TY - JOUR
T1 - Epiregulin is a potent Pan-ErbB ligand that preferentially activates heterodimeric receptor complexes
AU - Shelly, Maya
AU - Pinkas-Kramarski, Ronit
AU - Guarino, Bradley C.
AU - Waterman, Hadassa
AU - Wang, Ling Mei
AU - Lyass, Ljuba
AU - Alimandi, Mauricio
AU - Kuo, Angera
AU - Bacus, Sarah S.
AU - Pierce, Jacalyn H.
AU - Andrews, Glenn C.
AU - Yarden, Yosef
PY - 1998/4/24
Y1 - 1998/4/24
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0032562561&partnerID=8YFLogxK
U2 - 10.1074/jbc.273.17.10496
DO - 10.1074/jbc.273.17.10496
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
AN - SCOPUS:0032562561
VL - 273
SP - 10496
EP - 10505
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 17
ER -