We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Bivalence of EGF-like ligands drives the ErbB signaling network.
- Authors
Tzahar, Eldad; Pinkas-Kramarski, Ronit; Moyer, James D.; Klapper, Leah N.; Alroy, Iris; Levkowitz, Gil; Shelly, Maya; Henis, Sivan; Eisenstein, Miriam; Ratzkin, Barry J.; Sela, Michael; Andrews, Glenn C.; Yarden, Yosef
- Abstract
Signaling by epidermal growth factor (EGF)-like ligands is mediated by an interactive network of four ErbB receptor tyrosine kinases, whose mechanism of ligandinduced 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.
- Subjects
EPIDERMAL growth factor; LIGANDS (Biochemistry); PROTEIN-tyrosine kinases; BINDING sites; PROTEINS; MOSAICISM
- Publication
EMBO Journal, 1997, Vol 16, Issue 16, p4938
- ISSN
0261-4189
- Publication type
Article
- DOI
10.1093/emboj/16.16.4938