Localization of plasminogen on cell surfaces is a crucial control point for positive regulation of cell surface plasmin proteolytic activity that facilitates both physiological and pathological processes requiring cell migration. The long-term goal of our laboratory is to understand mechanisms by which plasminogen receptors regulate pathological and physiological processes. This proposal is based on our discovery of a new protein, the plasminogen receptor, Plg-RKT that has a unique structure: Plg-RKT is an integral membrane protein that exposes a C-terminal lysine on the cell surface, in an orientation to bind plasminogen. Plg-RKT functions as a developmentally regulated plasminogen receptor that promotes plasminogen activation on monocytes and regulates invasion of monocytes through extracellular matrices. Plg-RKT is necessary for optimal plasminogen- dependent macrophage recruitment in the inflammatory response in vivo. In other novel results, Plg-RKT is highly co-localized with the receptor for the major plasminogen activator synthesized by macrophages, the urokinase plasminogen activator receptor (uPAR) and physically associates with uPAR. The objective of this application is to elucidate the molecular mechanisms by which Plg-RKT regulates plasminogen-dependent macrophage recruitment in the inflammatory response. The central hypothesis to be addressed is that Plg-RKT regulates plasminogen-dependent macrophage recruitment by promoting plasminogen activation, extracellular matrix invasion and chemotaxis. To address our hypothesis, our specific aims are: 1) to test the hypothesis that Plg-RKT regulates specific uPAR-dependent functions and that uPAR regulates specific Plg-RKT-dependent functions in plasminogen activation and cell migration;2) to identify molecular determinants of the physical association of Plg-RKT with uPAR;3) To identify mechanisms by which Plg-RKT regulates functions of plasminogen in vivo. Studies will be performed in cell based assays and in vivo using novel function blocking anti- Plg-RKT antibodies, peptide mimetics and a new Plg-RKT knockout mouse model. We expect that accomplishment of our specific aims will provide fundamental insights that should apply to understanding mechanisms of regulation of inflammation as well as regulation of other physiological and pathological processes dependent on cell migration.
The proposed research is relevant to public health because new knowledge of mechanisms by which cell migration is regulated will be acquired. This knowledge is directly applicable to understanding the multitude of diseases with key inflammatory components (notably cardiovascular disease), as well as additional pathological processes dependent on cell migration (notably, cancer metastasis). In addition the results of these studies are expected to identify new potential targets for development of new therapies for these diseases.
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