Hsp90 restrains ErbB-2/HER2 signalling by limiting heterodimer formation |
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Authors: | Citri Ami Gan Judith Mosesson Yaron Vereb Gyorgi Szollosi Janos Yarden Yosef |
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Affiliation: | Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel. |
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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. |
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