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 neddy...

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Bibliographic Details
Published in:The Journal of biological chemistry 2006-08, Vol.281 (31), p.21640-21651
Main Authors: Oved, Shlomo, Mosesson, Yaron, Zwang, Yaara, Santonico, Elena, Shtiegman, Keren, Marmor, Mina D., Kochupurakkal, Bose S., Katz, Menachem, Lavi, Sara, Cesareni, Gianni, Yarden, Yosef
Format: Article
Language:English
Subjects:
Animals
Binding Sites
CHO Cells
Cricetinae
Down-Regulation
ErbB Receptors - metabolism
HeLa Cells
Humans
Lysosomes - metabolism
NEDD8 Protein
Protein Transport
Proto-Oncogene Proteins c-cbl - metabolism
Receptor Protein-Tyrosine Kinases - metabolism
Ubiquitin-Protein Ligases - metabolism
Ubiquitins - metabolism
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Summary: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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M513034200