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)

Low-density lipoprotein receptor family members (LRs) play a key role in the catabolism of many membrane-associated proteins, such as complexes between proteinases and their receptors, in addition to being involved in lipoprotein metabolism as suspected by the hitherto well-established functions of low-density lipoprotein receptor, in a variety of tissues. Recent studies using receptor-deficient or -overexpressing animals and cells have suggested that certain LRs are important regulators of the migration (and proliferation) of vascular smooth muscle cells (SMCs). LR expression is markedly induced in intimal or medial SMCs during the formation of atherosclerotic lesions. Because LRs can modulate the activity of the urokinase-type plasminogen activator (uPA) receptor and possibly of the platelet-derived growth factor (PDGF) receptor, LRs may influence the migration of SMCs through functional modulation of these membrane receptors. Therefore, SMC migration may be regulated by time-restricted expression of LRs. In agreement with the concept of functional interaction between LRs and membrane signaling receptors, a negative regulator of uPA receptor protein catabolism, LR11, has been identified. Statins modulate the PDGF-induced migration of intimal SMCs via the LR11/uPA receptor cascade. Selective modification of the LRs/uPA receptor/PDGF receptor systems in SMCs may be important for suppression of atherosclerotic plaque formation as well as for preventing intimal thickening after angioplasty.
 ...
PMID:Modulation of smooth muscle cell migration by members of the low-density lipoprotein receptor family. 1657 89

Angiopoietin-2 (Ang-2) is a growth factor, which was identified originally as playing a critical role in vessel remodeling during angiogenesis. More recent evidence has indicated additional involvement in vascular homeostatic responses such as coagulation and inflammation, which are central to wound healing. We therefore determined whether a relationship existed between Ang-2 and monocytes, one of the initial cell types to be recruited to a wound, in the context of fibrin clot invasion. Ang-2 significantly increased monocyte invasion of fibrin in the presence of serum. In the absence of serum, it required a combination of Ang-2 and platelet-derived growth factor BB (PDGF-BB) to increase invasion by threefold. Furthermore, it was shown that the heightened invasion was dependent on serine proteases and matrix metalloproteinases (MMPs) and that the combination of Ang-2 and PDGF-BB increased urokinase plasminogen-activator receptor expression, as well as MMP-9 and membrane type 1 MMP expression. These data give further credence to the concept of Ang-2 as a key regulator of several essential phases of wound healing.
 ...
PMID:Ang-2 and PDGF-BB cooperatively stimulate human peripheral blood monocyte fibrinolysis. 1739 86

Members of the platelet-derived growth factor (PDGF) family are mitogens for cells of mesenchymal origin and have important functions during embryonic development, blood vessel maturation, fibrotic diseases and cancer. In contrast to the two classical PDGFs, the novel and less well-characterized members, PDGF-CC and PDGF-DD, are latent factors that need to be processed extracellularly by activating proteases, before they can mediate PDGF receptor activation. Here, we elucidate the structural requirements for urokinase plasminogen activator (uPA)-mediated activation of PDGF-DD, as well as the intricate interplay with uPA receptor (uPAR) signalling. Furthermore, we show that activated PDGF-DD, in comparison to latent, more potently transforms NIH/3T3 cells in vitro. Conversely, xenograft studies in nude mice demonstrate that cells expressing latent PDGF-DD are more tumorigenic than those expressing activated PDGF-DD. These findings imply that a fine-tuned proteolytic activation, in the local milieu, controls PDGF-DD bioavailability. Moreover, we suggest that proteolytic activation of PDGF-DD reveals a retention motif mediating interactions with pericellular components. Our proposed mechanism, where uPA not only generates active PDGF-DD, but also regulates its spatial distribution, provides novel insights into the biological function of PDGF-DD.
 ...
PMID:The uPA/uPAR system regulates the bioavailability of PDGF-DD: implications for tumour growth. 1899 17

Prostate cancer (CaP) is one of the most prevalent malignant diseases among men in Western countries. There is currently no cure for metastatic castrate-resistant CaP, and median survival for these patients is about 18 months; the high mortality rate seen is associated with widespread metastases. Progression of CaP from primary to metastatic disease is associated with several molecular and genetic changes that can affect the expression of specific tumor-associated antigens (TAAs) or receptors on the cell surface. Targeting TAAs is emerging as an area of promise for controlling late-stage and recurrent CaP. Several reviews have summarized the progress made in targeting signaling pathways for CaP but will not be discussed here. We describe some important CaP TAAs. These include prostate stem-cell antigen, prostate-specific membrane antigen, MUC1, epidermal growth factor receptor, platelet-derived growth factor and its receptor, urokinase plasminogen activator and its receptor, and extracellular matrix metalloproteinase inducer. We summarize recent advancements in our understanding of their role in CaP metastasis, as well as potential therapeutic options for targeting CaP TAAs. We also discuss the origin, identification, and characterization of prostate cancer stem cells (CSCs) and the potential benefits of targeting prostate CSCs to overcome chemoresistance and CaP recurrence.
 ...
PMID:Promising tumor-associated antigens for future prostate cancer therapy. 1953 65

Urinary trypsin inhibitor (UTI), an inhibitor of urokinase plasminogen activator relevant to proteolytic processing from the inactive into the active form of platelet-derived growth factor-D (PDGF-D) to activate PDGF-betabeta receptor (PDGF-betabetaR), inhibited fetal bovine serum-stimulated migration of human malignant mesothelioma, with the extent varying among the cell types. The more effective inhibition was found in NCIH-2052 and -2452 cells, with the higher expression of PDGF-betabetaR. The results of the present study suggest that UTI suppresses malignant mesothelioma cell migration by neutralizing active dimer of PDGF-D (PDGF-DD)/PDGF-betabetaR-mediated signal transduction.
 ...
PMID:Urinary trypsin inhibitor suppresses migration of malignant mesothelioma. 1966 Aug 58

Factor VII-activating protease (FSAP) circulates as an inactive zymogen in the plasma. FSAP also regulates fibrinolysis by activating pro-urokinase or cellular activation via cleavage of platelet-derived growth factor BB (PDGF-BB). As the Marburg I polymorphism of FSAP, with reduced enzymatic activity, is a risk factor for atherosclerosis and liver fibrosis, the regulation of FSAP activity is of major importance. FSAP is activated by an auto-catalytic mechanism, which is amplified by heparin. To further investigate the structural requirements of polyanions for controlling FSAP activity, we performed binding, activation and inhibition studies using heparin and derivatives with altered size and charge, as well as other glycosaminoglycans. Heparin was effective in binding to and activating FSAP in a size- and charge density-dependent manner. Polyphosphate was more potent than heparin with regard to its interactions with FSAP. Heparin was also an effective co-factor for inhibition of FSAP by plasminogen activator inhibitor 1 (PAI-1) and antithrombin, whereas polyphosphate served as co-factor for the inhibition of FSAP by PAI-1 only. For FSAP-mediated inhibition of PDGF-BB-induced vascular smooth muscle cell proliferation, heparin as well as a polyphosphate served as efficient co-factors. Native mast cell-derived heparin exhibited identical properties to those of unfractionated heparin. Despite the strong effects of synthetic polyphosphate, the platelet-derived material was a weak activator of FSAP. Hence, negatively charged polymers with a high charge-to-size ratio are responsible for the activation of FSAP, and also act as co-factors for its inhibition by serine protease inhibitors.
 ...
PMID:High negative charge-to-size ratio in polyphosphates and heparin regulates factor VII-activating protease. 1966 58

The PDGF (platelet-derived growth factor) family members are potent mitogens for cells of mesenchymal origin and serve as important regulators of cell migration, survival, apoptosis and transformation. Tumour-derived PDGF ligands are thought to function in both autocrine and paracrine manners, activating receptors on tumour and surrounding stromal cells. PDGF-C and -D are secreted as latent dimers, unlike PDGF-A and -B. Cleavage of the CUB domain from the PDGF-C and -D dimers is required for their biological activity. At present, little is known about the proteolytic processing of PDGF-C, the rate-limiting step in the regulation of PDGF-C activity. In the present study we show that the breast carcinoma cell line MCF7, engineered to overexpress PDGF-C, produces proteases capable of cleaving PDGF-C to its active form. Increased PDGF-C expression enhances cell proliferation, anchorage-independent cell growth and tumour cell motility by autocrine signalling. In addition, MCF7-produced PDGF-C induces fibroblast cell migration in a paracrine manner. Interestingly, PDGF-C enhances tumour cell invasion in the presence of fibroblasts, suggesting a role for tumour-derived PDGF-C in tumour-stromal interactions. In the present study, we identify tPA (tissue plasminogen activator) and matriptase as major proteases for processing of PDGF-C in MCF7 cells. In in vitro studies, we also show that uPA (urokinase-type plasminogen activator) is able to process PDGF-C. Furthermore, by site-directed mutagenesis, we identify the cleavage site for these proteases in PDGF-C. Lastly, we provide evidence suggesting a two-step proteolytic processing of PDGF-C involving creation of a hemidimer, followed by GFD-D (growth factor domain dimer) generation.
 ...
PMID:Platelet-derived growth factor-C (PDGF-C) activation by serine proteases: implications for breast cancer progression. 2203 41

Mesenchymal stromal cells (MSCs) have received much attention as a potential treatment of ischemic diseases, including ischemic tissue injury and cardiac failure. The beneficial effects of MSCs are thought to be mediated by their ability to provide proangiogenic factors, creating a favorable microenvironment that results in neovascularization and tissue regeneration. To study this in more detail and to explore the potential of the horse as a valuable translational model, the objectives of the present study were to examine the presence of angiogenic stimulating factors in the conditioned medium (CM) of peripheral blood-derived equine mesenchymal stromal cells (PB-MSCs) and to study their in vitro effect on angiogenesis-related endothelial cell (EC) behavior, including proliferation and vessel formation. Our salient findings were that CM from PB-MSCs contained significant levels of several proangiogenic factors. Furthermore, we found that CM could induce angiogenesis in equine vascular ECs and confirmed that endothelin-1, insulin growth factor binding protein 2, interleukin-8, and platelet-derived growth factor-AA, but not urokinase-type plasminogen activator, were responsible for this enhanced EC network formation by increasing the expression level of vascular endothelial growth factor-A, an important angiogenesis stimulator.
...
PMID:Peripheral Blood-Derived Mesenchymal Stromal Cells Promote Angiogenesis via Paracrine Stimulation of Vascular Endothelial Growth Factor Secretion in the Equine Model. 2531 2

We studied the effect of urokinase, its recombinant forms, and domain fragments on migration and proliferation of adipose tissue mesenchymal stromal cells (MSCs) and MMP secretion by these cells. Urokinase, but not its recombinant forms, slightly induced directed migration of MSCs. Spontaneous migration of MSCs increased under the action of urokinase or its isolated kringle domain. Migration induced by platelet-derived growth factor was inhibited by proteolytically inactive form of urokinase, the kringle domain, and blocking antibody to urokinase receptor. Urokinase, its proteolytically inactive form, and kringle domain produced no effect on MSC proliferation. In contrast to platelet-derived growth factor, all urokinase forms induced secretion of MMP-9 by MSCs.
 ...
PMID:Regulatory Effects of Urokinase on Mesenchymal Stromal Cell Migration, Proliferation, and Matrix Metalloproteinase Secretion. 2778 4

Factor VII (FVII)-activating protease (FSAP) is a serine protease in plasma, which was initially described to play a role in coagulation by activation of FVII, independent of tissue factor, and in fibrinolysis by cleavage of single-chain urokinase. Recent studies, however, suggest that FSAP-mediated FVII cleavage is negligible and that FSAP may exert procoagulant functions via cleavage of tissue factor pathway inhibitor. Meanwhile, many substrates of FSAP have been identified, such as platelet-derived growth factor, basic fibroblast growth factor/epidermal growth factor, histones, and high-molecular-weight kininogen. FSAP has also shown to induce DNA released from dead cells. Given its propensity for autoproteolysis and degradation, studies on the activation and regulation of FSAP are difficult to perform. Recent animal studies suggest a role of FSAP in the pathogenesis of arteriosclerosis, vascular integrity and probably also in the regulation of coagulation initiation. This review will focus on the biochemical properties of FSAP, regulation of FSAP activation, and finally its role in vascular disease and acute systemic inflammatory diseases, such as sepsis.
 ...
PMID:Factor VII-Activating Protease: Hemostatic Protein or Immune Regulator? 2917 15


<< Previous 1 2 3 4 5 Next >>