The oncogenic ErbB-2/ErbB-3 heterodimer is a surrogate receptor of the epidermal growth factor and betacellulin

Oncogene. 1998 Mar 12;16(10):1249-58. doi: 10.1038/sj.onc.1201642.


The ErbB-1 receptor tyrosine kinase binds to six different growth factors, whose prototype is the epidermal growth factor (EGF). Two homologous epithelial receptors, ErbB-3 and ErbB-4, bind all isoforms of another family of growth factors, the Neu differentiation factors (NDFs/neuregulins). The fourth member of the ErbB family, ErbB-2, acts as the preferred heterodimeric partner of ligand-occupied complexes of the three other ErbB proteins. Here we report that at high concentrations, EGF can induce cell growth and differentiation in the absence of ErbB-1. This function is shared by betacellulin, but not by three other ligands, including the transforming growth factor alpha (TGFalpha). The functional receptor was identified as a heterodimer between ErbB-3 and ErbB-2, a previously identified oncogenic complex. When singly expressed, neither ErbB-3 nor ErbB-2 can mediate signaling by EGF. In addition, when co-expressed, blocking either receptor by using site-specific antibodies inhibited EGF and betacellulin activities, indicating strict cooperativity between ErbB-3 and ErbB-2. Through analysis of chimeras between EGF and TGFalpha, we identified the middle portion of EGF (loop B) as the site that enables activation of ErbB-2/ErbB-3. In conclusion, cooperative and promiscuous binding of stroma-derived growth factors by the epithelium-expressed ErbB-2/ErbB-3 heterodimer may be significant to cancer development. The mechanistic implications of our results for a model that attributes receptor dimerization to ligand bivalency, as well as to a recently proposed mechanism of secondary dimerization, are discussed.

Publication types

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

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Betacellulin
  • Binding Sites
  • Breast Neoplasms
  • Cell Differentiation / drug effects
  • Cell Division / drug effects
  • Dimerization
  • Epidermal Growth Factor / metabolism
  • Epidermal Growth Factor / pharmacology
  • ErbB Receptors / chemistry
  • ErbB Receptors / metabolism*
  • Female
  • Growth Substances / metabolism
  • Growth Substances / pharmacology*
  • Hematopoietic Stem Cells
  • Humans
  • Intercellular Signaling Peptides and Proteins*
  • Ligands
  • Mice
  • Phosphorylation
  • Proto-Oncogene Proteins / chemistry
  • Proto-Oncogene Proteins / metabolism*
  • Receptor, ErbB-2 / chemistry
  • Receptor, ErbB-2 / metabolism*
  • Receptor, ErbB-3
  • Recombinant Proteins / metabolism
  • Recombinant Proteins / pharmacology
  • Transfection
  • Tumor Cells, Cultured
  • Tyrosine / metabolism


  • Antibodies, Monoclonal
  • BTC protein, human
  • Betacellulin
  • Btc protein, mouse
  • Growth Substances
  • Intercellular Signaling Peptides and Proteins
  • Ligands
  • Proto-Oncogene Proteins
  • Recombinant Proteins
  • Tyrosine
  • Epidermal Growth Factor
  • ErbB Receptors
  • Receptor, ErbB-2
  • Receptor, ErbB-3