A Novel Biochemical Pathway of ErbB2 Down-Regulation
Abstract
This proposal will examine a novel hypothesis that the HSP90/HSP70-associated co-chaperone CHIP functions as a selective ErbB2-directed ubiquitin ligase. This hypothesis is based on studies that while Cb1 ubiquitin ligase negatively regulates ErbB1 (EGF receptor) by promoting its lysosomal traffic, lack of Cb1 recruitment to ErbB2 upon heregulin stimulation promotes receptor recycling; however, ErbB2 can be targeted for ubiquitination via heterodimerization with ErbB1 or treatment with a therapeutic anti-ErbB2 antibody, highlighting the potential of ubiquitin ligase-mediated down-regulation of ErbB2 as a therapeutic strategy. We propose comprehensive strategies to test if CHIP functions as an ErbB2-selective ubiquitin ligase independent of Cb1, whether Cbl and CHIP can synergize to induce the ubiquitination and subsequent down-regulation of ErbB2 and reduction of cancer cell proliferation, and examine the mechanism of CHIP-mediated down-regulation of ErbB2. Validation of our hypothesis will be a major advance in ErbB receptor biology, and will provide a rationale to synergize anti-ErbB2 antibody therapy (e.g., with ansamycins or related drugs) of ErbB2-overexpressing breast cancer patients to increase the proportion of responders and to reduce toxicity.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2004
- Accession Number
- ADA435699
Entities
People
- Hamid Band
Organizations
- Brigham and Women's Hospital