Cell Surface Regulation of Matrix Metalloproteinases in Breast Cancer Cells
Abstract
Metastasis is the major cause of death in breast cancer patients and is partly caused by the action of proteolytic enzymes that degrade extracellular matrix (ECM). We have focused on the gelatinases, MMP-2, and MMP-9, two ECM-degrading enzymes that are members of the matrix metalloproteinase (MMP) family of proteases. The gelatinases are associated with the surface of breast cancer cells. MMP-2 surface binding plays a role in activation by MT1-MMP, a membrane-bound MMP that is also expressed in breast cancer cells. MMP-2 activation is mediated by the action of TIMP-2, a metalloproteinase inhibitor. We characterized in detail the process of pro-MMP-2 activation by MT1-MMP and demonstrated the role of TIMP-2 in this process. The regulation of MT1-MMP on the cell surface was also investigated. These studies demonstrated that MT1-MMP undergoes autocatalytic processing and ectodomain shedding, which serve to control the level of MT1-MMP on the cell surface and produce active enzyme at both the cell membrane and in the extracellular space. MT1- MMP initiates a cascade of zymogen activation on the cell surface that leads to the generation of active MMP-2 and active MMP-9. This process is regulated by TIMP-2. A novel mechanism-based inhibitor for the gelatinases that binds with high affinity and irreversible has been characterized. Together, these studies have defined some key aspects that regulate the function of the MT1-MMP/gelatinase axis on the surface of breast cancer cells and develop new approaches to counteract their action in tumor tissues.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2003
- Accession Number
- ADA423044
Entities
People
- Rafael Fridman
Organizations
- Wayne State University