BIVALENCE OF EGF-LIKE LIGANDS DRIVES THE ERBB SIGNALING NETWORK

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-intri nsic dimerization site and a ligand bivalence model, Analysis of a Neu differentiation factor (NDF)-induced heterodimer between ErbB-3 and E rbB-2 favors a bivalence model; the ligand simultaneously binds both E rbB-3 and ErbB-2, but, due to low-affinity of the second binding event , ligand bivalence drives dimerization only when the receptors are mem brane anchored, Results obtained with a chimera and isoforms of NDF/ne uregulin predict that each terminus of the ligand molecule contains a distinct binding site, The C-terminal low-affinity site has broad spec ificity, but it prefers interaction with ErbB-2, an oncogenic protein acting as a promiscuous low-affinity subunit of the three primary rece ptors, Thus, ligand bivalence enables signal diversification through s elective recruitment of home-and heterodimers of ErbB receptors, and i t may explain oncogenicity of erbB-2/HER2.