Different Epidermal Growth Factor Receptor (EGFR) Agonists Produce Unique Signatures for the Recruitment of Downstream Signaling Proteins

J Biol Chem. 2016 Mar 11;291(11):5528-5540. doi: 10.1074/jbc.M115.710087. Epub 2016 Jan 19.


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.

Keywords: cancer biology; epidermal growth factor (EGF); epidermal growth factor receptor (EGFR); growth factor; receptor tyrosine kinase; systems biology.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CHO Cells
  • Cricetulus
  • Epidermal Growth Factor / metabolism*
  • ErbB Receptors / agonists*
  • ErbB Receptors / metabolism*
  • Ligands
  • Signal Transduction / drug effects*


  • Ligands
  • Epidermal Growth Factor
  • ErbB Receptors