Regulation of plasminogen activation by human U937 promonocytic cells

• Published in: The Journal of biological chemistry 1994-08, Vol.269 (33), p.21353-21357
• Main Authors: Duval-Jobe, C, Parmely, M J
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Analytical, structural and metabolic biochemistry; Biological and medical sciences; Cells, Cultured; Enzyme Activation; Enzyme Precursors - metabolism; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Hematopoietic Stem Cells; Humans; Hydrolases; Hydrolysis; Interferon-gamma - metabolism; Molecular Sequence Data; Monocytes - metabolism; Plasminogen - metabolism; Protease Inhibitors - blood; Substrate Specificity; Urokinase-Type Plasminogen Activator - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/s0021-9258(17)31969-5

Urokinase-type plasminogen activator (uPA) is initially produced by cells as a single-chain precursor (pro-uPA), which can be cleaved by the serine protease plasmin to form the two-chain molecule uPA. This latter protease efficiently converts the inactive zymogen plasminogen into plasmin. Cell surface binding of both pro-uPA and plasminogen is known to enhance the rate of plasminogen activation. It has been postulated that this may be due, in part, to an enhanced plasmin-mediated feedback activation of pro-uPA. This study directly demonstrates the enhancement by cells of this feedback activation loop by showing that uPA is generated more rapidly from pro-uPA and plasminogen in the presence of human promonocytic U937 cells than it is under fluid-phase conditions. Moreover, the enhanced activation of pro-uPA and plasminogen observed in the presence of cells was significantly less susceptible to inhibition by alpha 2-antiplasmin. Finally, the presence of cells not only potentiated the production of plasmin, as measured using a plasmin-specific peptide substrate, it also potentiated the cleavage of a natural protein substrate, 125I-labeled recombinant interferon-gamma, even in the presence of alpha 2-antiplasmin or alpha 2-macroglobulin. These results demonstrate that cell-associated plasmin mediates a positive feedback amplification of plasminogen activation and thereby potentiates the proteolysis of natural plasmin substrates, even in the presence of plasma protease inhibitors.