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

Ronit Pinkas-Kramarski, Anne E.G. Lenferink, Sarah S. Bacus, Ljuba Lyass, Monique L.M. Van De Poll, Leah N. Klapper, Eldad Tzahar, Michael Sela, Everardus J.J. Van Zoelen, Yosef Yarden*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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 a (TGFα). 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 TGFα, 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.

Original languageEnglish
Pages (from-to)1249-1258
Number of pages10
JournalOncogene
Volume16
Issue number10
DOIs
StatePublished - 12 Mar 1998
Externally publishedYes

Funding

FundersFunder number
National Cancer InstituteR01CA051712
Susan G. Komen
Israel Science Foundation

    Keywords

    • Epidermal growth factor
    • ErbB/HER family
    • Oncogene
    • Signal transduction
    • Tyrosine kinase

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