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.
Oved
Shlomo
S
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
Mosesson
Yaron
Y
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
Zwang
Yaara
Y
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
Santonico
Elena
E
Department of Biology, University of Rome Tor Vergata, Via Della Ricerca Scientifica, 00133 Rome, Italy.
Shtiegman
Keren
K
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
Marmor
Mina D
MD
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
Kochupurakkal
Bose S
BS
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
Katz
Menachem
M
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
Lavi
Sara
S
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
Cesareni
Gianni
G
Department of Biology, University of Rome Tor Vergata, Via Della Ricerca Scientifica, 00133 Rome, Italy.
Yarden
Yosef
Y
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel. Electronic address: Yosef.yarden@weizmann.ac.il.
D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D006224:Cricetinae; D015536:Down-Regulation; D066246:ErbB Receptors / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D000075687:NEDD8 Protein; D021381:Protein Transport; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism*
D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D014452:Ubiquitins; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; C067419:CBL protein, human