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J Biol Chem, Vol. 274, Issue 32, 22151-22154, August 6, 1999
From the Department of Biological Regulation, The Weizmann
Institute of Science, Rehovot 76100, Israel
Ligand-induced activation of surface receptors,
including the epidermal growth factor receptor (EGFR), is followed by a
desensitization process involving endocytosis and receptor degradation.
c-Cbl, a tyrosine phosphorylation substrate shared by several signaling pathways, accelerates desensitization by recruiting EGFR and increasing receptor polyubiquitination. Here we demonstrate that the RING type
zinc finger of c-Cbl is essential for ubiquitination and subsequent
desensitization of EGFR. Mutagenesis of a single cysteine residue
impaired the ability of c-Cbl to enhance both down-regulation and
ubiquitination of EGFR in living cells, although the mutant retained
binding to the activated receptor. Consequently, the mutant form of
c-Cbl acquired a dominant inhibitory function and lost the ability to
inhibit signaling downstream to EGFR. In vitro reconstitution of EGFR ubiquitination implies that the RING finger plays an essential direct role in ubiquitin ligation. Our results attribute to the RING finger of c-Cbl a causative role in endocytic sorting of EGFR and desensitization of signal transduction.
COMMUNICATION
The RING Finger of c-Cbl Mediates Desensitization of the
Epidermal Growth Factor Receptor
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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