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. 1997 Aug 15;16(16):4938–4950. doi: 10.1093/emboj/16.16.4938

Bivalence of EGF-like ligands drives the ErbB signaling network.

E Tzahar 1, R Pinkas-Kramarski 1, J D Moyer 1, L N Klapper 1, I Alroy 1, G Levkowitz 1, M Shelly 1, S Henis 1, M Eisenstein 1, B J Ratzkin 1, M Sela 1, G C Andrews 1, Y Yarden 1
PMCID: PMC1170129  PMID: 9305636

Abstract

Signaling by epidermal growth factor (EGF)-like ligands is mediated by an interactive network of four ErbB receptor tyrosine kinases, whose mechanism of ligand-induced dimerization is unknown. We contrasted two existing models: a conformation-driven activation of a receptor-intrinsic dimerization site and a ligand bivalence model. Analysis of a Neu differentiation factor (NDF)-induced heterodimer between ErbB-3 and ErbB-2 favors a bivalence model; the ligand simultaneously binds both ErbB-3 and ErbB-2, but, due to low-affinity of the second binding event, ligand bivalence drives dimerization only when the receptors are membrane anchored. Results obtained with a chimera and isoforms of NDF/neuregulin predict that each terminus of the ligand molecule contains a distinct binding site. The C-terminal low-affinity site has broad specificity, but it prefers interaction with ErbB-2, an oncogenic protein acting as a promiscuous low-affinity subunit of the three primary receptors. Thus, ligand bivalence enables signal diversification through selective recruitment of homo- and heterodimers of ErbB receptors, and it may explain oncogenicity of erbB-2/HER2.

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Selected References

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