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Thromb Haemost 2010; 104(06): 1133-1142
DOI: 10.1160/TH10-02-0121
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Differential endocytosis of tissue plasminogen activator by serpins PAI-1 and PAI-2 on human peripheral blood monocytes

Jodi A. Lee
1   School of Biological Sciences, University of Wollongong, Northfields Avenue, Wollongong, New South Wales, Australia
,
David R. Croucher
2   Cancer Research Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia
,
Marie Ranson
1   School of Biological Sciences, University of Wollongong, Northfields Avenue, Wollongong, New South Wales, Australia
› Author Affiliations
Further Information

Publication History

Received: 16 February 2010

Accepted after major revision: 23 July 2010

Publication Date:
24 November 2017 (online)

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Summary

Generation of the broad spectrum protease plasmin is facilitated by the tissue (t-PA) and urokinase (u-PA) plasminogen activators, within multiple physiological and disease states. Finely tuned control of this proteolytic cascade is exerted by the plasminogen activator inhibitors type-1 (PAI-1/SERPINE1) and 2 (PAI-2/SERPINB2). Expression of this network of activators and inhibitors by cells of myeloid lineage appears to be highly interchangeable between physiological environments, and whilst the role of PAI-1 and PAI-2 in regulating u-PA-dependent functions is well established, the interaction between t-PA and PAI-2 on these cell types is poorly characterised. To this end, we used freshly isolated peripheral blood monocytes (PBM) as a model of a t-PA-dependent cellular environment. We demonstrate that while both PAI-1 and PAI-2 could inhibit surface-bound t-PA and are internalised predominately via low-density-lipoprotein receptor family members, PAI-1 enhanced the endocytosis of t-PA, whereas PAI-2 did not. Surface plasmon resonance analyses revealed differential binding affinities between the very-low-density-lipoprotein receptor and t-PA and t-PA:PAI-1 complexes in addition to those previously described with low-density-lipoprotein receptor-related protein. Moreover, t-PA:PAI-2 bound to both endocytosis receptors with similar kinetics to t-PA. These differential biochemical interactions between t-PA and the t-PA:PAI complexes may underlie the observed differences in endocytosis mechanisms on the PBMs. This suggests that while PAI-1 and PAI-2 function similarly in the control of cellular plasmin generation by t-PA, they may have disparate effects on the alternative functions of t-PA via modulation of its engagement with endocytosis receptors.

Keywords

Cell surface protein - endocytosis - protein-protein interactions - serpin - tissue plasminogen activator (t-PA) - peripheral blood monocytes - plasminogen activator inhibitor type-1 - plasminogen activator inhibitor type-2

 

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