Protease-nexin: A cellular component that links thrombin and plasminogen activator and mediates their binding to cells

Baker, Joffre B.; Low, David A.; Simmer, Robert L.; Cunningham, Dennis D.

doi:10.1016/0092-8674(80)90112-9

Cited by 421 publications

(298 citation statements)

References 24 publications

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“…Cultured human fibroblasts secrete protease-nexin, an inhibitor of Uk that forms SDS-resistant complexes with either Uk or thrombin (13). The reported Mr of Uk complexed with protease-nexin is comparable to that obtained with the monocyte-released ligand.…”

Section: The Uk Inhibitor Secreted By Monocytes-macrophages and U 937mentioning

confidence: 74%

“…Taken together, these data suggest the formation of a 1:1 Uk-ligand complex. The ligand does not react with thrombin, nor with plasmin (unpublished observations); thus it is different from protease-nexin, a protease inhibitor released by human fibroblasts that forms similar complexes with Uk and thrombin (13). A further characterization of the monocyte-macrophage inhibitor is under way: since the inhibitor can be detected amongst biosynthetically labeled products of U 937 cells, it must be synthesized during the culture; the currently available data allow it to be distinguished from all characterized inhibitors, with the possible exception of the fibrinolytic inhibitor originally described in human placenta (33,34).…”

Section: Discussionmentioning

confidence: 99%

“…These proteins were labeled using Iodogen as described (13), except that spun Sephadex G-50 columns (28) In addition, the increased levels of PA present in conditioned media from PMA (100 ng/ml)-or concanavalin A (10 ug/ml)-treated monocytes-macrophages and U 937 cells could be entirely accounted for by an increase in the production of the same enzyme. Thus, all the PA produced by monocytes-macrophages and U 937 cells is immunologically related to Uk, but not to TA.…”

Section: Methodsmentioning

confidence: 99%

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Concomitant secretion of prourokinase and of a plasminogen activator-specific inhibitor by cultured human monocytes-macrophages.

Vassalli¹,

Dayer²,

Wohlwend³

et al. 1984

The Journal of Experimental Medicine

410

195

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The plasminogen activator (PA) produced by freshly purified human monocytes-macrophages and histiocytic, lymphoma-derived U 937 cells was analyzed by zymography after sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and found to migrate with an apparent Mr of 55,000, identical to that of urokinase (Uk). By immunoprecipitation with antibodies specific for the two different types of PA, the enzyme was shown to be immunologically related to urokinase, and not to tissue PA. Urokinase was secreted in the form of the inactive Mr 55,000 zymogen prourokinase , and could be converted to the active Mr 55,000 enzyme by limited proteolysis with plasmin. Conditioned media from cultures of U 937 cells and monocytes-macrophages inhibited the fibrinolytic activity of exogenously added urokinase. Using [125I]-labeled urokinase we observed the formation of an enzyme-ligand complex, which was not dissociated by boiling in SDS and migrated with an apparent Mr 40,000 daltons higher than the free enzyme; since complexed urokinase was functionally inactivated as a PA, the ligand is an inhibitor of urokinase. This inhibitor is different from fibroblast-produced protease- nexin , in that it did not interact with thrombin. These results suggest that plasminogen activation by mononuclear phagocytes can be modulated through the secretion of both (pro)enzyme and a specific inhibitor.

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Section: The Uk Inhibitor Secreted By Monocytes-macrophages and U 937mentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Concomitant secretion of prourokinase and of a plasminogen activator-specific inhibitor by cultured human monocytes-macrophages.

Vassalli¹,

Dayer²,

Wohlwend³

et al. 1984

The Journal of Experimental Medicine

410

195

View full text Add to dashboard Cite

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“…Serpins form covalent complexes with their target protease(s), and they can therefore be revealed by a highly sensitive functional assay (Baker et al, 1980). Using radiolabelled uPA, we have detected high levels of a uPA ligand in extracts of adult mouse and rat seminal vesicles.…”

Section: Introductionmentioning

confidence: 97%

“…We have identified this ligand as protease nexin I (PN-I), a serpin released by human fibroblasts (Baker et al, 1980) and identical to glia-derived nexin (GDN) (Gloor et al, 1986;Sommer et al, 1987;McGrogan et al, 1988), first detected as a factor promoting neurite outgrowth in vitro (Guenther et al, 1985) that is found in different structures of the nervous system (Reinhard et al, 1988;Meier et al, 1989). PN-I reacts with and inhibits thrombin, uPA, tissuetype PA (tPA), trypsin and plasmin (Baker et al, 1980;Eaton and Baker, 1983;Guenther et al, 1985;Stone et al, 1987). In addition, we have shown that the abundance of PN-I protein and mnRNA in the mouse seminal vesicle is under androgen control.…”

Section: Introductionmentioning

confidence: 99%

Protease-nexin I as an androgen-dependent secretory product of the murine seminal vesicle.

et al. 1993

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A search for inhibitors of urokinase-type plasminogen activator (uPA) in the male and female murine genital tracts revealed high levels of a uPA ligand in the seminal vesicle. This ligand is functionally, biochemically and immunologically indistinguishable from protease-nexin I (PN-I), a serpin ligand of thrombin and uPA previously detected only in mesenchymal cells and astrocytes. A survey of murine tissues indicates that PN-I mRNA is most abundant in seminal vesicles, where it represents 0.2-0.4% of the mRNAs. PN-I is synthesized in the epithelium of the seminal vesicle, as determined by in situ hybridization, and is secreted in the lumen of the gland. PN-I levels are much lower in immature animals, and strongly decreased upon castration. Testosterone treatment of castrated males rapidly restores PN-I mRNA levels, indicating that PN-I gene expression is under androgen control.

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Developmental regulation of the serpin, protease nexin I, localization during activity-dependent polyneuronal synapse elimination in mouse skeletal muscle

et al. 1998

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During vertebrate neuromuscular development, all muscle fibers are transiently innervated by more than one neuron. Among the numerous factors shown to potentially influence the passage from poly- to mononeuronal innervation, serine proteases and their inhibitors appear to play important roles. In this regard, protease nexin I (PNI), a potent inhibitor of the serine protease, thrombin, is highly localized to the neuromuscular junction (NMJ). In turn, thrombin is responsible for activity-dependent synapse elimination both in an in vitro model, and in vivo. In the present study, we used a monospecific anti-PNI polyclonal antibody to study the developmental kinetics of PNI expression in mouse leg skeletal muscle. By using immunoblotting, we detected PNI at embryonic day 16 (E16), as a 48-kDa band. This 48-kDa PNI band became prominent in leg muscle extracts at postnatal day 5 (P5) and remained so in extracts from adult muscle. In contrast, a higher molecular weight immunoreactive PNI band, which was sodium dodecyl sulfate- and beta-mercaptoethanol-resistant, was first detected at E16, increased at birth (P0), and then decreased at P15, i.e., after the wave of polyneuronal synapse elimination had occurred in these muscles. The results of an enzyme-linked immunosorbent assay, measuring active, complexed, and truncated PNI, correlated with Western blot data. We used immunocytochemistry to probe the localization of PNI at the NMJ and found that PNI was present in the cytoplasm of myotubes at E16, but neither then nor at birth did it colocalize with acetylcholine receptors. PNI became localized at NMJs by P5 and increased by P15, after which it remained stably concentrated there in the adult. Finally, we studied the gene expression of PNI mRNA, by using Northern blotting, and showed that PNI mRNA was present in skeletal muscle and remained stable throughout the time-course studies, suggesting that developmental regulation of muscle PNI occurs principally at the translational and/or post-translational levels. These results suggest that the localization of PNI, through a binding site or "receptor" may play an important role in differentiation and maintenance of synapse.

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Protease-nexin: A cellular component that links thrombin and plasminogen activator and mediates their binding to cells

Cited by 421 publications

References 24 publications

Concomitant secretion of prourokinase and of a plasminogen activator-specific inhibitor by cultured human monocytes-macrophages.

Concomitant secretion of prourokinase and of a plasminogen activator-specific inhibitor by cultured human monocytes-macrophages.

Protease-nexin I as an androgen-dependent secretory product of the murine seminal vesicle.

Developmental regulation of the serpin, protease nexin I, localization during activity-dependent polyneuronal synapse elimination in mouse skeletal muscle

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