CONTROL OF TYPE-IV COLLAGENASE ACTIVITY BY COMPONENTS OF THE UROKINASE-PLASMIN SYSTEM - A REGULATORY MECHANISM WITH CELL-BOUND REACTANTS

The urokinase-type plasminogen activator (uPA) and the matrix-degradin g metalloproteinases MMP-2 and MMP-9 (type TV collagenases/gelatinases ) have been implicated in a variety of invasive processes, including t umor invasion, metastasis and angiogenesis. MMP-2 and MMP-9 are secret ed in the form of inactive zymogens that are activated extracellularly , a fundamental process for the control of their activity. The physiol ogical mechanism(s) of gelatinase activation are still poorly understo od; their comprehension may provide tools to control cell invasion. Th e data reported in this paper show multiple roles of the uPA-plasmin s ystem in the control of gelatinase activity: (i) both gelatinases are associated with the cell surface; binding of uPA and plasmin(ogen) to the cell surface results in gelatinase activation without the action o f other metallo- or acid proteinases; (ii) inhibition of uPA or plasmi nogen binding to the cell surface blocks gelatinase activation; (iii) in soluble phase plasmin degrades both gelatinases; and (iv) gelatinas e activation and degradation occur in a dose- and time-dependent manne r in the presence of physiological plasminogen and uPA concentrations. Thus, the uPA-plasmin system may represent a physiological mechanism for the control of gelatinase activity.