EPIREGULIN IS A POTENT PAN-ERBB LIGAND THAT PREFERENTIALLY ACTIVATES HETERODIMERIC RECEPTOR COMPLEXES

The ErbB signaling network consists of four transmembrane receptor tyr osine kinases and more than a dozen ligands sharing an epidermal growt h factor (EGF) motif. The multiplicity of ErbB-specific ligands is inc ompletely understood in terms of signal specificity because all ErbB m olecules signal through partially overlapping pathways. Here we addres sed the action of epiregulin, a recently isolated ligand of ErbB-1. By employing a set of factor-dependent cell lines engineered to express individual ErbBs or their combinations, we found that epiregulin is th e broadest specificity EGF-like ligand so far characterized: not only does it stimulate homodimers of both ErbB-1 and ErbB-4, it also activa tes all possible heterodimeric ErbB complexes. Consistent with its rel axed selectivity, epiregulin binds the various receptor combinations w ith an affinity that is approximately 100-fold lower than the affinity of ligands with more stringent selectivity, including EGF. Neverthele ss, epiregulin's action upon most receptor combinations transmits a mo re potent mitogenic signal than does EGF. This remarkable discrepancy between binding affinity and bioactivity is permitted by a mechanism t hat prevents receptor down-regulation, and results in a weak, but prol onged, state of receptor activation.