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Fredriksson, L. Collen, D. Program , 1 —9. Google Scholar. Verheijen, J. Medline Google Scholar. Qian, Z. Carroll, P. Yepes, M. Nicole, O. Gilbertson, D. Green, S. Eriksson, A. Hehenberger, K. Eliasson, M. Pinsky, D. Schacke, W. Docagne, F. Saed, G. Midgley, V. Kazlauskas, A. Siegfried, G.
Urokinase-type plasminogen activator
Castellino, F. Ding, L. Bork, P. Beebe, D. Hajjar, K. Kim, H. Carroll, V. Bu, G. Boucher, P. Cameron, N. The secretion and the retention of tPA contribute to the effective activation of plg bound on the surface of VECs, and to effective fibrinolysis when fibrin is generated Other biological roles in inflammation, immunity and tumor growth have been suggested 43 , In addition to plasma and VEC surfaces, the surface of activated platelets was also suggested to be involved in similar regulation of plg activation under shear 17 , This interaction forces the linker region between kringle 3 and kringle 4 to shield the activation sequence, and thus protects this proenzyme from unnatural activation.
In this case, the activation sequence is shielded by the linker region between K3 and K4 A. Modified from 66 with permission. Plg activation by tPA is ineffective in the fluid phase. These solid phases function as templates for tPA and plg binding. The importance of this mechanism was also demonstrated in more physiological environments. In the lytic process, plg is observed at the lytic edge of partially digested fibrin nets 15 , 16 , 19 Fig.
Plasminogen: Structure, Activation, and Regulation
Although a difference in affinity between fibrin and the VEC surfaces is likely to be a driving force for tPA to relocate, the mechanism whereby tPA is transferred from VEC surfaces to fibrin remains to be elucidated. A part of this figure has been previously published 15 , When tPA was administered to this model, plg accumulated further in the thrombi, and eventually the thrombi dissolved Initiation of fibrinolysis after accumulation of plg was also demonstrated on the surfaces of activated platelets in an in vitro system under either shear 53 or a static condition As a result, PS exposed on platelet surfaces contributes to thrombin generation and subsequent fibrin formation, and also triggers plg activation by assembling plg and tPA on their surfaces Activated platelet surfaces appear to be one of the more important regions for the native machinery of plg activation to take place and subsequently to evoke effective fibrinolysis.
This carboxypeptidase was also identified as a plg binding protein and named procarboxypeptidase B TAFI is produced mainly in the liver and circulates in plasma, but this protein is also present in platelets and is released upon platelet activation These include C3a, C5a, bradykinin and partially digested fibrin 74 , However, studies with a variant TM in humans were suggestive of the physiological relevance of TAFI in normal hemostasis In this variant, p.
CysStop 88 , the soluble TM levels in plasma were elevated and the plasma clot lysis time was delayed. Our in vitro experiments also suggest a relevant role for TAFI in hemostasis. When tPA was added, fibrinolysis was clearly observed originating from the coagulation initiation site i.
When soluble TM was supplemented to mimic the function of TM expressed by VECs, the accumulation of plg was abolished and clot lysis was highly prolonged Fig. This was reversed by including a carboxypeptidase inhibitor. Reproduced from 16 with permission. Available evidence clearly indicates that the existence of TM in proximity to thrombin is required for TAFI to be activated and to successfully suppress fibrinolysis.
Although much attention has been paid to TM from the viewpoints of protein C activation and anticoagulation, the physiological role of TM in platelets needs to be considered from the viewpoint of fibrinolysis. Thus fibrin, including soluble fibrin, but not fibrinogen, is considered the physiological target of plm in vivo. The structure of fibrin itself modulates the efficacy of fibrinolysis by changing both the rate of plg activation and clot permeability, both of which are modified by clot retraction Clot retraction, which itself is facilitated by fibrinolysis 93 , renders the clot resistant to lysis by modifying the overall structure of the blood clot and the shape and function of the involved platelets and red blood cells RBCs In addition, the binding of RBCs to fibrin through a specific receptor also modifies fibrin structure to become more resistant to fibrinolysis Most of these studies suggest that a tight structure of the fibrin clot makes it resistant to lysis.
The results obtained from this novel technology also deepened the understanding of the spatiotemporal regulation of fibrinolysis, which included the participation of VECs, platelets and Newtonian vs. The acquired knowledge is expected to provide approaches to develop novel safe and effective strategies to manage thrombotic patients. Urano, F. Castellino and Y. Suzuki designed the structure of the manuscript and wrote it. Urano and Y. Suzuki prepared the figures. The other authors state that they have no conflict of interests. Regulation of plasminogen activation on cell surfaces and fibrin.
J Thromb Haemost ; 16 : — National Center for Biotechnology Information , U. Journal of Thrombosis and Haemostasis. J Thromb Haemost. Published online Jun Urano , 1 F. Castellino , 2 and Y. Suzuki 1. Castellino 2 W. Author information Article notes Copyright and License information Disclaimer. Urano, Email: pj. Corresponding author. Received Dec 7. This article has been cited by other articles in PMC.
Summary The fibrinolytic system dissolves fibrin and maintains vascular patency. Table 1 Modifications of plasminogen plg activation proved by imaging techniques. On fibrin surfaces Accumulation of plg at the lytic edge of the fibrin net 15 , 16 , 18 , Open in a separate window. Figure 1. Figure 2. Plg activation Plg activation by tPA is ineffective in the fluid phase.
Figure 3. Figure 4. Fibrin structure The structure of fibrin itself modulates the efficacy of fibrinolysis by changing both the rate of plg activation and clot permeability, both of which are modified by clot retraction Addendum T. Disclosure of Conflict of Interests T. Reitsma Final decision: P. Reitsma, 3 May References 1. New insights into the molecular mechanisms of the fibrinolytic system.
J Thromb Haemost ; 7 : 4— Collen D. The plasminogen fibrinolytic system. Thromb Haemost ; 82 : — Relationships between euglobulin clot lysis time and the plasma levels of tissue plasminogen activator and plasminogen activator inhibitor 1. Thromb Haemost ; 63 : 82—6. Thromb Haemost ; 66 : —8. Blood ; : — Gebbink MF. Purified tPA was used to define maximal p NA formation.
Serum-free conditioned media were collected 48 h after transfection, proteins were trichloroacetic acid-precipitated, and PDGF-C was detected by immunoblotting using specific polyclonal antibodies. The coated beads were incubated with conditioned serum-free medium from COS-1 cells transfected with the tPA truncation mutants illustrated in Fig.
Following incubation with tPA the beads were thoroughly washed and the His 6 -tagged proteins specifically eluted from the beads using a buffer containing m m imidazole. Co-elution of interacting tPA species was analyzed by immunoblotting using polyclonal anti-c- myc antibodies. The serum-free medium was then collected, and the proteins were trichloroacetic acid-precipitated and subjected to SDS-PAGE under reducing conditions. A CUB domain is a common structural module found in many different kinds of proteins and is believed to participate in protein-protein or protein-carbohydrate interactions The stoichiometry of the activation reaction is such that generation of each molecule of receptor-active PDGF-C dimer will generate two molecules of the inhibitory free CUB domain.
Whether this autoregulatory mechanism is used in vivo is unknown at present, but it may provide a potent regulatory mechanism controlling the activation of PDGF-CC. The different domains of tPA have been reported to mediate interaction between tPA and various proteins, e. The kringle-2 interacts with both the CUB and the growth factor domains of PDGF-CC, possibly allowing the hinge region to loop out and thus positioning the cleavage site such that the protease domain in tPA can cleave.
The kringle-2 domain has been demonstrated to inhibit FGFinduced endothelial cell proliferation and migration 39 , 40 , and recently PDGF-CC has been shown to have a direct stimulatory effect on endothelial cell migration 6. Interestingly, tPA induces blood-brain barrier opening via interaction with the low density lipoprotein receptor-related protein and proteolysis of an as yet unidentified substrate We have suggested previously that the genes for the classical and novel PDGFs separated early during evolution and that the novel PDGFs then arose from a common ancestor Using a computer-based strategy we could identify several serine proteases with similar domain organization as tPA, including the other plasminogen activator, uPA urokinase PA.
Non-healing foot ulcers in diabetic patients are a common and expensive complication partially caused by reduced fibroblast activity To develop rational therapeutic strategies it has become a major priority to characterize the pathophysiological mechanism of the delayed wound healing and the impaired fibroblast activity in diabetic patients. It is worth noting that hyperbaric oxygen therapy is used to accelerate the rate of healing of diabetic foot ulcers Although it is known that ectopically applied PDGF-CC can enhance delayed wound healing in diabetic mice 21 it still remains to be established whether PDGF-C expression is impaired in diabetic conditions.
Eriksson, unpublished observation.
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