title: Different Epidermal Growth Factor Receptor (EGFR) Agonists Produce Unique Signatures for the Recruitment of Downstream Signaling Proteins.
abstract: The EGF receptor can bind seven different agonist ligands. Although each agonist appears to stimulate the same suite of downstream signaling proteins, different agonists are capable of inducing distinct responses in the same cell. To determine the basis for these differences, we used luciferase fragment complementation imaging to monitor the recruitment of Cbl, CrkL, Gab1, Grb2, PI3K, p52 Shc, p66 Shc, and Shp2 to the EGF receptor when stimulated by the seven EGF receptor ligands. Recruitment of all eight proteins was rapid, dose-dependent, and inhibited by erlotinib and lapatinib, although to differing extents. Comparison of the time course of recruitment of the eight proteins in response to a fixed concentration of each growth factor revealed differences among the growth factors that could contribute to their differing biological effects. Principal component analysis of the resulting data set confirmed that the recruitment of these proteins differed between agonists and also between different doses of the same agonist. Ensemble clustering of the overall response to the different growth factors suggests that these EGF receptor ligands fall into two major groups as follows: (i) EGF, amphiregulin, and EPR; and (ii) betacellulin, TGFα, and epigen. Heparin-binding EGF is distantly related to both clusters. Our data identify differences in network utilization by different EGF receptor agonists and highlight the need to characterize network interactions under conditions other than high dose EGF.
authors.affiliation: From the Department of Biomedical Engineering and Center for Biological Systems Engineering and.
authors.forename: Tom
authors.initials: T
authors.lastname: Ronan
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110 and.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Macdonald-Obermann
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110 and.
authors.forename: Lorel
authors.initials: L
authors.lastname: Huelsmann
authors.affiliation: the Department of Biochemistry and Biophysics, Graduate Group in Biochemistry and Molecular Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104-6059.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Bessman
authors.affiliation: From the Department of Biomedical Engineering and Center for Biological Systems Engineering and. Electronic address: knaegle@wustl.edu.
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Naegle
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110 and. Electronic address: pike@biochem.wustl.edu.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Pike
mesh_terms: D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000819:agonists* / Q000378:metabolism*; D008024:Ligands; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D008024:Ligands; D004815:Epidermal Growth Factor; D066246:ErbB Receptors
keywords: cancer biology; epidermal growth factor (EGF); epidermal growth factor receptor (EGFR); growth factor; receptor tyrosine kinase; systems biology