Molecular and Cellular Endocrinology, 68 (1990) 1-19 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCB Elsevier Scientific Publishers Ireland, Ltd. MOLCEL 02184 Review Plasrninogen activator inhibitors: hormonally regulated serpins Peter A. Andreasen 1,2 Birgitte Georg I, Leif R. Lund 3, ‘ 45 Andrea Riccio ’ and Simon N. Stacey 3 I Institute of Biochemistry C, University of Copenhagen, Copenhagen DK-2200 N, Denmark, 2 Institute of Molecular Biology, University of Arhus, Arhus DK-8000 C, Denmark, 3 Finsen Laboratory, Rigshospitalet, Copenhagen DK-2100 0, Denmark, ’ Institute of Microbiology, University of Copenhagen, Copenhagen DK-1353 K, Denmark, and ’ Centro di Endocrinologia ed Oncologia Sperimentale, Consiglio Nazionale delle Richerche, Naples, Italy Key words: Serpins; Serine proteases; Plasminogen activators; Plasminogen activator inhibitors zyxwvutsrqponmlkjihgfedcbaZYXWVU 1. Introduction Plasmin is an extracellular broad-spectrum serine protease, which is formed by cleavage of a peptide bond in the single polypeptide chain of the inactive proenzyme plasminogen. Plasminogen activation is catalyzed by two other, highly specific serine proteases, urokinase-type plasminogen acti- vator (u-PA) and tissue-type plasminogen activa- tor (t-PA). Both are released from cells as single- chain forms with no (u-PA) and low (t-PA) activ- ity, with cleavage of a polypeptide bond leading to the fully active forms. Other identified proteins of the plasminogen activation system are the specific and fast-acting plasmin inhibitor a,-antiplasmin, two specific and fast-acting plasminogen activator inhibitors, type 1 and type 2 (PAI- and PAI-2), and a cell surface u-PA binding protein, the u-PA receptor (u-PAR) (see Fig. 1; for reviews, see Reich, 1978; Collen, 1980; Thorsen et al., 1984; Dano et al., 1985; Erickson et al., 1985; Blasi et al., 1987; Sprengers and Kluft, 1987; Thorsen and Philips, 1987; Blasi, 1988; Kruithof, 1988a, b; Saksela and Rifkin, 1988; Schleef and Loskutoff, 1988). Plasmin generation in the extracellular space is initiated by cellular release of the single-chain Address for correspondence: Peter A. Andreasen, Institute of Biochemistry C, University of Copenhagen, 3 Blegdamsvej, Copenhagen DK-2000 N, Denmark. forms of the plasminogen activators and their subsequent activation. Plasmin is the proteolytic enzyme primarily responsible for degradation of fibrin (see Collen, 1980; Thorsen et al., 1984). A variety of extracellular matrix proteins are also t-PA u-PA - .u-PA. I + fibrin degradation extracellular products matrix proteins Fig. 1. Components of the plasminogen activation system. Abbreviations: t-PA, tissue-type plasminogen activator; u-PA, urokinase-type plasminogen activator; u-PAR, u-PA receptor; PAI-1, type-l plasminogen activator inhibitor; PAI-2, type-2 plasminogen activator inhibitor; Plg, plasminogen; Pl, plas- min; LX,-AP, cY,-antiplasmin. 0303-7207/ 90/ $03.50 0 1990 Elsevier Scientific Publishers Ireland, Ltd.