Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.7 (plasmin)
 9,023 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human A431 epidermoid carcinoma cells in culture exhibit epidermal growth factor (EGF)-induced "down-regulation" of cell-surface and total cellular (Triton X-100 extractable) EGF receptors caused entirely by an enhanced rate (4-fold) of receptor inactivation [Krupp, M. N., Connolly, D. T. & Lane, M. D. (1982) J. Biol. Chem. 257, 11489-11496]. The following observations show that this enhanced rate of EGF receptor inactivation is closely correlated with an increased cellular activity of plasminogen activator (PA), a serine protease. First, EGF-induced down-regulation of cell-surface and total cellular EGF receptors and the concomitant increase in cellular PA activity occur with identical kinetics, the t 1/2 for both processes being 3-3.5 hr. Second, the EGF dose-response curves for down-regulation of total cellular EGF receptor and increased PA activity are similar. The EGF concentrations for half-maximal responses of both processes are 10-15 nM and 20 nM, respectively. Third, the removal of EGF from previously down-regulated cells results in the recovery of total cellular EGF binding activity with a concurrent loss of cellular PA activity. Fourth, blocking PA synthesis or activity with cycloheximide or dexamethasone prevents down-regulation of the EGF receptor. Fifth, the addition of leupeptin, an inhibitor of PA and plasmin action, blocks EGF-induced receptor down-regulation as well as the increase of PA activity. That EGF receptor down-regulation is independent of plasminogen per se in the culture medium suggests that PA-mediated events may initiate the rapid inactivation of the EGF receptor that occurs during down-regulation.
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PMID:Down-regulation of epidermal growth factor receptor correlates with plasminogen activator activity in human A431 epidermoid carcinoma cells. 630 Sep 5

Normal as well as neoplastic cells traverse extracellular matrix barriers by mobilizing proteolytic enzymes in response to epidermal growth factor (EGF)-EGF receptor (EGFR) or hepatocyte growth factor/scatter factor (SF)-c-Met interactions. The plasminogen activator-plasminogen axis has been proposed to play a key role during cell invasion, but the normal development of plasminogen activator- as well as that of plasminogen-deficient mice supports the existence of alternate proteolytic systems that permit cells to traverse extracellular matrix barriers. To characterize the role that matrix-degrading proteinases play in EGF- or SF-stimulated invasion, a human squamous carcinoma cell line (UM-SCC-1) was triggered atop the matrices of type I collagen or human dermal explants in a three-dimensional culture system. During EGF- or SF-induced invasion, UM-SCC-1 cells expressed urokinase-type plasminogen activator (uPA) and uPA receptor as well as the matrix metalloproteinases (MMPs), membrane-type MMP-1, collagenase 1, stromelysin 1, and gelatinase B. Despite the presence of a positive correlation between uPA receptor-uPA expression and growth factor-stimulated invasion, UM-SCC-1 invasion was not affected by inhibitors directed against the plasminogen activator-plasminogen axis. In contrast, both recombinant and synthetic MMP inhibitors completely suppressed invasion by either EGF- or SF-stimulated cells without affecting either proteinase expression or cell motility across collagen-coated surfaces. These data demonstrate that MMPs, but not the plasminogen activator-plasmin system, can directly regulate the ability of either EGF- or SF-stimulated tumor cells to invade interstitial matrix barriers.
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PMID:Role of the plasminogen activator and matrix metalloproteinase systems in epidermal growth factor- and scatter factor-stimulated invasion of carcinoma cells. 982 36

The serine-protease urokinase (uPA) and its specific membrane receptor uPAR controls matrix degradation through the conversion of plasminogen into plasmin and play a crucial role in a number of biological processes including local fibrinolysis, inflammation, angiogenesis, matrix remodelling during wound healing, tumor invasion and metastasis. Most of the cellular responses modulated by the uPA/uPAR system, including migration, cellular adhesion, differentiation, proliferation and apoptosis require transmembrane signaling, which is mediated by direct contacts of uPAR with a variety of extracellular proteins and membrane receptors, such as integrins, EGF receptor, high molecular weight kininogen, caveolin and the G-protein-coupled receptor FPRL1. As a result of these interactions, uPAR activates intracellular signalling molecules such as tyrosine- and serine-protein kinases, Src, focal adhesion kinase (FAK), Rac, extracellular-signal-regulated kinase (ERK)/mitogen- activated protein kinase (MAPK) and JAK/STAT, being part of a large "signalosome" interacting with several molecules on both the outside and inside of the cell. This review is focused on the biochemistry of the pathways affected by uPAR and its partners.
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PMID:The urokinase receptor as an entertainer of signal transduction. 1927 72

Adhesive small bowel obstruction remains a common problem for surgeons. After surgery, platelet aggregation contributes to coagulation cascade and fibrin clot formation. With clotting, fibrin degradation is simultaneously enhanced, driven by tissue plasminogen activator-mediated cleavage of plasminogen to form plasmin. The aim of this study was to investigate the cellular events and proteolytic responses that surround plasminogen activator inhibitor (PAI-1; Serpine1) inhibition of postoperative adhesion. Peritoneal adhesion was induced by gauze deposition in the abdominal cavity in C57BL/6 mice and those that were deficient in fibrinolytic factors, such as Plat-/- and Serpine1-/- In addition, C57BL/6 mice were treated with the novel PAI-1 inhibitor, TM5275. Some animals were treated with clodronate to deplete macrophages. Epidermal growth factor (EGF) experiments were performed to understand the role of macrophages and how EGF contributes to adhesion. In the early phase of adhesive small bowel obstruction, increased PAI-1 activity was observed in the peritoneal cavity. Genetic and pharmacologic PAI-1 inhibition prevented progression of adhesion and increased circulating plasmin. Whereas Serpine1-/- mice showed intra-abdominal bleeding, mice that were treated with TM5275 did not. Mechanistically, PAI-1, in combination with tissue plasminogen activator, served as a chemoattractant for macrophages that, in turn, secreted EGF and up-regulated the receptor, HER1, on peritoneal mesothelial cells, which led to PAI-1 secretion, further fueling the vicious cycle of impaired fibrinolysis at the adhesive site. Controlled inhibition of PAI-1 not only enhanced activation of the fibrinolytic system, but also prevented recruitment of EGF-secreting macrophages. Pharmacologic PAI-1 inhibition ameliorated adhesion formation in a macrophage-dependent manner.-Honjo, K., Munakata, S., Tashiro, Y., Salama, Y., Shimazu, H., Eiamboonsert, S., Dhahri, D., Ichimura, A., Dan, T., Miyata, T., Takeda, K., Sakamoto, K., Hattori, K., Heissig, B. Plasminogen activator inhibitor-1 regulates macrophage-dependent postoperative adhesion by enhancing EGF-HER1 signaling in mice.
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PMID:Plasminogen activator inhibitor-1 regulates macrophage-dependent postoperative adhesion by enhancing EGF-HER1 signaling in mice. 2827 May 19