The role of plasminogen activator inhibitor type 1 in the clearance of tissue-type plasminogen activator by rat hepatoma cells.
The role of plasminogen activator inhibitor type 1 (PAI-1) in the clearance of tissue-type plasminogen activator (t-PA) by hepatocyte-like cells was studied. Rat (Novikoff) hepatoma cells were able to bind and degrade t-PA in a PAI-1 independent fashion, but PAI-1 markedly increased the rate of degradation and t-PA/PAI-1 was a more efficient inhibitor of 125I-t-PA or of 125I-t-PA/PAI-1 degradation than free t-PA. Competition studies revealed that the effect of PAI-1 is unlikely to involve determinants located on the PAI-1 part of the complex: 1) an excess of free PAI had no effect on the rate of degradation of 125I-t-PA/PAI-1.2) Complexes of PAI-1 with urokinase-type PA or with a t-PA mutant lacking the finger and growth factor domains were unable to compete for the binding and degradation of free or PAI-1-complexed 125I-t-PA.3) t-PA KHRR296-299AAAA, a mutant which reacts 2 orders of magnitude slower with PAI-1 than wild type t-PA, behaved similar to wild type t-PA. The clearance via both the PAI-1-dependent and the PAI-1-independent mechanisms was inhibited by the receptor-associated protein, a general inhibitor of clearance mediated by the LDL receptor-related protein. We conclude that t-PA can be cleared by rat hepatoma cells in a PAI-1 independent fashion, but after complex formation with PAI-1, binding of t-PA to the cells is increased and clearance accelerated. Both mechanisms seem to involve the same receptor.
Camani
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C
Department of Internal Medicine, University Hospital CHUV, Lausanne, Switzerland.
Bachmann
F
F
Kruithof
E K
EK
D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D006528:Carcinoma, Hepatocellular; D006224:Cricetinae; D007457:Iodine Radioisotopes; D008099:Liver / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000502:physiology*; D051381:Rats; D010959:Tissue Plasminogen Activator / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D007457:Iodine Radioisotopes; D017395:Plasminogen Activator Inhibitor 1; D010959:Tissue Plasminogen Activator