Elastase released from human granulocytes stimulated with <i>N</i>‐formyl‐chemotactic peptide prevents activation of tumor cell prourokinase (pro‐uPA)

Kanayama, Naohiro; Henschen, Agnes; Hollrieder, A.; Hafter, R.; Gulba, Dietrich C.; Jänicke, F.; Graeff, H.

doi:10.1016/0014-5793(89)81065-8

Cited by 33 publications

(18 citation statements)

References 21 publications

(34 reference statements)

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“…In addition, uPA complexes with PAI-I or -2, or complexes with the uPA-receptor were detected. Exposure of uPA to various proteases did not affect the determination (Schmitt et al, 1989).…”

Section: Laboratory Assaymentioning

confidence: 85%

Urokinase and macrophages in tumour angiogenesis

Hildenbrand

Dilger²,

Hörlin³

et al. 1995

Br J Cancer

109

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Summary Recent studies have shown that elevated levels of urokinase plasminogen activator (uPA) and plasminogen activator inhibitor 1 (PAI-1) in breast cancer correlate with an increased risk of a reduced relapse-free survival time and shortened overall survival times. Urokinase PA and PAI-I are independent prognostic indicators for breast cancer (Goldfarb and Liotta, 1986). Among the diverse extracellular proteolytic enzymes produced by tumours, urokinase plasminogen activator (uPA) is considered to play a pivotal role in tissue invasion, vascular invasion and formation of metastases (Dano et al., 1985).Tumour cells synthesise and secrete uPA as an inactive proenzyme (pro-uPA) (Stump, 1986), which binds to specific receptors on the cell surface (Vasalli et al., 1985). After binding, pro-uPA is activated by cathepsin B or plasmin (Kobayashi et al., 1990). Receptor-bound active uPA converts plasminogen to plasmin. Subsequently, plasmin is also bound to a different receptor on the tumour cell surface (Miles and Plow, 1988). Plasmin then degrades components of the stroma (e.g. fibrin, fibronectin, proteoglycans, laminin), and may activate procollagenase type IV, which then degrades collagen type IV, a major part of the basement membrane (Dvorak, 1986). Thus uPA promotes the dissolution of the tumour matrix and the basement membrane, which is a prerequisite for invasion and metastases. This implies that the proteolytic activity of uPA also causes a degradation of vessel walls. Vessel wall dissolution is one of the first steps in neovascularisation (Mahadevan and Hart, 1990). Furthermore, some ECM molecules become angiogenic after hydrolytic degradation (West et al., 1985

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“…In addition, uPA complexes with PAI-I or -2, or complexes with the uPA-receptor were detected. Exposure of uPA to various proteases did not affect the determination (Schmitt et al, 1989).…”

Section: Laboratory Assaymentioning

confidence: 85%

Urokinase and macrophages in tumour angiogenesis

Hildenbrand

Dilger²,

Hörlin³

et al. 1995

Br J Cancer

109

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“…The central molecule in the surface pathway for plasminogen activation appears to be the uPA receptor (Vassalli, et al, 1985;Blasi et al, 1987;Estreicher et al, 1989 SD<20% in all samples; cP<0.05; dp < 0.O l. Pannell, 1987;Schmitt et al, 1989;Schmitt et al, 1991;Kobayashi et al, 1991;Goretzki et al, 1992). Receptorbound pro-uPA can be converted to the two-chain form of uPA-molecule, or alternatively can first be activated by plasmin or cathepsin B and then bind to the uPA receptor Kobayashi et al, 1991).…”

Section: Discussionmentioning

confidence: 99%

“…N-terminal amino acid sequence determination and amino acid analysis The proteinase-mediated cleavage site in pro-uPA was determined by N-terminal amino acid sequence analysis (Schmitt et al, 1989). Separated uPA polypeptides were subjected to six Edman degradation cycles.…”

Section: Methodsmentioning

confidence: 99%

Saturation of tumour cell surface receptors for urokinase-type plasminogen activator by amino-terminal fragment and subsequent effect on reconstituted basement membranes invasion

Kobayashi

Ohi²,

Shinohara³

et al. 1993

Br J Cancer

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Single-chain urokinase-type plasminogen activator (pro-uPA) is bound to a specific surface receptor on ovarian cancer HOC-I cells that is incompletely saturated. Saturation of uncovered receptors by uPA polypeptides with intact amino-terminal fragment (ATF) derived from pro-uPA by limited proteolysis (human leucocyte elastase [HLE] or V8 protease) has been studied. HOC-I cells preferentially invaded reconstituted basement membranes in a time- and plasminogen-dependent manner. This process was inhibitable by preincubation with uPA polypeptides in the medium at levels which suggested that complete saturation of cell surface uPA receptors occurred. This result indicates that occupation of uPA receptors by enzymatically inactive uPA fragments or prevention of rebinding of pro-uPA synthesised by tumour cells to the receptors specifically reduces the invasion of the tumour cells through basement membranes in vitro. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 6

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“…Proteinases have been found to either activate or inactivate [9,11,20,21,28, 291 scu-PA. Whereas the activation occurs by cleavage of the molecule between Lys158-Ile159, the inactivation occurs either at one amino acid after the activation site by cleavage of Ile159-Ile160 (e.g., by elastase [28] or by cathepsin G [ll]) or two amino acids before the activation site by cleavage of Arg156-Phe157 (e.g., by thrombin [9]).…”

Section: Discussionmentioning

confidence: 99%

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

Nauland¹,

Rijken²

1994

European Journal of Biochemistry

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Single-chain urokinase-type plasminogen activator (scu-PA) is inactivated by thrombin, which cleaves the peptide bond between Arg156 and Phe157. In a search for potential activators of thrombin-cleaved two-chain urokinase-type plasminogen activator (tcu-PA/T), we found that the lysosoma1 aminopeptidase dipeptidyl-peptidase I or cathepsin C efficiently activates tcu-PA/T. Cathepsin C was as active towards tcu-PA/T as the bacterial proteinase thermolysin and about 300-times more active than plasmin. The activation by cathepsin C proceeded in a concentration-dependent and time-dependent manner with a pH optimum between 5 and 7. Furthermore, the effect of cathepsin C was inhibited by cystatin and stimulated by cysteine, typical for the action of a thiol proteinase. As no degradation of the tcu-PA/T molecule by cathepsin C was visible on SDS/PAGE, we suggest that activation of tcu-PA/T occurs by cleavage between Lys158-Ile159 and removal of the two Nterminal amino acid residues (Phe157-Lys158) of the B chain of tcu-PA/T. We conclude that both thrombin and dipeptidyl-peptidases like cathepsin C might play a regulatory role in the plasminogenplasmin system by inactivating scu-PA and activating tcu-PA/T, respectively.Single-chain urohnase-type plasminogen activator (scu-PA) or pro-urokinase is the precursor of two-chain urokinasetype plasminogen activator (tcu-PA; for review see [l]). scu-PA seems to have little or no intrinsic plasminogen-activator activity [2 -51. In contrast, tcu-PA efficiently converts plasminogen into the active serine proteinase plasmin, which plays a key role in extracellular proteolysis, including fibrinolysis.Activation of scu-PA to tcu-PA occurs by cleavage of a thermolysin, a bacterial proteinase was found to activate both tcu-PA/T and scu-PA with about the same efficiency [17].In the present study we were interested to discover if there was any physiological enzyme which was able to activate tcu-PNT. As a possible candidate for removing the two N-terminal amino acid residues (Phe157-Lys158) from the B-chain of tcu-PA/T we studied the effect of the thiol proteinase dipeptidyl-peptidase I (DPP I) also called cathepsin C [16, 18, 191. Thrombin does not activate scu-PA, but cleaves the protein two residues before the activation site at Argl56-Phe157 [9], resulting in an apparently inactive tcu-PA [9, 20, 211. The action of thrombin on scu-PA is accelerated by thrombomodulin [22, 231, and recently we found evidence for the occurrence of thrombin-cleaved tcu-PA (tcu-PA/T) in plasma, in synovial fluid and in peritoneal fluid [24]. It has been shown that tcu-PA/T can still be activated by plasmin, but about 500-times less efficiently than scu-PA [25]. Recently scu-PA from a transformed human kidney cell line (specific activity: 144000 U/mg; 99.3% zymogen) was kindly provided by Dr F. Hammerschmid, Sandoz (Vienna, Austria). Plasmin and 5-oxoprolyl-Gly-Arg-p-nitroanilide (S-2444) were purchased from Kabi AB. Hirudin was from Pentapharm and aprotinin (TrasylolR) was from Bayer AG. Thermolysin, cathe...

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Elastase released from human granulocytes stimulated with N‐formyl‐chemotactic peptide prevents activation of tumor cell prourokinase (pro‐uPA)

Cited by 33 publications

References 21 publications

Urokinase and macrophages in tumour angiogenesis

Urokinase and macrophages in tumour angiogenesis

Saturation of tumour cell surface receptors for urokinase-type plasminogen activator by amino-terminal fragment and subsequent effect on reconstituted basement membranes invasion

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

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