhances subsequent ubiquitylation, as well as sorting ... of EGFR for degradation. Multiple lysine residues, located within the tyrosine kinase domain of EGFR, serve as attachment sites for Nedd8. A set of clathrin coat-associated binders of ubiquitin also bind Nedd8, but they undergo ubiquitylation, not neddylation. We discuss the emerging versatility of the concerted action of ubiquitylation and neddylation in the process that desensitizes growth factor-activated receptor tyrosine kinases.
Mesh Terms:
Animals, Binding Sites, CHO Cells, Cricetinae, Down-Regulation, Hela Cells, Humans, Lysosomes, Protein Transport, Proto-Oncogene Proteins c-cbl, Receptor Protein-Tyrosine Kinases, Receptor, Epidermal Growth Factor, Ubiquitin-Protein Ligases, Ubiquitins
Animals, Binding Sites, CHO Cells, Cricetinae, Down-Regulation, Hela Cells, Humans, Lysosomes, Protein Transport, Proto-Oncogene Proteins c-cbl, Receptor Protein-Tyrosine Kinases, Receptor, Epidermal Growth Factor, Ubiquitin-Protein Ligases, Ubiquitins
J. Biol. Chem.
Date: Aug. 04, 2006
PubMed ID: 16735510
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