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

Jodi A. Lee; David R. Croucher; Marie Ranson

doi:10.1160/TH10-02-0121

Thrombosis and Haemostasis, Table of Contents

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

¹School of Biological Sciences, University of Wollongong, Northfields Avenue, Wollongong, New South Wales, Australia

,

David R. Croucher

²Cancer Research Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia

,

Marie Ranson

¹School of Biological Sciences, University of Wollongong, Northfields Avenue, Wollongong, New South Wales, Australia

› Author Affiliations

Abstract

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

Full Text

References

References
1 Kruithof EK, Baker MS, Bunn CL. Biological and clinical aspects of plasminogen activator inhibitor type 2. Blood 1995; 86: 4007-4024.
2 Ling Q, Jacovina T, Deora A. et al. Annexin II regulates fibrin homeostasis and neoangiogenesis in vivo. J Clin Invest 2004; 113: 38-48.
3 Strickland DK, Gonias SL, Argraves WS. Diverse roles for the LDL receptor family. Trends Endocrinol Metab 2002; 13: 66-74.
4 Kassam G, Le BH, Choi KS. et al. The p11 subunit of the annexin II tetramer plays a key role in the stimulation of t-PA-dependent plasminogen activation. Biochemistry 1998; 37: 16958-16966.
5 McWilliam N, Robbie L, Booth N. et al. Plasminogen activator in acute myeloid leukaemic marrows: u-PA in contrast to t-PA in normal marrow. Br J Haematol 1998; 101: 626-631.
6 Missen MA, Haylock D, Whitty G. et al. Stage specific gene expression of serpins and their cognate proteases during myeloid differentiation. Br J Haematol 2006; 135: 715-724.
7 Hart PH, Vitti GF, Burgess DR. et al. Human monocytes can produce tissue-type plasminogen activator. J Exp Med 1989; 169: 1509-1514.
8 Hajjar KA. Homocysteine-induced modulation of tissue plasminogen activator binding to its endothelial cell membrane receptor. J Clin Invest 1993; 91: 2873-2879.
9 Rijken DC, Collen D. Purification and characterization of the plasminogen activator secreted by human melanoma cells in culture. J Biol Chem 1981; 256: 7035-7041.
10 Hoylaerts M, Rijken DC, Lijnen HR. et al. Kinetics of the activation of plasminogen by human tissue plasminogen activator. Role of fibrin. J Biol Chem 1982; 257: 2912-2919.
11 Felez J, Chanquia CJ, Levin EG. et al. Binding of tissue plasminogen activator to human monocytes and monocytoid cells. Blood 1991; 78: 2318-2327.
12 Noorman F, Braat EA, Rijken DC. Degradation of tissue-type plasminogen activator by human monocyte-derived macrophages is mediated by the mannose receptor and by the low-density lipoprotein receptor-related protein. Blood 1995; 86: 3421-3427.
13 Lobov S, Croucher DR, Saunders DN. et al. Plasminogen activator inhibitor type 2 inhibits cell surface associated tissue plasminogen activator in vitro: potential receptor interactions. Thromb Haemost 2008; 100: 319-329.
14 Ljungner H, Holmberg L, Kjeldgaard A. et al. Immunological characterisation of plasminogen activators in the human vessel wall. J Clin Pathol 1983; 36: 1046-1049.
15 Jorgensen M, Philips M, Thorsen S. et al. Plasminogen activator inhibitor-1 is the primary inhibitor of tissue-type plasminogen activator in pregnancy plasma. Thromb Haemost 1987; 58: 872-878.
16 Saunders DN, Jankova L, Harrop SJ. et al. Interaction between the P14 residue and strand 2 of beta-sheet B is critical for reactive center loop insertion in plasminogen activator inhibitor-2. J Biol Chem 2001; 276: 43383-43389.
17 Silverman GA, Bird PI, Carrell RW. et al. The serpins are an expanding super-family of structurally similar but functionally diverse proteins. Evolution, mechanism of inhibition, novel functions, and a revised nomenclature. J Biol Chem 2001; 276: 33293-33296.
18 Ritchie H, Robbie LA, Kinghorn S. et al. Monocyte plasminogen activator inhibitor 2 (PAI-2) inhibits u-PA-mediated fibrin clot lysis and is cross-linked to fibrin. Thromb Haemost 1999; 81: 96-103.
19 Thorsen S, Philips M, Selmer J. et al. Kinetics of inhibition of tissue-type and urokinase-type plasminogen activator by plasminogen-activator inhibitor type 1 and type 2. Eur J Biochem 1988; 175: 33-39.
20 Estelles A, Gilabert J, Aznar J. et al. Changes in the plasma levels of type 1 and type 2 plasminogen activator inhibitors in normal pregnancy and in patients with severe preeclampsia. Blood 1989; 74: 1332-1338.
21 Astedt B, Lindoff C, Lecander I. Significance of the plasminogen activator inhibitor of placental type (PAI-2) in pregnancy. Semin Thromb Hemost 1998; 24: 431-435.
22 Chen CS, Lyons-Giordano B, Lazarus GS. et al. Differential expression of plasminogen activators and their inhibitors in an organotypic skin coculture system. J Cell Sci 1993; 106: 45-53.
23 Virtanen OJ, Siren V, Multanen J. et al. Plasminogen activators and their inhibitors in human saliva and salivary gland tissue. Eur J Oral Sci 2006; 114: 22-26.
24 Kinnby B. The plasminogen activating system in periodontal health and disease. Biol Chem 2002; 383: 85-92.
25 Brown JM, Watanabe K, Cohen RL. et al. Molecular characterization of plasminogen activators in human gingival crevicular fluid. Arch Oral Biol 1995; 40: 839-845.
26 Baker MS, Green SP, Goss N. et al. Plasminogen activator inhibitor 2 (PAI-2) is not inactivated by exposure to oxidants which can be released from activated neutrophils. Biochem Biophys Res Commun 1990; 166: 993-1000.
27 Otter M, Barrett-Bergshoeff MM, Rijken DC. Binding of tissue-type plasminogen activator by the mannose receptor. J Biol Chem 1991; 266: 13931-13935.
28 Ritchie H, Jamieson J, Booth NA. Thrombin modulates synthesis of plasminogen activator inhibitor type 2 by human peripheral blood monocytes. Blood 1995; 86: 3428-3435.
29 Wing LR, Hawksworth GM, Bennett B. et al. Clearance of t-PA, PAI-1, and t-PAPAI-1 complex in an isolated perfused rat liver system. J Lab Clin Med 1991; 117: 109-114.
30 Nguyen G, Self SJ, Camani C. et al. Demonstration of a specific clearance receptor for tissue-type plasminogen activator on rat Novikoff hepatoma cells. J Biol Chem 1992; 267: 6249-6256.
31 Camani C, Bachmann F, Kruithof EK. The role of plasminogen activator inhibitor type 1 in the clearance of tissue-type plasminogen activator by rat hepatoma cells. J Biol Chem 1994; 269: 5770-5775.
32 Horn IR, van den Berg BM, Moestrup SK. et al. Plasminogen activator inhibitor 1 contains a cryptic high affinity receptor binding site that is exposed upon complex formation with tissue-type plasminogen activator. Thromb Haemost 1998; 80: 822-828.
33 Camani C, Gavin O, Kruithof EK. Cellular degradation of free and inhibitor-bound tissue-type plasminogen activator--requirement for a co-receptor?. Thromb Haemost 2000; 83: 290-296.
34 Simon DI, Xu H, Vaughan DE. Cathepsin D-like aspartyl protease activity mediates the degradation of tissue-type plasminogen activator/plasminogen activator inhibitor-1 complexes in human monocytes. Biochim Biophys Acta 1995; 1268: 143-151.
35 Ranson M, Andronicos NM, O’Mullane MJ. et al. Increased Plasminogen binding is associated with metastatic breast cancer cells: differential expression of plasminogen binding proteins. Br J Cancer 1998; 77: 1586-1597.
36 Croucher D, Saunders DN, Ranson M. The urokinase/PAI-2 complex: a new high affinity ligand for the endocytosis receptor low density lipoprotein receptor-related protein. J Biol Chem 2006; 281: 10206-10213.
37 Croucher DR, Saunders DN, Stillfried GE. et al. A structural basis for differential cell signaling by PAI-1 and PAI-2 in breast cancer cells. Biochem J 2007; 408: 203-210.
38 Cochran BJ, Gunawardhana LP, Vine KL. et al. The CD-loop of PAI-2 (SERPINB2) is redundant in the targeting, inhibition and clearance of cell surface uPA activity. BMC Biotechnol 2009; 9: 43.
39 Mulder M, Kohnert U, Fischer S. et al. The interaction of recombinant tissue type plasminogen activator and recombinant plasminogen activator (r-PA/BM 06.022) with human endothelial cells. Blood Coagul Fibrinolysis 1997; 8: 124-133.
40 Kuiper J, Otter M, Rijken M. et al. Characterization of the interaction in vivo of tissue-type plasminogen activator with liver cells. J Biol Chem 1988; 263: 18220-18224.
41 Stefansson S., Muhammad S., Cheng X.F.. et al. Plasminogen activator inhibitor-1 contains a cryptic high affinity binding site for the low density lipoprotein receptor-related protein. J Biol Chem 1998; 273: 6358-6366.
42 Brownstein C, Deora AB, Jacovina AT. et al. Annexin II mediates plasminogen-dependent matrix invasion by human monocytes: enhanced expression by macrophages. Blood 2004; 103: 317-324.
43 Hu K, Wu C, Mars WM. et al. Tissue-type plasminogen activator promotes murine myofibroblast activation through LDL receptor-related protein 1-mediated integrin signaling. J Clin Invest 2007; 117: 3821-3832.
44 Yepes M, Sandkvist M, Moore EG. et al. Tissue-type plasminogen activator induces opening of the blood-brain barrier via the LDL receptor-related protein. J Clin Invest 2003; 112: 1533-1540.
45 Reijerkerk A, Kooij G, van der Pol SM. et al. Tissue-type plasminogen activator is a regulator of monocyte diapedesis through the brain endothelial barrier. J Immunol 2008; 181: 3567-3574.
46 Cao C, Lawrence DA, Li Y. et al. Endocytic receptor LRP together with tPA and PAI-1 coordinates Mac-1-dependent macrophage migration. Embo J 2006; 25: 1860-1870.
47 Skeldal S, Larsen JV, Pedersen KE. et al. Binding areas of urokinase-type plasminogen activator-plasminogen activator inhibitor-1 complex for endocytosis receptors of the low-density lipoprotein receptor family, determined by site-directed mutagenesis. Febs J 2006; 273: 5143-5159.

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