Plasmin-Cellular Interactions in Breast Cancer Invasion and Metastasis.
Final rept. 30 Sep 94-22 Sep 98
VIRGINIA UNIV CHARLOTTESVILLE
Pagination or Media Count:
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 plasminogen. 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.
- Medicine and Medical Research