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J Biol Chem. 2006 Aug 4;281(31):21640-51. Epub 2006 May 30.

Conjugation to Nedd8 instigates ubiquitylation and down-regulation of activated receptor tyrosine kinases.

Author information

1
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.

Abstract

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.

PMID:
16735510
DOI:
10.1074/jbc.M513034200
[Indexed for MEDLINE]
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