Plasmin-Cellular Interactions in Breast Cancer Invasion and Metastasis.
Abstract
It has been recognized for many years that cancer invasion and metastasis are promoted by a cascade of extra-cellular proteinases which is organized on the external cell surface. This cascade is initiated by urokinase-type plasminogen activator (uPA) which binds to its cell surface receptor, uPAR, and then activates cell-associated plasminogen. The resulting plasmin may digest extracellular matrix proteins or promote the activation of other proteinases. The major goal of this research program was to characterize the role of cytokeratin 8 (CK8) as a newly- discovered cell-surface binding site for plasmin(ogen). Our results documented for the first time that CK8, an intracellular cytoskeletal protein, penetrates to the external cell surface in breast cancer cells. We characterized the biochemistry of CK-proteinase interactions, determined that CK8 is the principal plasminogen binding protein in certain breast cancer cell lines, and completed a molecular analysis of the binding sites for plasminogen and tissue- type plasminogen activator in CK. Importantly, CK8-associated plasminogen was not activated by uPAR-associated uPA. This led us to reassess the role of uPAR in breast cancer cell physiology. In new studies, we demonstrated a novel linkage between uPAR and breast cancer cell physiology, in which uPA triggers a signal transduction cascade which activates H-Ras, MAP kinase, and myosin light chain kinase to promote motility. Our studies contribute to a model in which proteinases regulate breast cancer cell physiology by multiple mechanisms.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 1998
- Accession Number
- ADA361516
Entities
People
- Steven L. Gonias
Organizations
- University of Virginia