cbl-b inhibits epidermal growth factor receptor signaling

The role of cbl-b in signaling by the epidermal growth factor receptor (EGF R),vas studied and compared with c-cbl, We demonstrate in vivo, that chl-b, like c-cbl, is phosphorylated and recruited to the EGFR upon EGF stimulati on and both cbl proteins can bind to the Grb2 adaptor protein, To investiga te the functional role of chi proteins in EGFR signaling, we transfected cb l-b or c-cbl into 32D cells overexpressing the EGFR (32D/EGFR), This cell l ine is absolutely dependent on exogenous IL-3 or EGF for sustained growth. 32D/EGFR cells overexpressing cbl-b showed markedly inhibited growth in EGF compared to c-cbl transfectants and vector controls, This growth inhibitio n by cbl-b was the result of a dramatic increase in the number of cells und ergoing apoptosis, Consistent with this finding, chl-b overexpression marke dly decreased the amplitude and duration of AKT activation upon EGF stimula tion compared to either vector controls or c-cbl overexpressing cells. In a ddition, the duration of EGF mediated MAP kinase and Jun kinase activation in cells overespressing cbl-b is shortened. These data demonstrate that cbl -b inhibits EGF-induced cell growth and that cbl-b and c-cbl have distinct roles in EGF mediated signaling.