Cbl-b-dependent coordinated degradation of the epidermal growth factor receptor signaling complex

Cbl proteins function as ubiquitin protein ligases for the activated epider mal growth factor receptor and, thus, negatively regulate its activity. Her e we show that Cbl-b is ubiquitinated and degraded upon activation of the r eceptor. Epidermal growth factor (EGF)-induced Cbl-b degradation requires i ntact RING finger and tyrosine kinase binding domains and requires binding of the Cbl-b protein to the activated EGF receptor (EGFR), Degradation of b oth the EGFR and the Cbl-b protein is blocked by lysosomal and proteasomal inhibitors, Other components of the EGFR-signaling complex (i.e. Grb2 and S hc) are also degraded in an EGF-induced Cbl-b-dependent fashion. Our result s suggest that the ubiquitin protein ligase function of Cbl-b is regulated by coordinated degradation of the Cbl-b protein along with its substrate. F urthermore, the data demonstrate that Cbl-b mediates degradation of multipl e proteins in the EGFR-signaling complex.