Structure of the EGF receptor transactivation circuit integrates multiple signals with cell context

Mol Biosyst. 2010 Jul;6(7):1293-306. doi: 10.1039/c003921g. Epub 2010 May 10.


Transactivation of the epidermal growth factor receptor (EGFR) is thought to be a process by which a variety of cellular inputs can be integrated into a single signaling pathway through either stimulated proteolysis (shedding) of membrane-anchored EGFR ligands or by modification of the activity of the EGFR. As a first step towards building a predictive model of the EGFR transactivation circuit, we quantitatively defined how signals from multiple agonists were integrated both upstream and downstream of the EGFR to regulate extracellular signal regulated kinase (ERK) activity in human mammary epithelial cells. By using a "non-binding" reporter of ligand shedding, we found that transactivation triggers a positive feedback loop from ERK back to the EGFR such that ligand shedding drives EGFR-stimulated ERK that in turn drives further ligand shedding. Importantly, activated Ras and ERK levels were nearly linear functions of ligand shedding and the effect of multiple, sub-saturating inputs was additive. Simulations showed that ERK-mediated feedback through ligand shedding resulted in a stable steady-state level of activated ERK, but also showed that the extracellular environment can modulate the level of feedback. Our results suggest that the transactivation circuit acts as a context-dependent integrator and amplifier of multiple extracellular signals and that signal integration can effectively occur at multiple points in the EGFR pathway.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cell Line
  • Dose-Response Relationship, Drug
  • Epithelial Cells / cytology
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism*
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism*
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Flavonoids / pharmacology
  • Gefitinib
  • Gene Regulatory Networks / drug effects
  • Hepatocyte Growth Factor / pharmacology
  • Humans
  • Imidazoles / pharmacology
  • Ligands
  • Lysophospholipids / pharmacology
  • Mammary Glands, Human / cytology
  • Phosphorylation / drug effects
  • Pyridines / pharmacology
  • Quinazolines / pharmacology
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Signal Transduction / physiology*
  • Transcriptional Activation / drug effects
  • Transforming Growth Factor alpha / pharmacology


  • Flavonoids
  • Imidazoles
  • Ligands
  • Lysophospholipids
  • Pyridines
  • Quinazolines
  • Transforming Growth Factor alpha
  • Hepatocyte Growth Factor
  • ErbB Receptors
  • Extracellular Signal-Regulated MAP Kinases
  • SB 203580
  • lysophosphatidic acid
  • Gefitinib
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one