Regulation of plasminogen activation by human U937 promonocytic cells.
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.
Duval-Jobe
C
C
Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City 66160-7420.
Parmely
M J
MJ
D000595:Amino Acid Sequence; D002478:Cells, Cultured; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism; D006412:Hematopoietic Stem Cells; D006801:Humans; D006868:Hydrolysis; D007371:Interferon-gamma / Q000378:metabolism; D008969:Molecular Sequence Data; D009000:Monocytes / Q000378:metabolism*; D010958:Plasminogen / Q000378:metabolism*; D011480:Protease Inhibitors / Q000097:blood; D013379:Substrate Specificity; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
D004792:Enzyme Precursors; D011480:Protease Inhibitors; D007371:Interferon-gamma; D010958:Plasminogen; D014568:Urokinase-Type Plasminogen Activator