The RING finger of c-Cbl mediates desensitization of the epidermal growth factor receptor

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.