Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.6 (thromboplastin)
 13,278 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mitogenesis, cell differentiation and immune-inflammatory responses are regulated by the coordinated assembly of proteases with specific cellular receptors. We have investigated the possibility that immune effector cells may express a high-affinity protease receptor. To address this hypothesis, we have generated mAb to factor V and its activated form Va, a circulating plasma protein that binds the serine protease of the coagulation cascade, factor Xa. Further, by flow microfluorimetry screening, we have isolated a panel of these mAb that recognize a surface molecule expressed on transformed monocytic cells. We now show that these mAb bind to blood monocytes, to CD3- CD16+ CD56+ NK cells, and with considerable heterogeneity, to neutrophils. A small subset of CD3+ cells (5 to 10%) was also identified by these probes and further phenotypically characterized by two-color flow microfluorimetry as predominantly coexpressing CD2, CD4 or CD8, CD57, CD11b, and alpha/beta TCR. This subset of CD3+ cells was expanded in vitro by both lectin- or Ag-specific stimulation. In addition, long term alloreactive stimulation resulted in approximately 8- to 10-fold increased expression of the molecule recognized by these mAb. Functional analyses were performed on a selected T cell clonal derivative of the transformed cell line HuT 78. These cells bound 125I-factor Xa in a specific reaction saturated at 194,000 +/- 26,000 molecules/cell with a Kd approximately 10 to 20 nM and inhibited by the mAb panel described above. These data suggest that immune effector cells express a dynamically regulated protease receptor that is immunologically related to the plasma coagulation protein factor V and its activated form Va. We propose the term effector cell protease receptor-1 to tentatively identify this molecule, and we speculate on its possible involvement in specialized protease-mediated effector functions.
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PMID:Identification of effector cell protease receptor-1. A leukocyte-distributed receptor for the serine protease factor Xa. 216 87

The alpha subunits of the leukocyte CD11/CD18 integrins contain an approximately 200 amino acid 'inserted' or I domain. The I domain of the cell-surface Mac-1 (CD11b/CD18) integrin has been shown to be the major recognition site for several adhesion ligands, including iC3b, fibrinogen, factor X, and ICAM-1. The I domain from the Mac-1 alpha subunit has been expressed in Escherichia coli as a soluble GST-fusion protein containing a factor Xa sensitive cleavage site. Analytical characterization of the purified I domain reveals that it is obtained in very high quality at high yields. CD and NMR spectra indicate that I domain adopts a predominantly folded structure in solution, independent of the remainder of the alpha subunit. Addition of Ca2+ and Mg2+ did not significantly perturb the structural conformation.
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PMID:Purification and structural characterization of the CD11b/CD18 integrin alpha subunit I domain reveals a folded conformation in solution. 764 57

Myocardial infarct size has been measured after 1 hr of mechanical occlusion of the circumflex coronary artery and 5 hr of reperfusion in control dogs infused with saline, and in dogs infused with activated protein C (aPC) (1mg/kg/hr i.v.). Infusion of aPC during reperfusion produced a sustained doubling of activated partial thromboplastin time and no change in thrombin time at a final plasma parent drug concentration of 1.25 +/- 0.11 mug/ml. aPC infusion did not alter systolic arterial pressure, cardiac rate or the rate pressure product when compared to time-related alterations observed in control dogs. ST-segment deviation and the intensity and duration of cardiac arrhythmias associated with reperfusion of ischemic myocardium also were similar between groups. Resultant infarct sizes were 34.8 +/- 3.9 and 33.2 +/- 6.2% of the left ventricular mass placed at risk of necrosis in control and aPC-treated dogs. respectively. aPC infusion was associated with a small reduction in leukocytosis in response to myocardial ischemic injury, but did not alter the localization of leukocytes within ischemic and infarcted myocardium. In vitro concentrations of aPC (0.3, 1 and 3 mug/ml), comparable to the plasma concentration that inhibited blood coagulation in dogs, did not alter superoxide production or CD11b/CD18-mediated adhesion of chemotactic factor f-Met-Leu-Phe-stimulated neutrophils. Present data indicate that aPC lacks cardioprotectant activity at an infusion rate inhibiting coagulation. Apart from inhibition of thrombin generation, no evidence of an anti-inflammatory effect of aPC was observed.
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PMID:Evaluation of activated protein C on canine infarct size in a nonthrombotic model of myocardial reperfusion injury. 878 41

Leucocyte initiation of coagulation preserves the haemostatic balance and may aberrantly contribute to vascular injury. In addition to the extrinsic activation mediated by tissue factor: factor VIIa, monocytes express an alternative procoagulant response after binding of the zymogen factor X to the integrin Mac-1 (CD11b/CD18). Here, factor X-activating activity was found in purified monocyte granules, and coincided with size-chromatographed fractions containing cathepsin G. In contrast, elastase-containing granule fractions did not activate factor X. In the presence of Ca2+ ions, purified cathepsin G, but not elastase, cleaved factor X to a approximately 54 kDa catalytically active derivative, structurally indistinguishable from the procoagulant product generated on monocytes after binding to Mac-1. Factor X activation by purified cathepsin G involved limited proteolysis of a novel Leu177-Leu178 peptide bond in the zymogen's activation peptide. Cathepsin G activation of factor X was completely inhibited by alpha 1 antichymotrypsin, or soybean trypsin inhibitor, or by a neutralizing antiserum to cathepsin G, while eglin, or an anti-elastase antibody, were ineffective. Affinity chromatography on active-site-dependent inhibitors Glu-Gly-Arg-chloromethyl ketone or benzamidine completely abolished factor Xa activity generated by cathepsin G. Cathepsin G was not constitutively detected on the monocyte surface by flow cytometry. However, inflammatory stimuli, including formyl peptide or phorbol ester, or Mac-1 engagement with its ligands fibrinogen, factor X or serum-opsonized zymosan, triggered monocyte degranulation and cathepsin G activation of factor X. These findings demonstrate that monocytes can alternatively initiate coagulation in a sequential three-step cascade, including (i) binding of factor X to Mac-1, (ii) discharge of azurophil granules, and (iii) limited proteolytic activation of membranebound factor X by cathepsin G. By rapidly forming thrombin and factor Xa in a protected membrane microenvironment, this pathway may contribute a "priming' signal for clotting, anticoagulation and vascular cell signal transduction, in vivo.
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PMID:Activation of Mac-1 (CD11b/CD18)-bound factor X by released cathepsin G defines an alternative pathway of leucocyte initiation of coagulation. 892 Sep 93

In this study, heparin-like poly(ethersulfone) (HLPES) was synthesized by a combination of polycondensation and post-carboxylation methods, and was characterized by Fourier transform infrared spectroscopy, nuclear magnetic resonance hydrogen spectrum and gel permeation chromatography. Owing to the similar backbone structure, the synthesized HLPES could be directly blended with pristine PES at any ratios to prepare PES/HLPES membranes. After the introduction of HLPES, the microscopic structure of the modified PES membranes was changed, while the hydrophilicity was significantly enhanced. Bovine serum albumin and bovine serum fibrinogen adsorption, activated partial thromboplastin time, thromb time and platelet adhesion for the modified PES membranes were investigated. The results indicated that the blood compatibility of the PES/HLPES membranes was significantly improved compared with that of pristine PES membrane. For the PES/HLPES membranes, obvious decreases in platelet activation on PF-4 level, in complement activation on C3a and C5a levels, and in leukocytes activation on CD11b levels were observed compared with those for the pristine PES membrane. The improved blood compatibility of the PES/HLPES membrane might due to the existence of the hydrophilic groups (-SO3Na, -COONa). Furthermore, the modified PES membranes showed good cytocompatibility. Hepatocytes cultured on the PES/HLPES membranes presented improved growth in terms of SEM observation, MTT assay and confocal laser scanning microscope observation compared with those on the pristine PES membrane. These results indicate that the PES/HLPES membranes present great potential in blood-contact fields such as hemodialysis and bio-artificial liver supports.
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PMID:Direct synthesis of heparin-like poly(ether sulfone) polymer and its blood compatibility. 2387 43