Role of the C-terminal linear region of EGF-like growth factors in ErbB specificity

The epidermal growth factor (EGF)-like growth factors bind their ErbB receptors in a highly selective manner. Recently, we have shown that the sequence YYDLL in the C-terminal linear region is compatible with binding to all ligand-binding ErbB receptors. In the present study, we show that introduction of the YYDLL sequence into the ErbB1 specific ligands EGF and transforming growth factor-alpha (TGFalpha) broadened their receptor specificity towards ErbB4. Upon introduction of the YYDLL sequence into epiregulin, which by itself binds ErbB1 and ErbB4 but not ErbB3, its binding specificity was broadened to ErbB3, concomitant with enhanced affinity for ErbB4. Introduction of the YYDLL sequence into NRG1beta resulted in a 10-fold increase in affinity for ErbB3, without affecting its receptor specificity. Remarkably, the strongly enhanced affinity for ErbB3 negatively influenced their mitogenic activity towards cells coexpressing ErbB2 and ErbB3. These observations are discussed in terms of the optimised ErbB affinity, selectivity and mitogenic potential that have taken place during evolution.