Activation of thrombin‐inactivated single‐chain urokinase‐type plasminogen activator by dipeptidyl peptidase I (cathepsin C)

Nauland, Uwe; Rijken, D.C.

doi:10.1111/j.1432-1033.1994.tb19018.x

Cited by 44 publications

(23 citation statements)

References 42 publications

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“…Furthermore, alveolar macrophage and mast cell derived CatC were seen to cleave extracellular matrix proteins such as fibronectin and collagen types I, III and IV, suggestive of a role of CatC in airway remodeling of chronic airway diseases such as asthma 12 . Finally, a contribution of CatC in coagulation as plasminogen 13 and thrombin regulator 14 and in angiogenesis have been documented 15 .…”

Section: Introductionmentioning

confidence: 99%

Leukocyte Cathepsin C Deficiency Attenuates Atherosclerotic Lesion Progression by Selective Tuning of Innate and Adaptive Immune Responses

Hérias

Biessen²,

Beckers³

et al. 2015

ATVB

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Objective The protein degrading activity of Cathepsin C, combined with its role in leukocyte granule activation, suggests a contribution of this cystein protease in atherosclerosis. However, no experimental data are available to validate this concept. Approach and results CatC gene and protein expression were increased in ruptured versus advanced stable human carotid artery lesions. To assess causal involvement of CatC in plaque progression and stability, we generated LDLr−/−//CatC−/− chimeras by bone marrow transplantation. CatC−/− chimeras presented attenuated plaque burden in carotids, descending aorta, aortic arch and root, at both the early and advanced plaque stage. CatC was abundantly expressed by plaque macrophages and foam cells. CatC expression and activity was dramatically downregulated in plaques of CatC−/− chimeras, supporting a hematopoietic origin of plaque CatC. Our studies unveiled an unexpected feedback of CatC deficiency on macrophage activation programs and T helper cell differentiation in as much as that CatC expression was upregulated in M1 macrophages, whereas its deficiency led to combined M2 (in vitro) and Th2 polarization (in vivo). Conclusions Our data implicate CatC has a role in the selective tuning of innate and adaptive immune responses, relevant to a chronic immune disease such as atherosclerosis.

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Section: Introductionmentioning

confidence: 99%

Leukocyte Cathepsin C Deficiency Attenuates Atherosclerotic Lesion Progression by Selective Tuning of Innate and Adaptive Immune Responses

Hérias

Biessen²,

Beckers³

et al. 2015

ATVB

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“…After washing 50 µl of the PF were added to the wells containing 50 µl of HEPES (20 mM) buffered saline, pH 7.4 (HBS), and incubated for 18 hours at 4°C. The plates were washed three times with HBS and wells intended for uPAt determination were treated with of Cathepsin C [20 nM in a phosphate (50 mM) buffer pH 6.0, supplemented with NaCl (100 mM), EDTA (2 mM), and L-cysteine (10 mM)] for 30 min at 37°C to reactivate uPAt [21]. The plate was next washed and incubated with PLG (10 µg/ml, 100 µl/well) for 2 hours at 37°C.…”

Section: Determination Of Upat In Patient and Rabbit Pfmentioning

confidence: 99%

Thrombin–thrombomodulin inhibits prourokinase-mediated pleural mesothelial cell-dependent fibrinolysis

Iakhiaev

Nalian

Koenig

et al. 2007

Thrombosis Research

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SummaryFibrin deposition is a hallmark of pleural inflammation and loculation but understanding of mechanisms by which mesothelial cells regulate intrapleural fibrinolysins remains incomplete. We speculated that pleural mesothelial cells regulate local fibrinolytic capacity via processing of single chain urokinase type plasminogen activator (scuPA). Pretreatment of human pleural mesothelial (MeT-5A) cells with TGF-β or thrombin, either alone or in combination, inhibited urokinase (uPA)-mediated fibrinolysis by MeT-5A. Thrombin, unlike TGF-β, inhibited fibrinolysis without induction of PAI-1, suggesting that thrombin-mediated cleavage of scuPA inhibits the fibrinolytic capacity of MeT-5A cells. Thrombin cleaves both purified scuPA as well as that secreted by MeT-5A cells and cell surface thrombomodulin accelerates thrombin-mediated cleavage of scuPA to inhibit cellular fibrinolytic activity. Molecular dynamics analyses demonstrated that thrombin-cleaved scuPA (uPAt) do not acquire a catalytically active conformation and that secondary plasminogen binding sites of uPA implicated in plasminogen activation are distorted in uPAt, explaining, at least in part, why uPAt is a poor enzyme. uPAt was detectable in transudative and exudative pleural effusions from patients. Intrapleural administration of scuPA generated increased levels of uPAt in PF of rabbits with pleural injury and loculation induced by tetracycline in vivo. This pathway is operative in diverse forms of pleural injury, restricts the urokinase-dependent fibrinolytic capacity of pleural mesothelial cells and contributes to local control of fibrinolytic activity via processing of endogenous or exogenous scuPA within the pleural compartment. Keywords fibrinolysis; single chain urokinase type plasminogen activator (scuPA); thrombin; thrombomodulin Fibrin deposition in the pleural space is a hallmark of inflammatory pleural disease [1,2]. Fibrin is deposited as a result of excessive activation of coagulation and insufficient fibrinolysis. Under physiological conditions, coagulation and fibrinolysis are precisely regulated and molecular links between these systems permit timely removal of ongoing or acutely induced fibrin deposits [3,4]. The major fibrinolytic protease -plasmin, is generated by activation of plasminogen (PLG) by both tissue type PLG activator (tPA) as well as by urokinase (uPA) [5,6,7]. Plasmin cleaves both tPA and uPA, transforming them from single chain forms to more Please address all correspondence to: Alexei Iakhiaev Ph.D., Assistant Professor of Biochemistry, The University of Texas Health Center at Tyler, 11937 US HWY 271, Tyler, TX 75708, Telephone: (903) FAX: (903) 877-5627, Email: alexei.iakhiaev@uthct.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable for...

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“…Nerve growth factor-, another serine protease, can also cleave pro-uPA at the plasmin cleavage site and activate pro-uPA to uPA in solution and on the cell surface (Wolf et al, 1993). uPA/Tis relatively resistant Brought to you by | The University of Auckland Library Authenticated Download Date | 5/27/15 5:47 AM to activation by plasmin (Gurewich and Pannell, 1987;Lijnen et al, 1987) but can be activated by cathepsin C (Nauland and Rijken, 1994). uPA/Tis relatively resistant Brought to you by | The University of Auckland Library Authenticated Download Date | 5/27/15 5:47 AM to activation by plasmin (Gurewich and Pannell, 1987;Lijnen et al, 1987) but can be activated by cathepsin C (Nauland and Rijken, 1994).…”

Section: Urokinase (Upa)mentioning

confidence: 99%

Review

1995

Biological Chemistry Hoppe-Seyler

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Keratinocytes are the major cellular constituent of stratified epithelia. Defects in these epithelia are reepithelialized by keratinocytes migrating from the edge of the defect into the wound. The cells form a monolayer with subsequent differentiation into a multilayered epithelium. It is thought that plasminogen activation by migrating keratinocytes is an important event during re-epithelialization. In the present report we summarize the studies on plasminogen activation by human keratinocytes in vitro and in vivo. Under the aspect of pericellular proteolysis the discussion is focused on the molecular mechanisms of plasminogen activation at the keratinocyte surface and on the cell-biological consequences of pericellular plasmin formation. We describe a cell surfaceassociated pathway of plasminogen activation which crucially depends on cell surface receptors for (pro)-uPA and plasmin(ogen). uPA bound to its receptor converts cell-bound plasminogen into the active protease plasmin. Compared to plasminogen activation in solution, activation at the keratinocyte cell surface is accelerated by a factor of approx. 7-10, and the plasmin generated and bound at the cell surface is protected against its specific inhibitor a 2 -antiplasmin. Plasmin thus provided in the pericellular space leads to detachment of cultured keratinocytes from the growth substratum. Plasmin interferes with the adhesion of keratinocytes to fibrin, but not with the adhesion to collagen type I. By demonstrating that keratinocytes of the epithelial outgrowth in healing skin wounds express uPA and the uPA-R and that plasmin(ogen) is colocalized with uPA and/or uPA-R, indirect evidence is provided that this pathway may be operative in vivo. In view of previous findings that plasminogen activation is also observed under certain pathologic conditions in the epidermis, we conclude that plasminogen activation by keratinocytes is rather related to tissue damage and subsequent repair mechanisms than to a specific pathologic situation.The urokinase-type plasminogen activator (uPA) is secreted as a single-chain inactive zymogen (pro-uPA). Upon its secretion, pro-uPA binds to its glycosylphosphatidylinositol-anchored specific cell receptor (uPAR). The activation of pro-uPA to the active twochain uPA is accelerated with uPAR-bound pro-uPA and is achieved by plasmin and proteases of other classes like cathepsins G and L. uPAR-bound uPA is susceptible to inhibition by its specific inhibitors (PAI-1, PAI-2, and PN-1). uPA-PAM and uPA-PN-1 complexes, but not free uPA, are readily internalized and degraded through a mechanism that involves the multiligand receptors u 2 -macroglobulin receptor/low density lipoprotein receptor-associated protein (a 2 -MR) and epithelial glycoprotein 330 (gp330). Upon uPA-inhibitor internalization, uPAR is itself endocytosed and recycled back to the cell surface. PMA-induced differentiation of myeloid cells is accompanied by inhibition of uPA-PAI-1 internalization/degradation and the down-regulation of

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Activation of thrombin‐inactivated single‐chain urokinase‐type plasminogen activator by dipeptidyl peptidase I (cathepsin C)

Cited by 44 publications

References 42 publications

Leukocyte Cathepsin C Deficiency Attenuates Atherosclerotic Lesion Progression by Selective Tuning of Innate and Adaptive Immune Responses

Leukocyte Cathepsin C Deficiency Attenuates Atherosclerotic Lesion Progression by Selective Tuning of Innate and Adaptive Immune Responses

Thrombin–thrombomodulin inhibits prourokinase-mediated pleural mesothelial cell-dependent fibrinolysis

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