Growth Factor Regulation of Brain Protease Inhibitors

Abstract

An important class of peptides which inhibit serine proteases are collectively known as serpins. These inhibitors are widely distributed in tissues and are involved in several processes including fibrinolysis, blood coagulation and complement activation ^1,2. Members of the serpin family include plasminogen activators (PAI), protease nexins, α₁-antichymotrypsin, C1-inhibitor, and α₂-antiplasmin. PAI-1 is one of two inhibitors of the highly specific serine proteases, urokinase-type plasminogen activator (u-PA) and tissue-type plasminogen activator (t-PA). Balance between plasminogen activators and activator inhibitors ultimately regulates levels of activated plasmin, itself a broad spectrum serine protease. Activated plasmin, formed by u-PA or t-PA cleavage of the inactive proenzyme plasminogen, proteolytically degrades fibrin and a variety of extracellular matrix and basement membrane proteins, and may be involved in biological processes reliant upon breakdown of extracellular matrix and basement membranes, such as cell migration, invasion, tissue remodeling, and tumor metastasis². Thus, balance between u-PA, t-PA and their inhibitors PAI-1 and PAI-2, may be critical to normal cellular and tissue growth and development, whereas their imbalance may contribute to the pathogenesis of certain tissue invasive diseases.