Different EGF Receptor Ligands Show Distinct Kinetics and Biased or Partial Agonism for Homodimer and Heterodimer Formation [Signal Transduction]

August 1st, 2014 by Macdonald-Obermann, J. L., Pike, L. J.

The EGF receptor has seven different cognate ligands. Previous work has shown that these different ligands are capable of inducing different biological effects even in the same cell. To begin to understand the molecular basis for this variation, we used luciferase fragment complementation to measure ligand-induced dimer formation and radioligand binding to study the effect of the ligands on subunit-subunit interactions in EGFR homodimers and EGFR/ErbB2 heterodimers. In luciferase fragment complementation imaging studies, AREG functioned as a partial agonist, inducing only about half as much total dimerization as the other three ligands. However, unlike the other ligands, AREG showed biphasic kinetics for dimer formation suggesting that its path for EGF receptor activation involves binding to both monomers and preformed dimers. EGF, TGFα and BTC appear to mainly stimulate receptor activation through binding to and dimerization of receptor monomers. In radioligand binding assays, EGF and TGFα exhibited increased affinity for EGFR/ErbB2 heterodimers as compared to EGFR homodimers. By contrast, BTC and AREG showed a similar affinity for both dimers. Thus, EGF and TGFα are biased agonists while BTC and AREG are balanced agonists with respect to selectivity of dimer formation. These data suggest that the differences in biological response to different EGF receptor ligands may result from partial agonism for dimer formation, differences in the kinetic pathway utilized to generate activated receptor dimers and biases in the formation of heterodimers vs homodimers.
  • Posted in Journal of Biological Chemistry, Publications
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