University of Virginia Health System

Dr. Steven L. Gonias

Cell surfaces and the pericellular microenvironment are sites rich in proteinases and proteinase inhibitors. Our major goal is to understand the macromolecular interactions which localize these proteins near the cell surface and understand how proteinases affect cell function. Our laboratory has characterized cellular binding sites for the proteinase, plasmin, on a variety of cell types including endothelial cells. Plasmin functions not only in fibrinolysis, but in processes that require cellular migration including angiogenesis and tissue remodeling. Very high concentrations of plasmins may be generated near the cell surface by plasminogen activators. A major focus for our group is to characterize growth factors and growth factor receptors as substrates for receptor-associated plasmin. Since most growth factors bind to multiple cellular receptors, we hypothesize that plasmin and other proteinases may alter cellular responsiveness to growth factors by specifically cleaving one of a group of receptors.

In related work, we are studying proteins which may serve to target growth factors to specific cell types. In particular, we are studying a2-macroglobulin, a proteinase inhibitor, which binds a variety of growth factors including transforming growth factor-b and platelet derived growth factor. a2-Macroglobulin synergizes the activity of growth factors towards cells that express the a2 macroglobulin receptor. The a2-macroglobulin receptor is also known as low density lipoprotein receptor-related protein (LRP). The complete growth regulatory loop includes growth factors a2-macroglobulin, growth factor receptors, and LRP. Not only are we interested in studying the function of the growth regulatory loop, but also the expression of each of the components.