Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.7 (plasmin)
 9,023 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Low-density lipoprotein receptor-related protein (LRP) mediates internalization of urokinase:plasminogen activator inhibitor complexes (uPA:PAI-1) and the urokinase receptor (uPAR). Here we investigated whether direct interaction between uPAR, a glycosyl-phosphatidylinositol-anchored protein, and LRP, a transmembrane receptor, is required for clearance of uPA:PAI-1, regeneration of unoccupied uPAR, activation of plasminogen, and the ability of HT1080 cells to invade extracellular matrix. We found that in the absence of uPA:PAI-1, uPAR is randomly distributed along the plasma membrane, whereas uPA:PAI-1 promotes formation of uPAR-LRP complexes and initiates redistribution of occupied uPAR to clathrin-coated pits. uPAR-LRP complexes are endocytosed via clathrin-coated vesicles and traffic together to early endosomes (EE) because they can be coimmunoprecipitated from immunoisolated EE, and internalization is blocked by depletion of intracellular K(+). Direct binding of domain 3 (D3) of uPAR to LRP is required for clearance of uPA-PAI-1-occupied uPAR because internalization is blocked by incubation with recombinant D3. Moreover, uPA-dependent plasmin generation and the ability of HT1080 cells to migrate through Matrigel-coated invasion chambers are also inhibited in the presence of D3. These results demonstrate that GPI-anchored uPAR is endocytosed by piggybacking on LRP and that direct binding of occupied uPAR to LRP is essential for internalization of occupied uPAR, regeneration of unoccupied uPAR, plasmin generation, and invasion and migration through extracellular matrix.
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PMID:Direct binding of occupied urokinase receptor (uPAR) to LDL receptor-related protein is required for endocytosis of uPAR and regulation of cell surface urokinase activity. 1135 36

Blood coagulation is essential to maintain hemostasis in organisms with a vascular network. Formation of a fibrin-rich clot at a site of vessel injury is a highly complex process that is orchestrated by the coagulation protease cascade. This cascade is regulated by 3 major anticoagulant pathways. Removal of a clot is mediated by the fibrinolytic system. Defects in the regulation of clot formation lead to either hemorrhage or thrombosis. Tissue factor, the primary cellular initiator of blood coagulation, is a transmembrane receptor that is expressed in a tissue-specific manner. The 3 major anticoagulants are tissue factor pathway inhibitor, antithrombin, and protein C, the latter requiring a transmembrane receptor called thrombomodulin for its activation. Tissue factor pathway inhibitor and thrombomodulin are expressed by endothelial cells in a tissue-specific manner, whereas antithrombin and protein C circulate in the plasma. Fibrinolysis requires the activation of plasminogen to plasmin, which is mediated by tissue-type plasminogen activator and urokinase-type plasminogen activator. Interestingly, tissue-type plasminogen activator is expressed by a subset of endothelial cells of discrete size and location. These observations, together with the phenotypes of mice that have defects in the procoagulant, anticoagulant, and fibrinolytic pathways, indicate that hemostasis is regulated in a tissue-specific manner.
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PMID:Tissue-specific hemostasis in mice. 1612 18