The oncogenic ErbB-2/ErbB-3 heterodimer is a surrogate receptor of the epidermal growth factor and betacellulin
| Autor: | Michael Sela, E.J.J. van Zoelen, S. S. Bacus, E Tzahar, Yosef Yarden, Ronit Pinkas-Kramarski, Anne E.G. Lenferink, Leah N. Klapper, Ljuba Lyass, M.L.M. van de Poll |
|---|---|
| Rok vydání: | 1998 |
| Předmět: |
Cancer Research
TGF alpha animal structures Receptor ErbB-3 Receptor ErbB-2 medicine.medical_treatment Breast Neoplasms Biology Ligands Transfection Receptor tyrosine kinase Mice Epidermal growth factor ErbB Cell surface receptor Proto-Oncogene Proteins Genetics medicine Tumor Cells Cultured Animals Humans Betacellulin Phosphorylation skin and connective tissue diseases Growth Substances neoplasms Molecular Biology Binding Sites Epidermal Growth Factor Growth factor Antibodies Monoclonal Cell Differentiation Cell Biology Hematopoietic Stem Cells Recombinant Proteins Cell biology ErbB Receptors Biochemistry biology.protein Neuregulin Intercellular Signaling Peptides and Proteins Tyrosine Female Dimerization Cell Division |
| Zdroj: | Oncogene, 16, pp. 1249-1258 Oncogene, 16, 1249-1258 |
| ISSN: | 0950-9232 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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