Urokinase-type plasminogen activator: proenzyme, receptor, and inhibitors

Abstract

N 'Ew information has recently become available that we believe may be of value for a more precise focusing of research on the role of plasminogen activators (PAs) in cellular physiology and pathology. PAs convert the abundant extracellular zymogen plasminogen into plasmin, an active protease that, directly or indirectly, can promote degradation of all components of the extracellular matrix. The urokinase-type PA (u-PA) is one of two activators with similar catalytic specificities that have been described in each mammalian species so far studied. Many cell types synthesize and secrete u-PA at different stages in their life cycle; it has been a consistent finding that the expression of u-PAcatalyzed proteolysis is under the control of hormonal-type mediators, the nature of which depends on the cell population considered, u-PA is thought to play a central role in regulating extracellular proteolysis in a variety of normal and pathological processes involving tissue destruction and cell migration, e.g., organ involution, inflammatory reactions, and invasive growth of trophoblasts and cancer cells (for reviews, see 8, 18, 44, 47, 49, 50). Recent findings show that u-PA is synthesized and released from mammalian cells as a proenzyme with little or no activity (pro-u-PA), that cells possess a specific binding site for u-PA and pro-u-PA, and that they can also synthesize different rapidly acting, high affinity inhibitors of PAs. Thus, activation of pro-u-PA, u-PA receptor occupancy, and PA-inhibitors may finely regulate the location and extent of plasminogen activation.