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

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, may promote the growth of carcinoma cells.