Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.73 (urokinase-type plasminogen activator)
 10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Many serine proteases play important regulatory roles in complex biological systems, but only a few have been linked directly with capillary morphogenesis and angiogenesis. Here we provide evidence that serine protease activities, independent of the plasminogen activation cascade, are required for microvascular endothelial cell reorganization and capillary morphogenesis in vitro. A homology cloning approach targeting conserved motifs present in all serine proteases, was used to identify candidate serine proteases involved in these processes, and revealed 5 genes (acrosin, testisin, neurosin, PSP and neurotrypsin), none of which had been associated previously with expression in endothelial cells. A subsequent gene-specific RT-PCR screen for 22 serine proteases confirmed expression of these 5 genes and identified 7 additional serine protease genes expressed by human endothelial cells, urokinase-type plasminogen activator, protein C, TMPRSS2, hepsin, matriptase/MT-SP1, dipeptidylpeptidase IV, and seprase. Differences in serine protease gene expression between microvascular and human umbilical vein endothelial cells (HUVECs) were identified and several serine protease genes were found to be regulated by the nature of the substratum, ie. artificial basement membrane or fibrillar type I collagen. mRNA transcripts of several serine protease genes were associated with blood vessels in vivo by in situ hybridization of human tissue specimens. These data suggest a potential role for serine proteases, not previously associated with endothelium, in vascular function and angiogenesis.
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PMID:Endothelial cell serine proteases expressed during vascular morphogenesis and angiogenesis. 1262 42

Adenosine deaminase (ADA) is expressed intracellularly by all cells, but in some tissues, it is also associated with the cell surface multifunctional glycoprotein CD26/dipeptidyl peptidase IV. By modulating extracellular adenosine, this "ecto-ADA" may regulate adenosine receptor signaling implicated in various cellular functions. CD26 is expressed on the surface of human prostate cancer 1-LN cells acting as a receptor for plasminogen (Pg). Since ADA and Pg bind to CD26 at distinct but nearby sites, we investigated a possible interaction between these two proteins on the surface of 1-LN cells. Human ADA binds to CD26 on the surface 1-LN cells and immobilized CD26 isolated from the same cells with similar affinity. In both cases, ADA binding is diminished by mutation of ADA residues known to interact with CD26. ADA was also found to bind Pg 2 in the absence of CD26 via the Pg kringle 4 (K4) domain. In the presence of 1-LN cells or immobilized CD26, exogenous ADA enhances conversion of Pg 2 to plasmin by 1-LN endogenous urinary plasminogen activator (u-PA), as well as by added tissue Pg Activator (t-PA), suggesting that ADA and Pg bind simultaneously to CD26 in a ternary complex that stimulates the Pg activation by its physiologic activators. Consistent with this, in melanoma A375 cells that bind Pg, but do not express CD26, the rate of Pg activation was not affected by ADA. Thus, ADA may be a factor regulating events in prostate cancer cells that occur when Pg binds to the cell surface and is activated.
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PMID:Cell surface adenosine deaminase binds and stimulates plasminogen activation on 1-LN human prostate cancer cells. 1501 24

The CC chemokine CCL14a is constitutively expressed in a large variety of tissues and its inactive proform CCL14a(1-74) circulates in high concentrations in plasma. CCL14a(1-74) is converted into CCL14a(9-74) by the proteases urokinase-type plasminogen activator and plasmin and is a highly active agonist for the chemokine receptors CCR1 and CCR5. In this study, a new CCL14a analog, CCL14a(12-74), was isolated from blood filtrate. To elucidate the functional role of the N terminus, a panel of N-terminally truncated CCL14a analogs were tested on the receptors CCR1 to CCR5 and on the human cytomegalovirus (HCMV)-encoded chemokine receptor US28. The rank order of binding affinity to these receptors and of the activation of CCR1 and CCR5-mediated intracellular Ca(2+) concentration mobilization is CCL14a(6-74)<(7-74)<(8-74)<<(9-74) = (10-74)>>(11-74)>>(12-74). The almost identical affinities of CCL14a(7-74), CCL14a(9-74), and CCL14a(10-74) for the US28 receptor and the inhibition of US28-mediated HIV infection of 293T cells by all of the N-terminally truncated CCL14a analogs support the promiscuous nature of the viral chemokine receptor US28. In high concentrations, CCL14a(12-74) did reveal antagonistic activity on intracellular Ca(2+) concentration mobilization in CCR1- and CCR5-transfected cells, which suggests that truncation of Tyr(11) might be of significance for an efficient inactivation of CCL14a. A putative inactivation pathway of CCL14a(9-74) to CCL14a(12-74) may involve the dipeptidase CD26/dipeptidyl peptidase IV (DPPIV), which generates CCL14a(11-74), and the metalloprotease aminopeptidase N (CD13), which displays the capacity to generate CCL14a(12-74) from CCL14a(11-74). Our results suggest that the activity of CCL14a might be regulated by stringent proteolytic activation and inactivation steps.
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PMID:Significance of N-terminal proteolysis of CCL14a to activity on the chemokine receptors CCR1 and CCR5 and the human cytomegalovirus-encoded chemokine receptor US28. 1955 44

In vitro cultured endothelial cells forming a continuous monolayer establish stable cell-cell contacts and acquire a "resting" phenotype; on the other hand, when growing in sparse conditions these cells acquire a migratory phenotype and invade the empty area of the culture. Culturing cells in different conditions, we compared expression and clustering of proteolytic enzymes in cells having migratory versus stationary behavior. In order to observe resting and migrating cells in the same microscopic field, a continuous cell monolayer was wounded. Increased expression of proteolytic enzymes was evident in cell membranes of migrating cells especially at sprouting sites and in shed membrane vesicles. Gelatin zymography and western blotting analyses confirmed that in migrating cells, expression of membrane-bound and of vesicle-associated proteolytic enzymes are increased. The enzymes concerned include MMP-2, MMP-9, MT1-MMP, seprase, DPP4 (DiPeptidyl Peptidase 4) and uPA. Shed membrane vesicles were shown to exert degradative activity on ECM components and produce substrates facilitating cell migration. Vesicles shed by migrating cells degraded ECM components at an increased rate; as a result their effect on cell migration was amplified. Inhibiting either Matrix Metallo Proteases (MMPs) or Serine Integral Membrane Peptidases (SIMPs) caused a decrease in the stimulatory effect of vesicles, inhibiting the spontaneous migratory activity of cells; a similar result was also obtained when a monoclonal antibody acting on DPP4 was tested. We conclude that proteolytic enzymes have a synergistic stimulatory effect on cell migration and that their clustering probably facilitates the proteolytic activation cascades needed to produce maximal degradative activity on cell substrates during the angiogenic process.
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PMID:Proteolytic Enzymes Clustered in Specialized Plasma-Membrane Domains Drive Endothelial Cells' Migration. 2715 13

The capillary morphogenesis gene 2 (CMG2), also known as the anthrax toxin receptor 2 (ANTXR2), is a transmembrane protein putatively involved in extracellular matrix (ECM) adhesion and tissue remodeling. CMG2 promotes endothelial cell proliferation and exhibits angiogenic properties. Its downregulation is associated with a worsened survival of breast carcinoma patients. Aim of this study was to analyze the CMG2 mRNA and protein expression in soft tissue sarcoma and their association with patient outcome. CMG2 mRNA was measured in 121 tumor samples of soft tissue sarcoma patients using quantitative real-time PCR. CMG2 protein was evaluated in 52 tumor samples by ELISA. CMG2 mRNA was significantly correlated with the corresponding CMG2 protein expression (rs = 0.31; p = 0.027). CMG2 mRNA expression was associated with the mRNA expressions of several ECM and tissue remodeling enzymes, among them CD26 and components of the uPA system. Low CMG2 mRNA expression was correlated with a worsened patients' disease-specific survival in Kaplan-Meier analyses (mean patient survival was 25 vs. 96 months; p = 0.013), especially in high-stage tumors. A decreased CMG2 expression is a negative prognostic factor for soft tissue sarcoma patients. CMG2 may be an interesting candidate gene for the further exploration of soft tissue sarcoma genesis and progression.
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PMID:CMG2 Expression Is an Independent Prognostic Factor for Soft Tissue Sarcoma Patients. 2921 51

Stem cell-based therapies could provide a permanent treatment for salivary gland (SG) hypofunction caused by ionizing radiation (IR) injury. However, current challenges for SG stem cells to reach the clinic include surgical invasiveness, amount of tissue needed, cell delivery, and storage methods. The objective of this study was to develop a clinically less invasive method to isolate and expand human SG stem cells and then to obtain a cell-free extract to be used as a therapy for IR-injured SGs. Human labial glands were biopsied, and labial stem cells (LSCs) were expanded by explant culture. The LSC extract (LSCE) was obtained by releasing the cellular components after 3 freeze-thaw cycles and 17,000g force centrifugation. LSCE was injected intravenously into mice that had their SGs injured with 13-Gy IR. Positive (non-IR) and negative (IR) control mice received injections of saline (vehicle control). Three pieces of labial glands (0.1 g weight) could expand 1 to 2 million cells. LSCs had a doubling time of 18.8 h; could differentiate into osteocytes, adipocytes, and chondrocytes; and were positive for mesenchymal stem cell markers. Both angiogenic (FGF-1, FGF-2, KGF, angiopoietin, uPA, VEGF) and antiangiogenic factors (PAI-1, TIMP-1, TSP-1, CD26) were detected in LSCE. In addition, some angiogenic factors (PEDF, PTX3, VEGF) possessed neurotrophic functions. Mice treated with LSCE had 50% to 60% higher salivary flow rate than saline-treated mice at 8 and 12 wk post-IR. Saliva lag time measurements also confirmed that LSCE restored SG function. Histologic analyses of parotids and submandibular glands reported comparable numbers of acinar cells, blood vessels, and parasympathetic nerves and cell proliferation rates in sham IR and LSCE-treated mice, though significantly lower in saline-treated mice. An explant culture method can harvest a large number of LSCs from small pieces of labial glands. LSCE showed clinical potential to mitigate IR-injured SGs.
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PMID:Labial Stem Cell Extract Mitigates Injury to Irradiated Salivary Glands. 3193 82