H. Waterman et al., The RING finger of c-Cbl mediates desensitization of the epidermal growth factor receptor, J BIOL CHEM, 274(32), 1999, pp. 22151-22154
Ligand-induced activation of surface receptors, including the epidermal gro
wth factor receptor (EGFR), is followed by a desensitization process involv
ing endocytosis and receptor degradation. c-Cbl, a tyrosine phosphorylation
substrate shared by several signaling pathways, accelerates desensitizatio
n by recruiting EGFR and increasing receptor polyubiquitination. Here we de
monstrate that the RING type zinc finger of c-Cbl is essential for ubiquiti
nation and subsequent desensitization of EGFR. Mutagenesis of a single cyst
eine residue impaired the ability of c-Cbl to enhance both downregulation a
nd ubiquitination of EG;FR in living cells, although the mutant retained bi
nding to the activated receptor. Consequently, the mutant form of c-Cbl acq
uired a dominant inhibitory function and lost the ability to inhibit signal
ing downstream to EGFR. In vitro reconstitution of EGFR ubiquitination impl
ies that the RING finger plays an essential direct role in ubiquitin ligati
on. Our results attribute to the RING finger of c-Cbl a causative role in e
ndocytic sorting of EGFR and desensitization of signal transduction.