Tissue factor pathway inhibitor 2 is a potent kallikrein-related protease 12 inhibitor

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Marion Lavergne ◽  
Audrey Guillon-Munos ◽  
Woodys Lenga Ma Bonda ◽  
Sylvie Attucci ◽  
Thomas Kryza ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Tissue Factor ◽  
Cancer Progression ◽  
Serine Proteases ◽  
Tissue Factor Pathway Inhibitor ◽  
Potent Inhibitor ◽  
Matrix Metalloproteases ◽  
Lung Tumour ◽  
Matrix Remodeling ◽  
Tissue Factor Pathway

Abstract The protease activities are tightly regulated by inhibitors and dysregulation contribute to pathological processes such as cancer and inflammatory disorders. Tissue factor pathway inhibitor 2 (TFPI-2) is a serine proteases inhibitor, that mainly inhibits plasmin. This protease activated matrix metalloproteases (MMPs) and degraded extracellular matrix. Other serine proteases are implicated in these mechanisms like kallikreins (KLKs). In this study, we identified for the first time that TFPI-2 is a potent inhibitor of KLK5 and 12. Computer modeling showed that the first Kunitz domain of TFPI-2 could interact with residues of KLK12 near the catalytic triad. Furthermore, like plasmin, KLK12 was able to activate proMMP-1 and -3, with no effect on proMMP-9. Thus, the inhibition of KLK12 by TFPI-2 greatly reduced the cascade activation of these MMPs and the cleavage of cysteine-rich 61, a matrix signaling protein. Moreover, when TFPI-2 bound to extracellular matrix, its classical localisation, the KLK12 inhibition was retained. Finally, TFPI-2 was downregulated in human non-small-cell lung tumour tissue as compared with non-affected lung tissue. These data suggest that TFPI-2 is a potent inhibitor of KLK12 and could regulate matrix remodeling and cancer progression mediated by KLK12.

scholarly journals Tissue Factor Pathway Inhibitor-1 Is a Valuable Marker for the Prediction of Deep Venous Thrombosis and Tumor Metastasis in Patients with Lung Cancer

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
Xianming Fei ◽  
Huan Wang ◽  
Wufeng Yuan ◽  
Mingyi Wo ◽  
Lei Jiang
Keyword(s):  
Lung Cancer ◽  
Venous Thrombosis ◽  
Deep Venous Thrombosis ◽  
Tissue Factor ◽  
Cancer Progression ◽  
Tumor Metastasis ◽  
Tissue Factor Pathway Inhibitor ◽  
Thrombotic Complication ◽  
Tissue Factor Pathway ◽  
Nsclc Patients

Activation of blood coagulation contributes to cancer progression. Tissue factor pathway inhibitor-1 (TFPI-1) is the main inhibitor of extrinsic coagulation pathway. The aim of this study is to assess the predicting significance of TFPI-1 for thrombotic complication and metastasis in lung cancer patients. Total of 188 non-small cell lung cancer (NSCLC) patients were included in this study. Plasma TFPI-1, D-dimer (D-D), antithrombin (AT), Fibrinogen (Fbg), and coagulating factor VIII activity (FVIII:C) were measured. In NSCLC patients, significantly decreased TFPI-1 and AT and increased D-D, Fbg, and FVIII:C levels were observed, and there was a significant correlation between TFPI-1 and other hemostatic parameters (P<0.001, resp.). NSCLC patients with deep venous thrombosis (DVT) or metastasis had significantly lower TFPI-1 levels than those without DVT or metastasis (P<0.01, resp.). Multivariate regression revealed that TFPI-1 acted as a predictor for DVT or tumor metastasis in NSCLC patients [OR: 4.15 or 3.28,P<0.05, resp.]. The area under ROC curve of TFPI-1 was 0.905 (95% CI, 0.842~0.967) or 0.828 (95% CI, 0.742~0.915) for predicting DVT or metastasis (P<0.001, resp.). The optimal point of TFPI-1 was 57.7 or 54.3 ng/mL for predicting DVT or metastasis, respectively. Combination of TFPI-1 and D-D measurements can improve the predicting power for DVT or metastasis in NSCLC patients. Our findings suggested that TFPI-1 was a valuable predictor of DVT and tumor metastasis in NSCLC patients.

scholarly journals Major Reservoir for Heparin-Releasable TFPIα (Tissue Factor Pathway Inhibitor α) Is Extracellular Matrix

2021 ◽  
Author(s):  
Julie A. Peterson ◽  
Susan A. Maroney ◽  
Nicholas D. Martinez ◽  
Alan E. Mast
Keyword(s):  
Extracellular Matrix ◽  
Endothelial Cells ◽  
Cell Surface ◽  
Tissue Factor ◽  
Tissue Factor Pathway Inhibitor ◽  
Umbilical Vein ◽  
Human Kidney ◽  
Laminin 5 ◽  
C Terminus ◽  
Tissue Factor Pathway

Objective: Human endothelial cells produce 2 alternatively spliced TFPI (tissue factor pathway inhibitor) isoforms that maintain anticoagulant properties of the vasculature. TFPIβ is glycosylphosphatidylinositol anchored on the cell surface. TFPIα has a basic C terminus sharing homology with VEGF (vascular endothelial growth factor) and is a heparin-releasable protein, suggesting it binds glycosaminoglycans on the endothelium surface. However, this is unclear because TFPIα is not on the surface of cultured endothelial cells. This study identifies the source of heparin-releasable TFPIα. Approach and Results: ELISA assays localized heparin-releasable TFPIα to the extracellular matrix (ECM) of Ea.hy926 cells and human umbilical vein endothelial cells. Immunofluorescence microscopy for TFPIα showed punctate intracytoplasmic staining and ECM staining beneath individual cells. Flow cytometry identified TFPIβ but not TFPIα on the cell surface. TFPIα localization to ECM was confirmed with ELISA and immunohistochemistry studies of umbilical cord veins. The TFPIα C terminus interacted with Ea.hy926 ECM glycosaminoglycans, and a homologous VEGF peptide competed for this binding, suggesting these interactions modulate VEGF responses. Immobilized TFPIα C-terminal peptide bound to several ECM proteoglycans in Ea.hy926 conditioned media. Immunofluorescence studies of human kidney colocalized TFPIα with 4 of these proteoglycans surrounding the microvasculature: glypican-1, syndecan-4, thrombospondin, and laminin-5. The absence of TFPIα on the surface of endothelial cells and its co-localization with specific ECM proteins suggests TFPIα binds to unique proteoglycan structures. Conclusions: ECM contained the primary vascular pool of heparin-releasable TFPIα. By localizing to ECM, TFPIα is positioned to inhibit the procoagulant activity of tissue factor surrounding the vasculature.

Tissue Factor Pathway Inhibitor is a Potent Inhibitor of Plasmin

1998 ◽  
Vol 4 (2) ◽  
pp. 114-117 ◽  
Author(s):  
Rainer J. Klauser ◽  
Debra Hoppensteadt ◽  
Jawed Fareed
Keyword(s):  
Tissue Factor ◽  
Tissue Factor Pathway Inhibitor ◽  
Potent Inhibitor ◽  
Plasma Kallikrein ◽  
Amidolytic Activity ◽  
Lysis Time ◽  
Tissue Plasminogen ◽  
Factor Xiia ◽  
Euglobulin Lysis Time ◽  
Tissue Factor Pathway

Recombinant tissue factor pathway inhibitor (TFPI) was found to be a potent inhibitor of plasmin. In an amidolytic assay the inhibition constant K i was found to be 2.86 x 10-8 M. TFPI in the same concentration range also inhibited the activation of plasminogen by tissue plasminogen activator (tPA). The amidolytic activity of tPA was not inhib ited by TFPI. Other proteinases relevant to fibrinolysis such as urokinase, α-factor XIIa, and β-factor XIIa were not inhibited by TFPI. Plasma kallikrein was weakly inhibited by TFPI. When added to plasma, TFPI also prolonged the euglobulin lysis time. The interaction of TFPI with heparin and a muco polysaccharide polysulfuric ester, a heparin-like glycosamino glycan, was studied. Heparin augmented plasmin inhibition by TFPI, while mucopolysaccharide polysulfuric ester had no ef fect. Key Words: Tissue factor pathway inhibitor (TFPI)— Plasmin—Inhibition—Fibrinolysis.

Proteases in blood clotting

2002 ◽  
Vol 38 ◽  
pp. 95-111 ◽  
Author(s):  
Peter N Walsh ◽  
Syed S Ahmad
Keyword(s):  
Tissue Factor ◽  
Blood Coagulation ◽  
Serine Proteases ◽  
Tissue Factor Pathway Inhibitor ◽  
Factor Viia ◽  
Cell Receptor ◽  
Factor Ix ◽  
Factor X ◽  
Sequence Of Events ◽  
Tissue Factor Pathway

The serine proteases, cofactors and cell-receptor molecules that comprise the haemostatic mechanism are highly conserved modular proteins that have evolved to participate in biochemical reactions in blood coagulation, anticoagulation and fibrinolysis. Blood coagulation is initiated by exposure of tissue factor, which forms a complex with factor VIIa and factor X, which results in the generation of small quantities of thrombin and is rapidly shutdown by the tissue factor pathway inhibitor. The generation of these small quantities of thrombin then activates factor XI, resulting in a sequence of events that lead to the activation of factor IX, factor X and prothrombin. Sufficient thrombin is generated to effect normal haemostasis by converting fibrinogen into fibrin. The anticoagulant pathways that regulate blood coagulation include the protein C anticoagulant mechanism, the serine protease inhibitors in plasma, and the Kunitz-like inhibitors, tissue factor pathway inhibitor and protease nexin 2. Finally, the fibrinolytic mechanism that comprises the activation of plasminogen into plasmin prevents excessive fibrin accumulation by promoting local dissolution of thrombi and promoting wound healing by reestablishment of blood flow.

Modulation of tissue factor and tissue factor pathway inhibitor-1 by neutrophil proteases

2008 ◽  
Vol 100 (12) ◽  
pp. 1068-1075 ◽  
Author(s):  
Birgit A. Steppich ◽  
Isabell Seitz ◽  
Gabi Busch ◽  
Andreas Stein ◽  
Ilka Ott
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Tissue Factor ◽  
Serine Proteases ◽  
Tissue Factor Pathway Inhibitor ◽  
Cell Damage ◽  
Umbilical Vein ◽  
Neutrophil Activation ◽  
Cathepsin G ◽  
Tissue Factor Pathway

SummaryDuring systemic inflammation, neutrophil activation is accompanied by endothelial cell damage and hypercoagulability. Activated neutrophils release serine proteases that participate in tissue injury.We sought to investigate the effects of neutrophil proteases on proinflammatory and procoagulant changes in endothelial cells.The effects of elastase (HNE), cathepsin G (CG), and proteinase 3 (PR3) on expression of tissue factor (TF) and tissue factor pathway inhibitor-1 (TFPI) were examined in human umbilical vein endothelial cells. Flow cytometry demonstrated that these proteases proteolytically degraded endothelial cell-bound TFPI. TFPI mRNA expression was reduced by HNE and CG. PR3, but not HNE or CG, increased surface expression of TF and TF mRNA.Yet, increased TF expression did not enhance TF activity suggesting induction of encrypted TF. Using antibodies and siRNA to inhibit and silence PAR-1 and PAR-2, we observed that PR3 upregulation of TF is at least in part mediated by PAR-1.Although CG and HNE cleaved PAR-1, antibody reactivity to the PAR-1 hirudin-like sequence demonstrated inactivating cleavage, accounting for the selective ability of PR3 to induce PAR-1-mediated procoagulant effects.This was supported by induction of p42/44 MAPK by PR3. In conclusion, PR3 degradation of TFPI increases the procoagulant activity of endothelial cells. Release of PR3 after neutrophil activation may represent an important step in neutrophil-mediated vascular injury.

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