Bivalence of EGF‐like ligands drives the ErbB signaling network

E Tzahar, R Pinkas‐Kramarski, J.D Moyer, L.N Klapper, I Alroy, G Levkowitz, M Shelly, S Henis, M Eisenstein, B.J Ratzkin, M Sela

Research output: Contribution to journalArticlepeer-review

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.
Original languageAmerican English
Pages (from-to)4938-4950
JournalThe EMBO Journal
Volume16
Issue number16
StatePublished - 1997

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