Dynamic analysis of the epidermal growth factor (EGF) receptor-ErbB2-ErbB3 protein network by luciferase fragment complementation imaging

J Biol Chem. 2013 Oct 18;288(42):30773-30784. doi: 10.1074/jbc.M113.489534. Epub 2013 Sep 6.

Abstract

ErbB3 is a member of the ErbB family of receptor tyrosine kinases. It is unique because it is the only member of the family whose kinase domain is defective. As a result, it is obliged to form heterodimers with other ErbB receptors to signal. In this study, we characterized the interaction of ErbB3 with the EGF receptor and ErbB2 and assessed the effects of Food and Drug Administration-approved therapeutic agents on these interactions. Our findings support the concept that ErbB3 exists in preformed clusters that can be dissociated by NRG-1β and that it interacts with other ErbB receptors in a distinctly hierarchical fashion. Our study also shows that all pairings of the EGF receptor, ErbB2, and ErbB3 form ligand-independent dimers/oligomers. The small-molecule tyrosine kinase inhibitors erlotinib and lapatinib differentially enhance the dimerization of the various ErbB receptor pairings, with the EGFR/ErbB3 heterodimer being particularly sensitive to the effects of erlotinib. The data suggest that the physiological effects of these drugs may involve not only inhibition of tyrosine kinase activity but also a dynamic restructuring of the entire network of receptors.

Keywords: Cancer Biology; Epidermal Growth Factor (EGF); Epidermal Growth Factor Receptor (EGFR); ErbB2; ErbB3; Growth Factors; Receptor Tyrosine Kinase.

Publication types

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

MeSH terms

  • Animals
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism*
  • Erlotinib Hydrochloride
  • Humans
  • Lapatinib
  • Luciferases / genetics
  • Luciferases / metabolism
  • Multienzyme Complexes / antagonists & inhibitors
  • Multienzyme Complexes / genetics
  • Multienzyme Complexes / metabolism*
  • Neuregulin-1 / genetics
  • Neuregulin-1 / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Protein Multimerization*
  • Quinazolines / pharmacology
  • Receptor, ErbB-2 / antagonists & inhibitors
  • Receptor, ErbB-2 / genetics
  • Receptor, ErbB-2 / metabolism*
  • Receptor, ErbB-3 / antagonists & inhibitors
  • Receptor, ErbB-3 / genetics
  • Receptor, ErbB-3 / metabolism*

Substances

  • Multienzyme Complexes
  • NRG1 protein, human
  • Neuregulin-1
  • Protein Kinase Inhibitors
  • Quinazolines
  • Lapatinib
  • Erlotinib Hydrochloride
  • Luciferases
  • EGFR protein, human
  • ERBB2 protein, human
  • ERBB3 protein, human
  • ErbB Receptors
  • Receptor, ErbB-2
  • Receptor, ErbB-3