title: Hsp90 restrains ErbB-2/HER2 signalling by limiting heterodimer formation.
abstract: ErbB-2/HER2 is an oncogenic tyrosine kinase that regulates a signalling network by forming ligand-induced heterodimers with several growth factor receptors of the ErbB family. Hsp90 and co-chaperones regulate degradation of ErbB-2 but not other ErbB members. Here, we report that the role of Hsp90 in modulating the ErbB network extends beyond regulation of protein stability. The capacity of ErbB-2 to recruit ligand-bound receptors into active heterodimers is limited by Hsp90, which is dissociated from ErbB-2 following ligand-induced heterodimerization. We show that Hsp90 binds a specific loop within the kinase domain of ErbB-2, thereby restraining heterodimer formation and catalytic function. These results define a role for Hsp90 as a molecular switch regulating the ErbB signalling network by limiting formation of ErbB-2-centred receptor complexes.
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Ami
authors.initials: A
authors.lastname: Citri
authors.forename: Judith
authors.initials: J
authors.lastname: Gan
authors.forename: Yaron
authors.initials: Y
authors.lastname: Mosesson
authors.forename: Gyorgi
authors.initials: G
authors.lastname: Vereb
authors.forename: Janos
authors.initials: J
authors.lastname: Szollosi
authors.forename: Yosef
authors.initials: Y
authors.lastname: Yarden
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D019281:Dimerization; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D018841:HSP90 Heat-Shock Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases