Epiregulin is a potent pan-ErbB ligand that preferentially activates heterodimeric receptor complexes.
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.
Shelly
M
M
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
Pinkas-Kramarski
R
R
Guarino
B C
BC
Waterman
H
H
Wang
L M
LM
Lyass
L
L
Alimandi
M
M
Kuo
A
A
Bacus
S S
SS
Pierce
J H
JH
Andrews
G C
GC
Yarden
Y
Y
D000818:Animals; D016466:CHO Cells; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D006224:Cricetinae; D019281:Dimerization; D015536:Down-Regulation; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066260:Epiregulin; D066246:ErbB Receptors / Q000378:metabolism*; D008024:Ligands; D010766:Phosphorylation; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism
D066260:Epiregulin; D008024:Ligands; D014443:Tyrosine; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D017871:Calcium-Calmodulin-Dependent Protein Kinases