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ErbB2 degradation mediated by the co-chaperone protein CHIP
Pengcheng Zhou1, Norvin Fernandes, Ingrid L Dodge
1Division of Rheumatology, Immunology, and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
The Journal of Biological Chemistry
|February 8, 2003
Summary
The carboxyl terminus of Hsc70-interacting protein (CHIP) ubiquitin ligase targets ErbB2 for degradation. CHIP, along with Hsp90 inhibitors like 17-AAG, promotes ErbB2 ubiquitinylation and down-regulation, offering a new anti-cancer strategy.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- ErbB2 overexpression is linked to aggressive cancers and poor prognosis.
- Targeting ErbB2 signaling is a key anti-cancer strategy.
- Cbl-mediated ubiquitinylation is a known ErbB2 down-regulation pathway.
Purpose of the Study:
- Identify the ubiquitin ligase responsible for Hsp90 inhibitor-induced ErbB2 down-regulation.
- Investigate the role of CHIP in ErbB2 ubiquitinylation and degradation.
- Elucidate the interplay between CHIP, Hsp90, and ErbB2 signaling.
Main Methods:
- In vitro assays to test ErbB2 as a substrate for CHIP.
- In vivo studies using overexpression of wild-type and mutant CHIP.
- Co-immunoprecipitation assays to assess protein interactions.
- Treatment with Hsp90 inhibitors like 17-AAG.
Main Results:
- ErbB2 is an in vitro substrate for the CHIP ubiquitin ligase.
- CHIP overexpression induces ErbB2 ubiquitinylation and reduces its levels.
- CHIP's activity is independent of Cbl and additive with 17-AAG.
- 17-AAG enhances CHIP-ErbB2 association and affects chaperone interactions.
Conclusions:
- ErbB2 is a direct target of CHIP ubiquitin ligase activity.
- CHIP plays a significant role in Hsp90 inhibitor-induced ErbB2 down-regulation.
- CHIP regulates ErbB2 association with Hsp70/Hsp90 chaperones.