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)

alpha 2-Macroglobulin (alpha 2M) is a potentially important regulator of platelet-derived growth factor-BB (PDGF-BB)-stimulated cell growth due to our previous observation that PDGF-BB binds to alpha 2M noncovalently (Bonner, J. C., Goodell, A. L., Lasky, J. A., and Hoffman, M. R. (1992) J. Biol. Chem. 267, 12837-12844). We examined the in vitro effect of native and plasmin-activated (receptor-recognized) alpha 2M on the PDGF-BB-induced proliferation of mouse Swiss 3T3 and rat lung fibroblasts. Nondenaturing polyacrylamide gel electrophoresis showed that plasmin converted alpha 2M to its electrophoretically "fast" form at a 2:1 molar ratio and that 125I-PDGF-BB bound both alpha 2M and alpha 2M-plasmin. PDGF-BB-induced growth was not affected by native alpha 2M (0.3 microM) or plasmin (0.6 microM). The combination of plasmin and alpha 2M (2:1 molar ratio) inhibited PDGF-BB-induced cell proliferation 80-90%. Complexes of PDGF-BB.alpha 2M purified by gel filtration chromatography retained growth promoting activity, but the PDGF-BB.alpha 2M-plasmin complex did not. Preincubation of fibroblasts (37 degrees C for 24 h) with alpha 2M-plasmin did not change 125I-PDGF-BB binding or affect gene expression of the 6.5-kilobase PDGF-alpha receptor or 5.2-kilobase PDGF-beta receptor mRNA. However, preincubation with alpha 2M-plasmin (0-4 degrees C for 4 h) increased 125I-PDGF-BB binding 2-fold, and this increase was blocked by a receptor-associated protein antagonist of the alpha 2M-receptor/low density lipoprotein receptor-related protein. The receptor-associated protein antagonist blocked 125I-alpha 2M-methylamine binding, inhibited PDGF-BB-alpha 2M-plasmin uptake from fibroblast-cultured supernatants, and abolished the inhibitory effect of alpha 2M-plasmin on PDGF-stimulated growth. These data suggest that inhibition of PDGF-stimulated proliferation by alpha 2M-plasmin is mediated in part by clearance of PDGF-BB-alpha 2M-plasmin through the lipoprotein receptor-related protein.
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PMID:Inhibition of platelet-derived growth factor-BB-induced fibroblast proliferation by plasmin-activated alpha 2-macroglobulin is mediated via an alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein-dependent mechanism. 753 12

The accumulation of excessive cholesterol-rich lipoproteins within vascular cells, the proliferation of vascular cells, and fibrin deposition are hallmark features of atherosclerosis. Evidence accumulated over the past few years supports the hypothesis that one member of the LDL receptor family, the low density lipoprotein receptor-related protein (LRP), affects the dynamics of each of these processes. LRP is expressed in several vascular cell types, including smooth muscle cells, and in macrophages, and is also expressed in these cells in atherosclerotic lesions. This receptor is a large endocytotic receptor that mediates the catabolism of a number of molecules known to be important in vascular biology, including apolipoprotein E- and lipoprotein lipase-enriched lipoproteins, thrombospondin, and plasminogen activators. The capacity of LRP to mediate lipoprotein catabolism may be a factor in the development of the lesion by contributing to the formation of foam cells. LRP has recently been shown to mediate the catabolism of thrombospondin, a molecule that has potent biological effects on cells of the vasculature. The regulation of its extracellular accumulation by LRP might modulate the dynamic processes of tissue remodeling associated with the response to vascular injury. In addition, LRP regulates the expression of plasmin activity by directly binding and mediating the cellular internalization of urokinase- and tissue-type plasminogen activators. The cellular removal of these two enzymes decreases the local profibrinolytic potential, possibly leading to a thrombotic state at lesion sites.
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PMID:LDL receptor-related protein: a multiligand receptor for lipoprotein and proteinase catabolism. 761 59

The present study was undertaken in order to determine the recognition site for tissue-type plasminogen activator-plasminogen activator inhibitor type 1 [t-PA-PAI-1] complexes in rat liver in vivo and in vitro. After intravenous injection into rats t-PA-PAI-1 complexes were rapidly removed from the plasma and the liver took up 80% of the injected dose. Within the liver parenchymal and endothelial liver cells contributed mainly to the uptake of t-PA-PAI-1, and were responsible for 62% and 24% of the liver uptake, respectively. The interaction of t-PA-PAI-1 with isolated rat parenchymal liver cells was of high affinity (Kd 17 nM). A well-known antagonist of the alpha 2-macroglobulin receptor (alpha 2MR/low-density lipoprotein receptor-related protein (LRP), GST-39kDa protein (GST-39kDaP) efficiently inhibited the binding (IC50 0.7 nM) of t-PA-PAI-1 to rat parenchymal liver cells. The interaction of t-PA-PAI-1 with LRP on rat parenchymal liver cells was not Ca2(+)-dependent and is most probably mediated by a specific determinant on PAI-1, since an anti-PAI-1 monoclonal antibody inhibited the binding of t-PA-PAI-1, where as free t-PA did not. The binding of t-PA-PAI-1 to rat hepatocytes could not be inhibited by a complex of plasmin and alpha 2-antiplasmin nor by various other ligands of LRP like beta-VLDL and lactoferrin. Binding of t-PA-PAI-1 to rat parenchymal liver cells was followed by internalization and subsequent degradation in the lysosomal compartment. It is concluded that parenchymal and endothelial liver cells mediate the removal of t-PA-PAI-1 complexes from the circulation. LRP on rat parenchymal liver cells is responsible for the uptake and degradation of t-PA-PAI-1 and may therefore be important for the regulation of the t-PA levels in the circulation.
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PMID:Characterization of the interaction of a complex of tissue-type plasminogen activator and plasminogen activator inhibitor type 1 with rat liver cells. 860 13

Smooth muscle cell (SMC) migration is an early response to vascular injury and contributes to the development of intimal thickening. Upregulation of several components of the plasminogen activator (PA) system has been documented after vascular injury. Utilizing a Transwell filter assay system and human umbilical vein SMCs, we sought to define the role of four different PA system components on SMC migration and matrix invasion: (1) PAs, (2) plasmin, (3) PA receptors, and (4) PA clearance receptors (ie, low density lipoprotein receptor-related protein [LRP]). Addition of active two-chain urokinase-type PA (UPA) stimulated random migration (192 +/- 30% of control, 0.36 nmol/L, P < .001). The stimulation was inhibited by pretreatment with diisopropylfluorophosphate, PA inhibitor type 1 (PAI-1), or aprotinin, a plasmin inhibitor. Augmented migration was also observed with either low-molecular-weight UPA or the amino terminal fragment of UPA (ATF), with the effects being additive. Stimulation by ATF alone, however, was not inhibited by aprotinin. The stimulatory effect was not specific for UPA, in that tissue-type PA (TPA) also increased migration (169 +/- 9% of control, 10 nmol/L, P < .001); the augmentation was inhibited by pretreatment with DFP, PAI-1, or aprotinin and was additive to the UPA effect. Antibodies to the UPA receptor but not 5'-nucleotidase (another glycosylphosphatidylinositol-anchored cell surface protein) inhibited baseline and UPA-stimulated migration. Similarly, both UPA and TPA stimulated invasion of a collagen gel; this augmentation was inhibited by aprotinin, whereas antibodies to the UPA receptor reduced baseline invasion. Finally, we tested whether inhibition of LRP function, which mediates internalization of PA/inhibitor complexes, affected either process. Both antibodies to LRP and recombinant receptor associated protein, a known inhibitor of ligand binding to the LRP, significantly inhibited migration but did not affect collagen gel invasion. These data demonstrate the ability of several components of the PA system to modulate SMC migration and invasion in vitro via plasmin-dependent and -independent mechanisms.
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PMID:Contrasting effects of plasminogen activators, urokinase receptor, and LDL receptor-related protein on smooth muscle cell migration and invasion. 885 24

We report characterization of the soluble form of the low density lipoprotein receptor-related protein (sLRP) which circulates in human plasma. Amino acid sequence analysis confirmed that sLRP isolated from human plasma contains the alpha-chain of LRP1. In addition, Western blot analysis identified a truncated beta-chain noncovalently associated with the purified alpha-chain. The molecular size (M(r) 55K) of the peptide portion of the truncated beta-chain indicates that the subunit comprises the extracellular portion of the beta-chain and terminates in a membrane-proximal region. We investigated the mechanism by which sLRP may be generated using the trophoblast cell line, BeWo, which releases sLRP in culture. Cell surface labeling experiments indicate that LRP is released from BeWo cells following expression at the cell surface. Incubation of BeWo cells in the presence of a metalloproteinase inhibitor, INH-3855-PI, results in a dose-dependent inhibition of LRP shedding. The metalloproteinase responsible for the shedding of LRP by BeWo cells is not up-regulated by phorbol ester and is not dependent on serine proteases, such as plasmin, for activity. The BeWo cell line is derived from a human gestational choriocarcinoma and preliminary studies suggest that LRP may be shed within the placenta during gestation. Increased levels of sLRP were detected in cord blood. In term placenta, LRP is expressed in the syncytium, which comprises the maternal-fetal interface. Increased levels of sLRP in cord blood may reflect cellular dysfunction and increased metalloproteinase activity at this important interface.
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PMID:Characterization of the soluble form of the low density lipoprotein receptor-related protein (LRP). 1047 28

The urokinase-type plasminogen activator system is a proteolytic system involved in tissue remodeling and cell migration. At the cell surface, receptor (uPAR)-bound urokinase (uPA) binds its inhibitor PAI-1, localized in the matrix, and the complex is internalized by endocytic receptors, such as the low-density lipoprotein receptor-related protein (LRP). We previously proposed a nonproteolytic role for the uPA system in human myogenic cell differentiation in vitro, i.e., cell fusion, and showed that myogenic cells can use PAI-1 as an adhesion matrix molecule. The aim of this study was to define the role of the uPA system in myogenic cell migration that is necessary for fusion. Using a two-dimensional motility assay and microcinematography, we showed that any interference with the [uPAR:uPA:PAI-1] complex formation, and interference with LRP binding to this complex, markedly decreased myogenic cell motility. This phenomenon was reversible and independent of plasmin activity. Inhibition of cell motility was associated with suppression of both filopodia and membrane ruffling activity. [uPAR:uPA:PAI-1:LRP] complex formation involves high-affinity molecular interactions and results in quick internalization of the complex. It is likely that this complex supports the membrane ruffling activity involved in the guidance of the migrating cell toward appropriate sites for attachment.
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PMID:Involvement of the [uPAR:uPA:PAI-1:LRP] complex in human myogenic cell motility. 1089 74

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

Axonal damage in multiple sclerosis (MS) lesions is associated with failure of fibrinolysis because of the inhibition of the plasminogen activator system. Plasma membrane receptors for tissue plasminogen activator (tPA) and plasminogen concentrate proteolytic activity on the cell surface and provide protection from inhibitors that in turn may locally enhance the fibrinolytic response. Therefore, we have investigated expression of two of these receptors in MS lesions, annexin II tetramer (AIIt) and low-density lipoprotein receptor-related protein (LRP). In acute MS lesions both AIIt and LRP were immunolocalized on macrophages and astrocytes while LRP was additionally found on neuronal cells in cortical gray matter. Western blot analysis confirmed a significant increase in AIIt in MS lesions and in a proportion of normal-appearing white matter samples, with a highly significant correlation between annexin II levels and factors associated with impeded fibrinolysis, such as plasminogen activator inhibitor-1. Immunoblotting analysis of plasmin(ogen) revealed increased levels of lysine-plasminogen in samples expressing high AIIt protein levels. Our results suggest that limited availability of tPA in MS lesions because of formation of tPA-plasminogen activator inhibitor-1 complexes reduces capability of tPA receptors to generate plasmin, which further diminishes fibrinolytic capacity in active MS lesions and possibly leads to axonal damage.
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PMID:tPA receptors and the fibrinolytic response in multiple sclerosis lesions. 1579 94

Tissue-type plasminogen activator (tPA), a serine protease well known for generating plasmin, has been demonstrated to induce matrix metalloproteinase-9 (MMP-9) gene expression and protein secretion in renal interstitial fibroblasts. However, exactly how tPA transduces its signal into the nucleus to control gene expression is unknown. This study investigated the mechanism by which tPA induces MMP-9 gene expression. Both wild-type and non-enzymatic mutant tPA were found to induce MMP-9 expression in rat kidney interstitial fibroblasts (NRK-49F), indicating that the actions of tPA are independent of its proteolytic activity. tPA bound to the low density lipoprotein receptor-related protein-1 (LRP-1) in NRK-49F cells, and this binding was competitively abrogated by the LRP-1 antagonist, the receptor-associated protein. In mouse embryonic fibroblasts (PEA-13) lacking LRP-1, tPA failed to induce MMP-9 expression. Furthermore, tPA induced rapid tyrosine phosphorylation on the beta subunit of LRP-1, which was followed by the activation of Mek1 and its downstream Erk-1 and -2. Blockade of Erk-1/2 activation by the Mek1 inhibitor abolished MMP-9 induction by tPA in NRK-49F cells. Conversely, overexpression of constitutively activated Mek1 induced Erk-1/2 phosphorylation and MMP-9 expression. In mouse obstructed kidney, tPA, LRP-1, and MMP-9 were concomitantly induced in the renal interstitium. Collectively, these results suggest that besides its classical proteolytic activity, tPA acts as a cytokine that binds to the cell membrane receptor LRP-1, induces its tyrosine phosphorylation, and triggers intracellular signal transduction, thereby inducing specific gene expression in renal interstitial fibroblasts.
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PMID:Tissue-type plasminogen activator acts as a cytokine that triggers intracellular signal transduction and induces matrix metalloproteinase-9 gene expression. 1630 71

Complete resection of malignant glioblastomas is usually impossible because of diffuse and widespread invasion of tumor cells, and complementary approaches need to be developed in order to improve the efficacy of current treatments. Consumption of fruits and berries has been associated with decreased risk of developing cancer and there is great interest in the use of molecules from dietary origin to improve anticancer therapies. In this work, we report that the aglycons of the most abundant anthocyanins in fruits, cyanidin (Cy), delphinidin (Dp), and petunidin (Pt), act as potent inhibitors of glioblastoma cell migration. Dp clearly exhibited the highest inhibitory potency, this effect being related to the ortho-dihydroxyphenyl structure on the B-ring and the presence of a free hydroxyl group at position 3. Dp decreases the expression of both urokinase-type plasminogen activator receptor (uPAR) and the low-density lipoprotein receptor-related protein (LRP), acting at the transcriptional levels. In addition, Dp upregulated urokinase-type plasminogen activator (uPA) and downregulated the plasminogen activator inhibitor-1 (PAI-1) but decreased, in a concentration-dependent manner, the uPA-dependent conversion of plasminogen to plasmin, indicating that the upregulation of uPA observed with these compounds was not associated with induction of the plasminolytic activity. Overall, these results demonstrate that Dp, Pt, and Cy affect plasminogen activation, thus leading to the inhibition of glioblastoma cell migration and therefore they may be helpful for the development of new strategies for cancer prevention and therapy.
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PMID:Anthocyanidins inhibit migration of glioblastoma cells: structure-activity relationship and involvement of the plasminolytic system. 1682 70


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