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

Shlomo Oved, Yaron Mosesson, Yaara Zwang, Elena Santonico, Keren Shtiegman, Mina D. Marmor, Bose S. Kochupurakkal, Menachem Katz, Sara Lavi, Gianni Cesareni, Yosef Yarden

Research output: Contribution to journalArticlepeer-review

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.Wediscuss the emerging versatility of the concerted action of ubiquitylation and neddylation in the process that desensitizes growth factor-activated receptor tyrosine kinases.

Original languageEnglish
Pages (from-to)21640-21651
Number of pages12
JournalJournal of Biological Chemistry
Volume281
Issue number31
DOIs
Publication statusPublished - Aug 4 2006

ASJC Scopus subject areas

  • Biochemistry

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