Regulation of ErbB-2 Metabolic Stability
Abstract
This grant has focused on the mechanism by which geldanamycin controls the metabolic stability of ErbB-2, a co-receptor tyrosine kinase. ErbB-2 is overexpressed in breast cancer and is known to increase cell proliferation. Geldanamycin decreases ErbB-2 levels in cells and is in clinical trials for the treatment of breast cancer. Our studies in this grant have examined the mechanism by which geldanamycin decreases ErbB-2 levels. Published data demonstrate that geldanamycin provokes prpteolytic cleavage events within the ErbB-2 intracellular domain and thereby decreases the level of the mature form of ErbB-2. One of these cleavage events occurs in the carboxyterminal domain of ErbB-2, while another takes place in the kinase domain. We have identified sequences within the kinase domain that are required for this molecule's sensitivity to geldanamycin. Once these initial cleavage events occur the resultant fragments of ErbB-2 are rapidly degraded. However, these fragments may induce novel biologic activities within cells particularly if ErbB-2 is overexpressed. We have identified a short sequence within the kinase domain of ErbB-2 that is able to induce cell death. This could account for the cellular toxicity of geldanamycin.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2004
- Accession Number
- ADA425964
Entities
People
- Graham F. Carpenter
Organizations
- Vanderbilt University Medical Center