PMID- 25086039 OWN - NLM STAT- MEDLINE DCOM- 20150202 LR - 20220318 IS - 1083-351X (Electronic) IS - 0021-9258 (Print) IS - 0021-9258 (Linking) VI - 289 IP - 38 DP - 2014 Sep 19 TI - Different epidermal growth factor (EGF) receptor ligands show distinct kinetics and biased or partial agonism for homodimer and heterodimer formation. PG - 26178-26188 LID - S0021-9258(20)48450-9 [pii] LID - 10.1074/jbc.M114.586826 [doi] AB - 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 EGF receptor (EGFR) homodimers and EGFR/ErbB2 heterodimers. In luciferase fragment complementation imaging studies, amphiregulin (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, TGFalpha, and betacellulin (BTC) appear to mainly stimulate receptor activation through binding to and dimerization of receptor monomers. In radioligand binding assays, EGF and TGFalpha exhibited increased affinity for EGFR/ErbB2 heterodimers compared with EGFR homodimers. By contrast, BTC and AREG showed a similar affinity for both dimers. Thus, EGF and TGFalpha are biased agonists, whereas 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 versus homodimers. CI - (c) 2014 by The American Society for Biochemistry and Molecular Biology, Inc. FAU - Macdonald-Obermann, Jennifer L AU - Macdonald-Obermann JL AD - Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110. FAU - Pike, Linda J AU - Pike LJ AD - Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110. Electronic address: pike@biochem.wustl.edu. LA - eng GR - R01 GM099695/GM/NIGMS NIH HHS/United States GR - R01GM099695/GM/NIGMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20140801 PL - United States TA - J Biol Chem JT - The Journal of biological chemistry JID - 2985121R RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Ligands) RN - EC 2.7.10.1 (EGFR protein, human) RN - EC 2.7.10.1 (ERBB2 protein, human) RN - EC 2.7.10.1 (ErbB Receptors) RN - EC 2.7.10.1 (Receptor, ErbB-2) RN - K16AIQ8CTM (pertuzumab) RN - PQX0D8J21J (Cetuximab) SB - IM MH - Animals MH - Antibodies, Monoclonal, Humanized/pharmacology MH - Binding Sites MH - CHO Cells MH - Cetuximab MH - Cricetinae MH - Cricetulus MH - ErbB Receptors/agonists/*metabolism MH - Humans MH - Kinetics MH - Ligands MH - Protein Multimerization MH - Receptor, ErbB-2/metabolism MH - *Signal Transduction MH - Transcriptional Activation PMC - PMC4176247 OTO - NOTNLM OT - Amphiregulin OT - Betacellulin OT - Epidermal Growth Factor (EGF) OT - Growth Factor OT - Protein-Tyrosine Kinase (Tyrosine Kinase) OT - Receptor Structure-Function OT - Receptor Tyrosine Kinase OT - Signal Transduction OT - Transforming Growth Factor alpha (TGF-alpha) EDAT- 2014/08/03 06:00 MHDA- 2015/02/03 06:00 PMCR- 2015/09/19 CRDT- 2014/08/03 06:00 PHST- 2014/08/03 06:00 [entrez] PHST- 2014/08/03 06:00 [pubmed] PHST- 2015/02/03 06:00 [medline] PHST- 2015/09/19 00:00 [pmc-release] AID - S0021-9258(20)48450-9 [pii] AID - M114.586826 [pii] AID - 10.1074/jbc.M114.586826 [doi] PST - ppublish SO - J Biol Chem. 2014 Sep 19;289(38):26178-26188. doi: 10.1074/jbc.M114.586826. Epub 2014 Aug 1.