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J. Biol. Chem., Vol. 275, Issue 48, 37645-37650, December 1, 2000

This Article Full Text Full Text (PDF) All Versions of this Article: 275/48/37645    most recent M006475200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lijnen, H. R. Articles by Declerck, P. J. Search for Related Content PubMed PubMed Citation Articles by Lijnen, H. R. Articles by Declerck, P. J. Social Bookmarking                      What's this?

Inactivation of Plasminogen Activator Inhibitor-1 by Specific Proteolysis with Stromelysin-1 (MMP-3)^*

H. Roger Lijnen^§, Begona Arza, Berthe Van Hoef, Désiré Collen, and Paul J. Declerck^¶

From the  Center for Molecular and Vascular Biology and ^¶ Laboratory for Pharmaceutical Biology and Phytopharmacology, University of Leuven, B-3000 Leuven, Belgium

Matrix metalloproteinase-3 (MMP-3 or stromelysin-1) specifically hydrolyzes the Ser³³⁷-Ser³³⁸ (P10-P9) and Val³⁴¹-Ile³⁴² (P6-P5) peptide bonds in human plasminogen activator inhibitor-1 (PAI-1). Cleavage is completely abolished in the presence of the metal chelators EDTA or 1,10-phenanthroline. A stabilized active PAI-1 variant was also cleaved by MMP-3. At an enzyme/substrate ratio of 1/10 at 37 °C, PAI-1 protein cleavage occurred with half-lives of 27 or 14 min for active or stable PAI-1 and was associated with rapid loss of inhibitory activity toward tissue-type plasminogen activator with half-lives of 15 or 13 min, respectively. A substrate-like variant of PAI-1, lacking inhibitory activity but with exposed reactive site loop, was cleaved with a half-life of 23 min, whereas latent PAI-1 in which a major part of the reactive site loop is inserted into the molecule, was resistant to cleavage. Biospecific interaction analysis indicated comparable binding of active, stable, and substrate PAI-1 to both proMMP-3 and MMP-3 (K_A of 12-22 × 10⁶ M¹), whereas binding of latent PAI-1 occurred with lower affinity (1.7-2.3 × 10⁶ M¹). Stable PAI-1 bound to vitronectin was cleaved and inactivated by MMP-3 in a manner comparable with that of free PAI-1; however, the cleaved protein did not bind to vitronectin. Cleavage and inactivation of PAI-1 by MMP-3 may thus constitute a mechanism decreasing the antiproteolytic activity of PAI-1 and impairing the potential inhibitory effect of vitronectin-bound PAI-1 on cell adhesion and/or migration.

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