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Hsp90 restrains ErbB-2/HER2 signalling by limiting heterodimer formation
Ami Citri1, Judith Gan, Yaron Mosesson
1Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
EMBO Reports
|November 30, 2004
Summary
Heat shock protein 90 (Hsp90) acts as a molecular switch, controlling the ErbB signalling network. Hsp90 limits ErbB-2 receptor complex formation and kinase activity, extending its role beyond protein stability.
Area of Science:
- Molecular Biology
- Cell Signalling
- Oncology
Background:
- ErbB-2/HER2 is an oncogenic tyrosine kinase crucial for cell signalling.
- Heat shock protein 90 (Hsp90) and co-chaperones regulate ErbB-2 protein degradation.
- The precise role of Hsp90 in modulating the broader ErbB signalling network is not fully understood.
Purpose of the Study:
- To investigate the role of Hsp90 in regulating the ErbB signalling network beyond protein stability.
- To elucidate the mechanism by which Hsp90 modulates ErbB-2 function and heterodimerization.
Main Methods:
- Investigated the interaction between Hsp90 and ErbB-2.
- Assessed the effect of Hsp90 on ligand-induced heterodimerization of ErbB receptors.
- Characterized the binding site of Hsp90 on the ErbB-2 kinase domain.
Main Results:
- Hsp90 limits the capacity of ErbB-2 to recruit ligand-bound receptors into active heterodimers.
- Hsp90 dissociates from ErbB-2 upon ligand-induced heterodimerization.
- Hsp90 binds a specific loop in the ErbB-2 kinase domain, restraining its catalytic function.
Conclusions:
- Hsp90 acts as a molecular switch regulating the ErbB signalling network.
- Hsp90's function extends to limiting the formation of ErbB-2-centered receptor complexes.
- This regulation is critical for controlling ErbB-2 signalling output.