Plasminogen activator is a proteinase found in a number of different cells and tissues which activates plasminogen to plasmin. In human epidermal cells the anticell surface pemphigus antibody increases plasminogen activator (PA) activity. PA activity appears to be related to: induction of synthesis of enzyme protein by a variety of stimuli, activation of precursor zymogen, compartmentalization of enzyme in the cell and the extra-cellular space, and interaction with cellular and serum proteinase inhibitors. PA may induce biological effects directly or through its activation of plasminogen to the broad specificity proteinase plamsin.
The aims of this proposal are directed towards an understanding of plasminogen activator in epidermal biology with special focus upon its modulation by the anti-cell surface pemphigus antibody. We will: (1) define the biochemistry of PA synthesis in human epidermis using enzymological and immunochemical means; (2) study the localization of PA within human epidermal cells in culture and in tissue using biochemical, immunochemical and immunocytological methods; (3) purify the epidermal proteinase inhibitors; (4) explore the effects of a variety of biological factors on PA synthesis and secretion of human epidermal cells in culture; (5) determine levels of messenger RNA for plasminogen activator; (6) determine the mechanism for enhancement of PA synthesis and secretion in pemphigus; (7) study early events in pemphigus activation, at the membrane, including studies of arachidonic acid metabolism and cyclic nucleotide metabolism; (8) evaluate a variety of monoclonal antibodies for their ability to induce PA synthesis; (9) evaluate the role of PA and plasmin in acantholysis in vivo, in humans and experimental animals; (10) define the effects of immunomodulators, such as lymphokines and light upon PA synthesis and secretion; (11) determine whether abnormalities of PA occur in other genetic acantholytic diseases.
