Epiregulin is a potent pan-ErbB ligand that preferentially activates heterodimeric receptor complexes

J Biol Chem. 1998 Apr 24;273(17):10496-505. doi: 10.1074/jbc.273.17.10496.


The ErbB signaling network consists of four transmembrane receptor tyrosine kinases and more than a dozen ligands sharing an epidermal growth factor (EGF) motif. The multiplicity of ErbB-specific ligands is incompletely understood in terms of signal specificity because all ErbB molecules signal through partially overlapping pathways. Here we addressed 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 the broadest specificity EGF-like ligand so far characterized: not only does it stimulate homodimers of both ErbB-1 and ErbB-4, it also activates all possible heterodimeric ErbB complexes. Consistent with its relaxed selectivity, epiregulin binds the various receptor combinations with an affinity that is approximately 100-fold lower than the affinity of ligands with more stringent selectivity, including EGF. Nevertheless, epiregulin's action upon most receptor combinations transmits a more potent mitogenic signal than does EGF. This remarkable discrepancy between binding affinity and bioactivity is permitted by a mechanism that prevents receptor down-regulation, and results in a weak, but prolonged, state of receptor activation.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • CHO Cells
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Cell Differentiation
  • Cell Line
  • Cricetinae
  • Dimerization
  • Down-Regulation
  • Enzyme Activation
  • Epidermal Growth Factor / metabolism*
  • Epiregulin
  • ErbB Receptors / metabolism*
  • Ligands
  • Phosphorylation
  • Signal Transduction
  • Tyrosine / metabolism


  • Epiregulin
  • Ligands
  • Tyrosine
  • Epidermal Growth Factor
  • ErbB Receptors
  • Calcium-Calmodulin-Dependent Protein Kinases