FUNCTIONS OF TISSUE PLASMINOGEN ACTIVATOR

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Tissue plasminogen activator, present in all tissues examined and also released into the body fluids, generates plasmin, a broad specificity protease active at physiological pH. Very importantly it does not activate plasminogen significantly except in the presence of a third protein component which acts as a regulatory signal; to date the fibrin clot and, as we observe, abnormal proteins serve this stimulatory function, preventing indiscriminate proteolysis throughout the body. The intensively studied generation of plasmin at the site of a fibrin clot appears to serve to digest pathological internal clots (thrombi). Our efforts focus primarily on the selective generation of plasmin in the presence of misfolded (denatured or chemically modified) proteins of many types, with the belief that this selective ability serves to scavenge unhealthy protein while not digesting healthy tissue. The fibrin clot may be considered a sub-case of this general role. Protein states which are in vitro "cofactors" of tissue activator (the enhancement in plasmin generation is up to 800-fold) are the fibrin clot; proteins denatured by acid, base, heat, urea, quanidine or many chemical modifications; burned tissue, cultured cells (native cells directly form tissues are not "cofactors"); and protein exposed to oxidizing unsaturated fats. The uncertain physiological relavance of these self-induced digestions of abnormal proteins, except the fibrin clot, are not known and constitute our long-term objectives. Roles of activator in selective catabolism of aged proteins (protein turnover), damaged tissue, abnormal (cancerous?) tissue and newly synthesized but misfolded proteins are possible considerations. Since direct experiments to test possible involvement of tissue activator in these functions is very difficult at present, our immediate proposals are restricted to biochemical characterization of the mechanism of response of activator to abnormal (denatured and chemically modified) proteins in vitro. These studies relate to fibrinolysis, a widely accepted role of tissue activator, and the more speculative roles briefly listed above. If the mechanism can be elucidated, and there are many technical reasons why it probably cannot be elucidated using the fibrin clot, the issue of physiological roles may be more readily approached.