PMID: 9540810Apr 16, 1998Paper

The ErbB-2/HER2 oncogenic receptor of adenocarcinomas: from orphanhood to multiple stromal ligands

Biochimica Et Biophysica Acta
E Tzahar, Y Yarden

Abstract

Extensive clinical and biochemical evidence implicates ErbB-2, a transmembrane tyrosine kinase related to growth factor receptors, in the development, metastasis, and resistance to therapy of multiple, common human carcinomas. Previous attempts to uncover an ErbB-2-specific ligand led to isolation of the neuregulin (NRG) family, but these ligands, like all other growth factors with an EGF-like motif, only indirectly active ErbB-2. On the other hand, biochemical and genetic evidence suggest a non-autonomous function of ErbB-2 in an interactive ErbB signaling network. Accordingly, the oncoprotein acts as a shared signaling subunit of primary growth factor receptors. By stabilizing heterodimers with other ErbB proteins, ErbB-2 prolongs and enhances signal transduction by a large group of stroma-derived growth factors. Furthermore, we have proposed a model in which all ErbB-2 ligands are bivalent and bind to ErbB-2 with low affinity, following high affinity binding to a primary receptor with which ErbB-2 is heterodimerized. Thus the presence of ErbB-2 in relevant ErbB heterodimeric structures on the surfaces of certain epithelial tumor cells can amplify signals arising from the binding of stromal ErbB ligands. This effect, in turn,...Continue Reading

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