title: Bivalence of EGF-like ligands drives the ErbB signaling network.
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.
authors.affiliation: Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: E
authors.initials: E
authors.lastname: Tzahar
authors.forename: R
authors.initials: R
authors.lastname: Pinkas-Kramarski
authors.forename: J D
authors.initials: JD
authors.lastname: Moyer
authors.forename: L N
authors.initials: LN
authors.lastname: Klapper
authors.forename: I
authors.initials: I
authors.lastname: Alroy
authors.forename: G
authors.initials: G
authors.lastname: Levkowitz
authors.forename: M
authors.initials: M
authors.lastname: Shelly
authors.forename: S
authors.initials: S
authors.lastname: Henis
authors.forename: M
authors.initials: M
authors.lastname: Eisenstein
authors.forename: B J
authors.initials: BJ
authors.lastname: Ratzkin
authors.forename: M
authors.initials: M
authors.lastname: Sela
authors.forename: G C
authors.initials: GC
authors.lastname: Andrews
authors.forename: Y
authors.initials: Y
authors.lastname: Yarden
mesh_terms: D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D006224:Cricetinae; D019281:Dimerization; D004815:Epidermal Growth Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D066246:ErbB Receptors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006023:Glycoproteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D016296:Mutagenesis; D020880:Neuregulins; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism*; D020893:Receptor, ErbB-3; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D006023:Glycoproteins; D008024:Ligands; D020880:Neuregulins; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D011994:Recombinant Proteins; C108365:biregulin