Plasminogen-Independent Initiation of the Pro-urokinase Activation Cascade in Vivo. Activation of Pro-urokinase by Glandular Kallikrein (mGK-6) in Plasminogen-Deficient Mice
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- 作者：Karin List ; Ole N. Jensen ; Thomas H. Bugge ; Leif R. Lund ; Michael Ploug ; Keld Dan
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- 刊名：Biochemistry
- 出版年：2000
- 出版时间：January 25, 2000
- 年：2000
- 卷：39
- 期：3
- 页码：508 - 515
- 全文大小：125K
- 年卷期：v.39,no.3(January 25, 2000)
- ISSN：1520-4995
文摘
The plasminogen activation (PA) system is involved in the degradation of fibrin and variousextracellular matrix proteins, taking part in a number of physiological and pathological tissue remodelingprocesses including cancer invasion. This system is organized as a classical proteolytic cascade, and asfor other cascade systems, understanding the physiological initiation mechanism is of central importance.The attempts to identify initiation routes for activation of the proform of the key enzyme urokinase-typeplasminogen activator (pro-uPA) in vivo have been hampered by the strong activator potency of the plasmin,that is generated during the progress of the cascade. Using gene-targeted mice deficient in plasminogen(Plg -/- mice) [Bugge, T. H., Flick, M. J., Daugherty, C. C., and Degen, J. L. (1995) Genes Dev. 9,794-807], we have now demonstrated and identified a component capable of initiating the cascade byactivating pro-uPA. The urine from Plg -/- mice contained active two-chain uPA as well as a proteinasecapable of activating exogenously added pro-uPA. The active component was purified and identified bymass spectrometry-based peptide mapping as mouse glandular kallikrein mGK-6 (true tissue kallikrein).The pro-uPA converting activity of the mGK-6 enzyme, as well as its ability to cleave a synthetic substratefor glandular kallikrein, was inhibited by the serine proteinase inhibitor leupeptin but not by other serineproteinase inhibitors such as aprotinin, antithrombin III, or 
1-antitrypsin. We suggest that mouse glandularkallikrein mGK-6 is an activator of pro-uPA in the mouse urinary tract in vivo. Since this kallikrein isexpressed in a number of tissues and also occurs in plasma, it can also be considered a candidate for aphysiological pro-uPA activator in other locations.
1-antitrypsin. We suggest that mouse glandularkallikrein mGK-6 is an activator of pro-uPA in the mouse urinary tract in vivo. Since this kallikrein isexpressed in a number of tissues and also occurs in plasma, it can also be considered a candidate for aphysiological pro-uPA activator in other locations.