Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.73 (urokinase-type plasminogen activator)
10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neoplastic transformation in the normal human brain occurs as a result of the accumulation of a series of genetic alterations. These genetic alterations include the loss, gain or amplification of different chromosomes which lead to altered expression of proteins that play important roles in the regulation of cell proliferation. Several common genetic alterations at the chromosomal level (loss of 17p, 13q, 9p, 19, 10, 22q, 18q and amplification of 7 and 12q) have been observed. These alterations lead to changes in the expression of several genes; protein 53 (p53), retinoblastoma (RB), interferon (INF) alpha/beta, cyclic AMP dependent kinase number 2 (CDKN2), mutated in multiple advanced cancers 1 (MMAC1), deleted-in-colon carcinoma (DCC), epidermal growth factor receptor (EGFR), platelet derived growth factor (PDGF), platelet derived growth factor receptor (PDGFR), MDM2, GL1, CDK4 and SAS during the genesis and progression of human gliomas. Recent studies suggest that altered expression of several other genes [MET; MYC; transforming growth factor beta (TGF beta); CD44; vascular endothelial growth factor (VEGF); human neurological-related cell adhesion molecule (hNr-CAM); neuroglial cell adhesion molecule (NCAM L1); p21waf1/Cip1; TRKA; mismatch repair genes (MMR); C4-2; D2-2] and proteins [e.g., cathepsins, tenascin, matrix metalloproteases, tissue inhibitors of metalloproteases, nitric oxide synthase, integrins, interleukin-13 receptor (IL-13R), Connexin43, urokinase-type plasminogen activator receptors (uPARs), extracellular matrix proteins and heat shock proteins] are associated with the genesis of human gliomas. Taken together, these findings point to the accumulation of multiple genetic mutations coupled with extensive changes in gene expression in the etiology of human gliomas.
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PMID:Molecular changes during the genesis of human gliomas. 940 26

Human gallbladder cancer is highly malignant and its prognosis is usually poor depending on the extent of surrounding tissue invasion. We examined in vitro the invasive activity of four gallbladder cancer cell lines (GB-d1, GB-h3, GB-d2 and FU-GBC-1) in the absence or presence of hepatocyte growth factor (HGF). In type 1 collagen gel culture, HGF stimulated cell proliferation and induced an invasive phenotype of arborizing structures in GB-d1, GB-h3 and GB-d2. In a Matrigel invasion assay, invasion was also induced in three of these cell lines by HGF but not in FU-GBC-1. Cellular motility was, however, stimulated by HGF in all of the four cell lines to various extents. Zymography for proteolytic enzymes demonstrated high levels of type IV collagenase and urokinase-type plasminogen activator (u-PA) activity in GB-d1, GB-h3 and GB-d2 even in the absence of HGF. In the presence of HGF, the 72 kDa type IV collagenase (MMP-2) activity of GB-h3 and u-PA activities of GB-d1, GB-h3 and GB-d2 were enhanced. In contrast, the MMPs and PAs activities of FU-GBC-1 were faint irrespective of the addition of HGF. A Western blot analysis demonstrated higher levels of 190 kDa c-MET product (HGF receptor) of GB-d1, GB-h3 and GB-d2 than that of FU-GBC-1. The invasion in the Matrigel assay stimulated by HGF was inhibited by protease inhibitors, aprotinin and FOY-305, as well as by anti-HGF antibody. These results thus suggest that, in addition to the importance of the proteolytic activity, the cellular motility induced via the HGF/HGF-receptor system is essential for the invasive progression of gallbladder carcinoma cells.
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PMID:Hepatocyte growth factor stimulates the invasion of gallbladder carcinoma cell lines in vitro. 950 79

Hepatocyte growth factor/scatter factor (HGF/SF) is synthesized by mesenchymal cells and is a paracrine effector of cells, predominantly epithelial, that express the Met tyrosine kinase receptor. We have demonstrated that autocrine Met-HGF/SF expression in mouse fibroblasts results in transformation and tumorigenesis. HGF/SF-treated cells expressing Met can respond in a variety of ways: mitogenically, by scattering (motility), and by forming branching tubules in gel matrices (branching morphogenesis). HGF/SF also induces in vitro invasiveness and is angiogenic in in vivo assays. A human cell line and several mouse cell lines that we have constructed to express Met-HGF/SF in an autocrine fashion are tumorigenic, invasive and metastatic in athymic nude mice. Thus, the very complex process of invasion and metastasis can be mediated by a ligand-receptor signalling pathway, and the cell lines we have developed provide important model systems for identifying the signalling molecules that mediate these phenotypes: For example Met-HGF/SF signalling activates the urokinase plasminogen proteolysis network, thus coupling this signal transduction pathway to the proteases that mediate dissolution of the extracellular matrix. Branching morphogenesis, mediated by Met-HGF/SF signalling, is dependent on this process, as well as the formation of cell-cell junctions and interaction with the extracellular matrix. We have proposed a hypothesis for the role of Met and downstream signalling molecules in generating normal ducts and lumenal structures, as well as a model for how interruption of this signalling leads to abnormal malignant progression. Is Met involved in human cancer? Human sarcomas often inappropriately express Met, suggesting that it is an important oncogene in these cancers, and an increasing number of reports have implicated Met-HGF/SF signalling in a variety of human cancers.
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PMID:Met-HGF/SF: tumorigenesis, invasion and metastasis. 952 67

Ecotin, a dimeric serine protease inhibitor from Escherichia coli, is a novel platform for inhibitor design. An approach using the three-dimensional structure of the ecotin-trypsin complex to guide combinatiorial design efforts was taken to create potent bidentate ecotin inhibitors for trypsin and human urokinase-type plasminogen activator (uPA). The ecotin surface loop that was redesigned is composed of residues 67 to 70 (60 s loop), and binds to the target protease at a region 25 A from the enzyme active site. Two ecotin phage display libraries were constructed to exploit the binding interactions at the 60 s loop. The ecotin 60X4 library, in which residues 67 to 70 of ecotin were randomized, was panned against rat and bovine trypsin in parallel for four rounds. Panning against bovine trypsin resulted in enrichment of ecotin phage but did not yield a consensus sequence. Panning against rat trypsin resulted in enrichment as well as the ecotin consensus sequence WGFP at positions 67 to 70. The variant ecotin encoded by this sequence inhibited rat trypsin at 80 pM, a 12-fold improvement over ecotin wild-type (WT). A second generation library, ecotin M84R+60X4 including an additional methionine to arginine substitution at position 84 in the primary binding site of ecotin, was generated for panning against uPA and rat trypsin. Panning against rat trypsin resulted in enrichment but no consensus sequence. Panning against uPA resulted in enrichment as well as the different ecotin consensus sequence WGYR at positions 67 to 70. Ecotin M84R+D70R bound to uPA at 50 pM, a 56,000-fold increase in binding compared to ecotin WT. Furthermore, ecotin M84R+D70R achieved a 13,680-fold preference of specificity towards uPA versus rat trypsin. The fact that the 60 s loop of ecotin plays different roles in binding to trypsin and uPA suggests this site can be used to introduce specificity and potency for other members of the serine proteases with a chymotrypsin fold.
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PMID:Engineering bidentate macromolecular inhibitors for trypsin and urokinase-type plasminogen activator. 964 77

Because hepatocyte growth factor (HGF) is a potent mitogen for normal human exocrine pancreas cells (NPCs) in vitro, we have analyzed the expression of HGF and its receptor, Met, in NPC and pancreas cancer cells and studied its effects in vitro. Using immunohistochemistry, Northern blotting, and reverse transcription-polymerase chain reaction, we examined the expression of HGF and Met in normal pancreas and pancreas cancer. Scatter assays, wound-healing assays, and migration through transwell filters were used to study HGF-stimulated motility of IMIM-PC-2 cancer cells. In tumors, HGF is mainly detected in stromal cells, whereas Met is overexpressed in cancer cells with an unpolarized distribution. In vitro, HGF stimulates motogenesis but not proliferation in cancer cells. Cell motility is accompanied by a rapid decrease in the cytoskeleton-bound E-cadherin, an acceleration of cellular adhesion to the substrate, an up-regulation of urokinase plasminogen activator (u-PA) RNA and protein, and a change in the solubility and proteolysis of the u-PA receptor. Cell motility is significantly reduced by inhibitors of u-PA proteolytic activity such as antibodies neutralizing u-PA activity, plasminogen activator inhibitor 1, and amiloride. These results show that a paracrine loop of HGF activation may participate in the development or progression of pancreas cancer. In vitro, the HGF-stimulated motogenesis of pancreas cancer cells involves the activation of the u-PA/u-PA receptor proteolytic system, suggesting its role in the invasive stages of tumor progression.
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PMID:Activation of the urokinase plasminogen activator/urokinase plasminogen activator receptor system and redistribution of E-cadherin are associated with hepatocyte growth factor-induced motility of pancreas tumor cells overexpressing Met. 966 81

Brain serine proteases are implicated in developmental processes, synaptic plasticity, and in disorders including Alzheimer's disease. The spectrum of the major enzymes expressed in brain has not been established previously. We now present a systematic study of the serine proteases expressed in adult rat and mouse hippocampus. Using a combination of techniques including polymerase chain reaction amplification and Northern blotting we show that tissue-type plasminogen activator (t-PA) is the major species represented. Unexpectedly, the next most abundant species were RNK-Met-1, a lymphocyte protease not reported previously in brain, and two new family members, BSP1 (brain serine protease 1) and BSP2. We report full-length sequences of the two new proteases; homologies indicate that these are of tryptic specificity. Although BSP2 is expressed in several brain regions, BSP1 expression is strikingly restricted to hippocampus. Other enzymes represented, but at lower levels, included elastase IV, proteinase 3, complement C2, chymotrypsin B, chymotrypsin-like protein, and Hageman factor. Although thrombin and urokinase-type plasminogen activator were not detected in the primary screen, low level expression was confirmed using specific polymerase chain reaction primers. In contrast, and despite robust expression of t-PA, the usual t-PA substrate plasminogen was not expressed at detectable levels.
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PMID:Serine proteases in rodent hippocampus. 972 24

The very low density lipoprotein receptor (VLDLr) binds diverse ligands, including urokinase-type plasminogen activator (uPA) and uPA-plasminogen activator inhibitor-1 (PAI-1) complex. In this study, we characterized the effects of the VLDLr on the internalization, catabolism, and function of the uPA receptor (uPAR) in MCF-7 and MDA-MB-435 breast cancer cells. When challenged with uPA.PAI-1 complex, MDA-MB-435 cells internalized uPAR; this process was inhibited by 80% when the activity of the VLDLr was neutralized with receptor-associated protein (RAP). To determine whether internalized uPAR is degraded, we studied the catabolism of [35S]methionine-labeled uPAR. In the absence of exogenous agents, the uPAR catabolism t(1)/(2) was 8.2 h. uPA.PAI-1 complex accelerated uPAR catabolism (t(1)/(2) to 1.8 h), while RAP inhibited uPAR catabolism in the presence (t(1)/(2) of 7.8 h) and absence (t(1)/(2) of 16.9 h) of uPA.PAI-1 complex, demonstrating a critical role for the VLDLr. When MCF-7 cells were cultured in RAP, cell surface uPAR levels increased gradually, reaching a new steady-state in 3 days. The amount of uPA which accumulated in the medium also increased. Culturing in RAP for 3 days increased MCF-7 cell motility by 2.2 +/- 0.1-fold and by 4.4 +/- 0.3-fold when 1.0 nM uPA was added. The effects of RAP on MCF-7 cell motility were entirely abrogated by an antibody which binds uPA and prevents uPA binding to uPAR. MCF-7 cells that were cultured in RAP demonstrated increased levels of activated mitogen-activated protein kinases. Furthermore, the MEK inhibitor, PD098059, decreased the motility of RAP-treated cells without affecting control cultures. These studies suggest a model in which the VLDLr regulates autocrine uPAR-initiated signaling and thereby regulates cellular motility.
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PMID:The very low density lipoprotein receptor regulates urokinase receptor catabolism and breast cancer cell motility in vitro. 1006 6

Met protein encoded by MET oncogene is the high affinity receptor for hepatocyte growth factor (HGF)/scatter factor (SF). HGF/SF has to be cleaved in its heterodimeric form by the urokinase-type plasminogen activator (uPA) to become active as a ligand for Met receptor. The expression of Met protein and of the high affinity receptor for uPA (uPA-R) was investigated in 39 samples of papillary carcinoma using immunohistochemistry. Reactivity for Met protein was present in 33 of 34 tumours, mostly with a diffuse pattern of staining. Reactivity for uPA-R was present in 78 per cent of papillary tumours and exhibited a pattern of staining similar to that of Met protein. Staining for uPA-R was present in 23 of 25 cases (92 per cent) of papillary carcinoma with prominent sclerosis, and in only 1 of 7 cases (14 per cent) without sclerosis. Peritumoural normal thyroid, follicular adenomas, and follicular carcinomas were negative for Met protein and for uPA-R. Hyperfunctioning tall thyroid cells showed weak membrane reactivity for uPA-R and for Met protein. The findings of immunohistochemistry were confirmed at the mRNA level using in situ hybridization, since the signal for uPA-R and Met RNAs was detected in most tumour cells of five cases of papillary carcinoma.
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PMID:Expression of Met protein and urokinase-type plasminogen activator receptor (uPA-R) in papillary carcinoma of the thyroid. 1021 Nov 18

Hepatocyte growth factor/scatter factor (HGF/SF) is a pleiotropic effector inducing invasion and metastasis of tumor cells that express the Met tyrosine kinase receptor. One of the effectors of HGF/SF is the urokinase-type plasminogen activator, a serine protease that facilitates tumor progression and metastasis by controlling the synthesis of the extracellular matrix degrading plasmin. Stimulation of NIH 3T3 cells that were stably transfected with the human Met receptor (NIH 3T3-Methum) with HGF/SF induced a trans-activation of the urokinase promoter and urokinase secretion. Induction of the urokinase promoter by HGF/SF via the Met receptor was blocked by co-expression of a dominant-negative Grb2 and Sos1 expression construct. Further, the expression of the catalytically inactive mutants of Ha-Ras, RhoA, c-Raf, and Erk2 or addition of the Mek1-specific inhibitor PD 098059 abrogated the stimulation of the urokinase promoter by HGF/SF. A sequence residing between -2109 and -1870 base pairs (bp) was critical for stimulation of the urokinase gene by HGF/SF. Mobility shift assays with oligonucleotides spanning an AP-1 site at -1880 bp or a combined PEA3/AP-1 site at -1967 bp showed binding of nuclear factors from NIH 3T3-Methum cells. Expression of an expression plasmid that inhibits DNA binding of AP-1 proteins (A-Fos) abrogated inducible and basal activation of the urokinase promoter. Nuclear extract from unstimulated NIH 3T3-Methum cells contained more JunD and showed a stronger JunD supershift with the AP-1 oligonucleotides, compared with HGF/SF-stimulated cells. Consistent with the levels of JunD expression being functionally important for basal expression of the urokinase promoter, we found that overexpression of wild type JunD inhibited the induction of the urokinase promoter by HGF/SF. These data suggest that the induction of urokinase by HGF/SF is regulated by a Grb2/Sos1/Ha-Ras/c-Raf/RhoA/Mek1/Erk2/c-++ +Jun-dependent mitogen-activated protein kinase pathway.
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PMID:Activation mechanisms of the urokinase-type plasminogen activator promoter by hepatocyte growth factor/scatter factor. 1034 97

Anchorage-independent myelomonocytic cells acquire adherence within minutes of differentiation stimuli, such as the proteolytically inactive N-terminal fragment of urokinase binding to its cognate glycosylphosphatidylinositol (GPI)-anchored receptor. Here, we report that urokinase-treated differentiating U937 monocyte-like cells exhibit a rapid and transient inhibition of p56/59(hck) and p55(fgr) whereas no changes in the activity of other Src family kinases, such as p53/56(lyn) and p59(fyn) were observed. U937 transfectants expressing a kinase-defective (Lys267 to Met) p56/59(hck) variant exhibit enhanced adhesiveness and a marked F-actin redistribution in thin protruding structures. Conversely, urokinase as well as expression of wild-type or constitutively active (Tyr499 to Phe) p56/59(hck) stimulates the directional migration of uninduced U937 cells. Accordingly, expression of constitutively active or kinase inactive p56/59(hck) selectively prevents urokinase receptor-dependent induction of either adhesion or motility, indicating that a specific activation state of p56/59(hck) is required for each cell response. In conclusion, modulation of the intracellular p56/59(hck) tyrosine kinase activity switches cell motility towards adherence, providing a mutually exclusive mechanism to regulate these properties during monocyte/macrophage differentiation in vivo.
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PMID:Urokinase receptor-dependent and -independent p56/59(hck) activation state is a molecular switch between myelomonocytic cell motility and adherence. 1035 14


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