Diversification of Neu differentiation factor and epidermal growth factor signaling by combinatorial receptor interactions

EMBO J. 1996 May 15;15(10):2452-67.


The ErbB family includes two receptors, ErbB-1 and ErbB-3, that respectively bind to epidermal growth factor and Neu differentiation factor, and an orphan receptor, ErbB-2. Unlike ErbB-1 and ErbB-2, the intrinsic tyrosine kinase of ErbB-3 is catalytically impaired. By using interleukin-3-dependent cells that ectopically express the three ErbB proteins or their combinations, we found that ErbB-3 is devoid of any biological activity but both ErbB-1 and ErbB-2 can reconstitute its extremely potent mitogenic activity. Transactivation of ErbB-3 correlates with heterodimer formation and is reflected in receptor phosphorylation and the transregulation of ligand affinity. Inter-receptor interactions enable graded proliferative and survival signals: heterodimers are more potent than homodimers, and ErbB-3-containing complexes, especially the ErbB-2/ErbB-3 heterodimer, are more active than ErbB-1 complexes. Nevertheless, ErbB-1 signaling displays dominance over ErbB-3 when the two receptors are coexpressed. Although all receptor combinations activate the mitogen-activated protein kinases ERK and c-Jun kinase, they differ in their rate of endocytosis and in coupling to intervening signaling proteins. It is conceivable that combinatorial receptor interactions diversify signal transduction and confer double regulation, in cis and in trans, of the superior mitogenic activity of the kinase-defective ErbB-3.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Base Sequence
  • Cell Line
  • Epidermal Growth Factor / chemistry
  • Epidermal Growth Factor / physiology*
  • ErbB Receptors / chemistry
  • ErbB Receptors / physiology*
  • Glycoproteins / physiology*
  • Hematopoietic Stem Cells / drug effects
  • Hematopoietic Stem Cells / metabolism
  • Humans
  • Interleukin-3 / pharmacology
  • Mice
  • Models, Biological
  • Molecular Sequence Data
  • Neuregulins
  • Phosphorylation
  • Protein Conformation
  • Protein Kinases / metabolism
  • Protein Multimerization
  • Protein Processing, Post-Translational
  • Proto-Oncogene Proteins / chemistry
  • Proto-Oncogene Proteins / physiology*
  • Receptor, ErbB-2 / physiology
  • Receptor, ErbB-3
  • Recombinant Proteins / drug effects
  • Recombinant Proteins / metabolism
  • Signal Transduction / drug effects*
  • Signal Transduction / physiology


  • Glycoproteins
  • Interleukin-3
  • Neuregulins
  • Proto-Oncogene Proteins
  • Recombinant Proteins
  • Epidermal Growth Factor
  • Protein Kinases
  • ErbB Receptors
  • Receptor, ErbB-2
  • Receptor, ErbB-3