Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The plasminogen activator urokinase promotes tumor invasion by converting plasminogen into plasmin, which degrades several extracellular matrix components. Urokinase can bind to a specific cell surface receptor, which leads to accelerated plasmin production. While there is good evidence indicating a role for this binding site in tumor invasion/metastasis, there is little information concerning the regulation of urokinase receptor expression in invasive cancer. To address this question a series of colon cancer cell lines, which demonstrate either a high or low ability to invade an extracellular matrix-coated porous filter, was characterized for receptor expression at the transcriptional and post-transcriptional levels. The invasive cell lines possessed 10-fold more receptors than their non-invasive counterparts as shown by cross-linking experiments and by Western blotting. Northern blotting indicated that this disparity in receptor number could be largely accounted for by a different amount of steady-state mRNA encoding the binding site. However, neither gene amplification nor enhanced mRNA stability could account for the augmented receptor protein observed for the invasive colon cancer cell types. In contrast, nuclear run-on experiments with representative cell lines revealed that the 10-fold difference in receptor display between the invasive-competent and invasive-deficient cells could be largely accounted for by differences in transcription rates. Transcription of the u-PAR gene in the receptor-deficient GEO cells, but not in the receptor-rich RKO cells, could be augmented by protein kinase C stimulation. These findings provide a clear rationale for studies to determine if the urokinase receptor promoter in invasive colon cancer is activated in cis or in trans.
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PMID:Transcriptional activation of the urokinase receptor gene in invasive colon cancer. 807 48

Urokinase-type plasminogen activator (uPA) is an important mediator of cellular invasiveness. Specifically, cell surface receptor-bound uPA activates plasminogen to the potent general protease plasmin, which then degrades extracellular matrix or basement membrane either directly or via proteolytic activation of latent collagenases. Thus, cell surface uPA initiates an extracellular proteolytic cascade with which invasive cells eliminate barriers to movement. Since cellular invasiveness plays important roles in several disease states, including cancer metastasis and invasion, arthritis and inflammation, and diabetic retinal neovascularization, the development of synthetic uPA inhibitors is an attractive therapeutic goal. Here we show that 4-substituted benzo[b]thiophene-2-carboxamidines represent an important new class of potent and selective synthetic uPA inhibitor. Two compounds in this class, B428 and B623, inhibit human uPA in plasminogen-linked assays with median inhibition concentration (IC50) values of 0.32 and 0.07 microM, respectively. This level of inhibition represents 20- and 100-fold increases in potency, respectively, relative to the 6-7 microM potencies reported for amiloride and 4-chlorophenylguanidine, the two most potent selective synthetic uPA inhibitors previously described. Importantly, both compounds show > 300-fold selectivity for uPA relative to tissue-type plasminogen activator and > 1000-fold selectivity relative to plasmin. Lineweaver-Burk analyses show uPA inhibition by B428 and B623 to be competitive in nature with inhibition constants (Ki) of 0.53 and 0.16 microM, respectively. Since it is cell surface uPA and not free or secreted uPA that is primarily responsible for cellular invasiveness, biologically effective uPA inhibitors must be capable of inhibiting cell surface uPA. B428 and B623 meet this criterion by inhibiting cell surface uPA on HT1080 human fibrosarcoma cells with IC50 values of 0.54 and 0.20 microM, respectively. Moreover, degradation of [3H]fibronectin by HT1080 cells via cell surface uPA-mediated, plasminogen-dependent mechanisms is inhibited by B428 and B623, with IC50 values of 1.5 and 0.39 microM, respectively. In summary, 4-substituted benzo[b]thiophene-2-carboxamidines such as B428 and B623 represent the most potent class of competitive synthetic uPA inhibitors currently known. Their ability to selectively inhibit both free and cell surface uPA as well as cell surface uPA-mediated cellular degradative functions suggests that this class of compounds may hold significant promise for further development as antiinvasiveness drugs.
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PMID:Inhibition of urokinase by 4-substituted benzo[b]thiophene-2-carboxamidines: an important new class of selective synthetic urokinase inhibitor. 849 19

Keratinocytes synthesize urokinase-type plasminogen activator (uPA) and a specific cell surface receptor for uPA (uPA-R, CD 87). Plasminogen is present in plasma and interstitial fluids from where it is bound to cell surfaces via plasmin(ogen) binding sites. uPA binds to the uPA-R in an autocrine manner and activates cell-bound plasminogen: a mechanism, which provides plasmin for pericellular proteolysis. Cell-bound uPA is regulated by plasminogen activator inhibitor type-1 (PAI-1) or type-2 (PAI-2). Bullous pemphigoid is an autoimmune inflammatory skin disease characterized by subepidermal blisters. Although circumstantial evidence suggested plasminogen activation in lesional epidermis of bullous pemphigoid, immunohistological data on the type of plasminogen activators, on the uPA-receptor or the type of plasminogen activator inhibitors in the lesions of bullous pemphigoid are lacking so far. To obtain this information we have performed the present immunohistological study. The presence of uPA and its receptor as well as PAI-2 was disclosed in epidermal keratinocytes in the roof of the subepidermal blisters. Moreover, keratinocytes at the bottom of the blister, which most likely represent keratinocytes during reepithelialization were stained. Co-localization was found for uPA and its receptor, uPA and plasmin(ogen) as well as for uPA and PAI-2. In non-lesional epidermis of bullous pemphigoid only PAI-2 was found. We propose that the expression of uPA and uPA-R, as well as the upregulation of PAI-2 in keratinocytes of lesional epidermis is part of the repair and reepithelialization process following lesion formation, i.e. epidermo-dermal dyshesion, in bullous pemphigoid.
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PMID:Plasminogen activation in bullous pemphigoid immunohistology reveals urokinase type plasminogen activator, its receptor and plasminogen activator inhibitor type-2 in lesional epidermis. 887 51

Pemphigus vulgaris (PV) is caused by autoantibodies against desmosomes and is characterized by intra-epidermal blisters. The pathology of PV has been linked with plasminogen activation in lesional epidermis. The plasminogen activator system (PA system) consists of urokinase-type plasminogen activator (uPA), tissue-type PA (tPA), as well as the two types of plasminogen activator inhibitors (PAI-1 and PAI-2). In keratinocytes, uPA binds to a specific cell surface receptor for uPA (uPA-R = CD87) in an autocrine manner. Cell-bound uPA is regulated by PAIs. The central PA system component plasminogen, which is present in plasma and interstitial fluids, is bound to the keratinocyte surface via plasmin(ogen) binding sites, where it can be activated by uPA-R-bound uPA. Cell surface-associated plasmin then mediates pericellular proteolysis. As the topographical organization of the distinct PA system components in lesional epidermis of PV remained elusive, we have performed the present immunohistological analysis of lesional and non-lesional epidermis of PV. In keratinocytes directly involved in the epidermal split formation, plasmin(ogen) was stained in nine of 10 cases, uPA-R and uPA in four of 10 cases and PAI-2 in seven of 10 cases. Together, acantholytic plasmin(ogen)+ keratinocytes appeared in three different phenotypes: uPA-R+/uPA+ and PAI-2+, uPA-R-/uPA- and PAI-2+, as well as uPA-R-/uPA- and PAI-2-. Our findings demonstrate that, in acantholytic keratinocytes of PV, PAs and PAIs appear as differentially regulated components of the PA system.
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PMID:Plasminogen activator system in pemphigus vulgaris. 897 72

The binding of urokinase-type plasminogen activator (u-PA) to a specific cell surface receptor (uPA-R) has been shown to enhance plasminogen activation, a process involved in extracellular matrix degradation and cell migration during angiogenesis and tumor growth. We investigated the expression of u-PA and uPA-R in renal cell carcinomas (n = 11). By immunohistochemistry using monoclonal and polyclonal anti-uPA-R antibodies, we found that tumoral capillary endothelial cells (von Willebrand factor and CD31 positive cells) overexpressed uPA-R, whereas vascular endothelial cells of the normal human kidney do not. In addition, tumor-associated macrophages (CD68-positive cells) strongly expressed uPA-R. In contrast, few tumoral cells and stromal fibroblasts expressed uPA-R. By in situ hybridization using a cDNA S35-labeled probe specific for uPA-R, we confirmed the local expression of uPA-R messenger RNA. We also detected the induction of u-PA in tumoral capillary endothelial cells and in tumor-associated macrophages. In two cases, tumoral cells themselves were also stained by anti-u-PA antibodies in focal areas. Finally tissue-type plasminogen activator (t-PA) was also overexpressed by tumoral capillary endothelial cells as compared with endothelial cells of normal human kidney vessels. These findings indicate an active invasive phenotype of endothelial cells in renal cell carcinoma and suggest a role for the plasminogen activation system in tumoral angiogenesis and invasion.
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PMID:Endothelial and macrophage upregulation of urokinase receptor expression in human renal cell carcinoma. 902 4

The plasminogen activation system is thought to be important in cell migration processes. A role for this system during smooth muscle cell migration after vascular injury has been suggested from several animal studies. However, not much is known about its involvement in human vascular remodelling. We studied the involvement of the plasminogen activation system in human smooth muscle cell migration in more detail using an in vitro wound assay and a matrix invasion assay. Inhibition of plasmin activity or inhibition of urokinase-type plasminogen activator (u-PA) activity resulted in approximately 40% reduction of migration after 24 h in the wound assay and an even stronger reduction (70-80%) in the matrix invasion assay. Migration of smooth muscle cells in the presence of inhibitory antibodies against tissue-type plasminogen activator (t-PA) was not significantly reduced after 24 h, but after 48 h a 30% reduction of migration was observed, whereas in the matrix invasion assay a 50% reduction in invasion was observed already after 24 h. Prevention of the interaction of u-PA with cell surface receptors by addition of soluble u-PA receptor or alpha2-macroglobulin receptor associated protein (RAP) to the culture medium, resulted in a similar inhibition of migration and invasion. From these results it can be concluded that both u-PA and t-PA mediated plasminogen activation can contribute to in vitro human smooth muscle cell migration and invasion. Furthermore, the interaction between u-PA and its cell surface receptor appears also to be involved in this migration and invasion process. The inhibitory effects on migration and invasion by the addition of RAP suggests an involvement of a RAP sensitive receptor of the LDL receptor family, possibly the LDL-receptor related protein (LRP) and/or the VLDL receptor.
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PMID:The migration of human smooth muscle cells in vitro is mediated by plasminogen activation and can be inhibited by alpha2-macroglobulin receptor associated protein. 926 89

Tumor cell migration and invasion into the surrounding tissue depend on the invasive capacity of cells leading to the loosening of cell-cell and cell-substratum contacts via cell surface associated proteolytic enzyme systems. Plasmin is one of the enzymes involved in these complex events. It is generated by the cleavage of the proenzyme plasminogen upon the action of the urokinase-type plasminogen activator (uPA). uPA is synthesized and secreted by tumor cells and normal cells and interacts with a specific cell surface receptor (uPAR) thereby focalizing enzymatic activity to the cell surface. The activity of uPA is controlled by plasminogen activator inhibitors type-1 and type-2. A strong statistically independent prognostic impact has been attributed to uPA and its inhibitor PAI-1 in a variety of malignancies. Besides its proteolytic activity, uPA in concert with uPAR exert biological effects characteristic for molecules with signal transducing properties including chemotaxis, migration/invasion, adhesion, and mitogenesis.
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PMID:Multifunctional potential of the plasminogen activation system in tumor invasion and metastasis (review). 977 77

Urokinase-type plasminogen activator (uPA) and its cell surface receptor (uPAR) have been shown to be expressed in macrophages in atherosclerotic arterial walls, but the regulatory mechanisms of their expression remain unclear. The present study was performed to examine the effects of lysophosphatidylcholine (lysoPC), an important atherogenic lipid, on the expression of uPA and uPAR in human monocyte-derived macrophages. LysoPC upregulated the mRNA expression of uPA and uPAR, and it increased the protein expression of uPA in the culture medium and bound to the cell surface and of uPAR in the particulate fraction of the cells. LysoPC significantly increased the binding of the amino-terminal fragment of uPA to the treated cells and the cell-associated plasminogen activator activity. LysoPC stimulated superoxide anion production and increased intracellular oxidant levels in the cells. The combined incubation with reduced glutathione diethyl ester or N-acetylcysteine, antioxidants, suppressed the upregulation of uPA and uPAR mRNA and the increase in plasminogen activator activity by lysoPC. uPA and uPAR mRNA expression was also induced by the incubation with xanthine and xanthine oxidase, a superoxide anion-generating system. The results suggest that lysoPC increased the expression of uPA and uPAR and their functional activities in human monocyte-derived macrophages, at least in part through a redox-sensitive mechanism. This coordinate increase in the expression of uPA and uPAR in human macrophages by lysoPC could play an important role in plaque formation and disruption, arterial remodeling, and angiogenesis in atherosclerotic arterial walls.
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PMID:Lysophosphatidylcholine induces urokinase-type plasminogen activator and its receptor in human macrophages partly through redox-sensitive pathway. 1063 25

Plasminogen activators and inhibitors may be important early in primate implantation but evidence for this is sparse in non-human primates. We define the expression of urokinase type plasminogen activator (uPA), tissue-type plasminogen activator (tPA), plasminogen activator inhibitor type 1 (PAI-1) and type 2 (PAI-2), the receptor for uPA (uPAR) and fibrin/fibrinogen in monkey implantation sites. In situ hybridization and immuno-histochemical localization of rhesus monkey implantation sites (day 15-16 postovulation) indicate: (1) uPA mRNA is localized to placental trophoblast, epithelial plaque and endometrial stroma. (2) tPA mRNA is mainly expressed in glandular cells of endometrium. (3) PAI-1 expression is linked to a specific population of trophoblasts that confront maternal cells, adding support to our view that it has a regulatory role in trophoblast invasion. (4) Localization of tPA antigen confirms that uterine glands are the major source of tPA and that it is also closely associated with fibrin(ogen) suggesting its possible function during implantation is fibrinolysis. (5) Unlike uPA mRNA, however, the distribution of uPA protein and its cell surface receptor uPAR suggests that it mediates trophoblast invasion and plays a significant role in angiogenesis. (6) PAI-2, the inhibitor associated with pregnancy in humans, was found in unidentified cells located specifically along the maternofetal junction. This localization adjacent to areas of cell death at the maternofetal junction implies that it may have a role as a protective curtain with anti-apoptotic function. In conclusion our results suggest that gene expression of PAs and PAIs in early implantation sites are tissue-specific, location-sensitive and function-related.
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PMID:Plasminogen activators and inhibitors are transcribed during early macaque implantation. 1117 Aug 23

The low density lipoprotein receptor-related protein-deleted in tumor (LRP1B, initially referred to as LRP-DIT) was cloned and characterized as a candidate tumor suppressor. It is a new member of the low density lipoprotein receptor gene family. Its overall domain structure and large size (approximately 600 kDa) are similar to LRP and suggest that it is a multifunctional cell surface receptor. Herein, we characterize a series of ligands for the receptor using cell lines that stably express it as a domain IV minireceptor (mLRP1B4). Ligands of LRP including receptor-associated protein, urokinase plasminogen activator, tissue-type plasminogen activator, and plasminogen activator inhibitor type-1 each demonstrate binding, internalization, and degradation via mLRP1B4. Interestingly, the kinetics of ligand endocytosis is distinctly different from that of LRP, with LRP1B exhibiting a markedly diminished internalization rate. In addition, tissue expression analysis reveals that the LRP1B gene is expressed in brain, thyroid, and salivary gland. These studies thus extend the physiological roles of members of the LDL receptor family.
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PMID:The putative tumor suppressor LRP1B, a novel member of the low density lipoprotein (LDL) receptor family, exhibits both overlapping and distinct properties with the LDL receptor-related protein. 1138 78


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