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Thromb Haemost 2017; 117(06): 1058-1071
DOI: 10.1160/TH16-12-0936
Coagulation and Fibrinolysis
Schattauer GmbH

Mechanism of plasmin generation by S100A10

Victoria A. Miller
1   Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada
,
Patricia A. Madureira
2   Centre for Biomedical Research (CBMR), University of Algarve, Campus of Gambelas, Faro, Portugal
,
Ain Adilliah Kamaludin
3   Department of Biochemistry & Molecular Biology, Dalhousie University, Halifax, Nova Scotia, Canada
,
Jeffrey Komar
3   Department of Biochemistry & Molecular Biology, Dalhousie University, Halifax, Nova Scotia, Canada
,
Vandna Sharma
4   Institute of Microbial Technology (C. S. I.R), Sector 39-A, Chandigarh, India
,
Girish Sahni
4   Institute of Microbial Technology (C. S. I.R), Sector 39-A, Chandigarh, India
,
Craig Thelwell
5   Haemostasis Section, Biotherapeutics Group, National Institute for Biological Standards and Control, South Mimms, Herts, UK
,
Colin Longstaff
5   Haemostasis Section, Biotherapeutics Group, National Institute for Biological Standards and Control, South Mimms, Herts, UK
,
David M. Waisman 
1   Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada
3   Department of Biochemistry & Molecular Biology, Dalhousie University, Halifax, Nova Scotia, Canada
› Author Affiliations Financial support: This work was supported by a grant from the Heart and Stroke Foundation of Canada (G-14–0005821). PAM is currently supported by an FCT Investigator contract, ref: IF/00614/2014 from Fundação para a Ciência e a Tecnologia, Portugal and by national Portuguese funding through FCT – Fundação para a Ciência e a Tecnologia, project ref. UID/BIM/04773/2013 CBMR.
Further Information

Publication History

Received: 16 December 2016

Accepted after major revision: 19 March 2017

Publication Date:
07 November 2017 (online)

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Summary

Plasminogen (Pg) is cleaved to form plasmin by the action of specific plasminogen activators such as the tissue plasminogen activator (tPA). Although the interaction of tPA and Pg with the surface of the fibrin clot has been well characterised, their interaction with cell surface Pg receptors is poorly understood. S100A10 is a cell surface Pg receptor that plays a key role in cellular plasmin generation. In the present report, we have utilised domain-switched/deleted variants of tPA, truncated plasminogen variants and S100A10 site-directed mutant proteins to define the regions responsible for S100A10-dependent plasmin generation. In contrast to the established role of the finger domain of tPA in fibrin-stimulated plasmin generation, we show that the kringle-2 domain of tPA plays a key role in S100A10-dependent plasmin generation. The kringle-1 domain of plasminogen, indispensable for fibrin-binding, is also critical for S100A10-dependent plasmin generation. S100A10 retains activity after substitution or deletion of the carboxyl-terminal lysine suggesting that internal lysine residues contribute to its plasmin generating activity. These studies define a new paradigm for plasminogen activation by the plasminogen receptor, S100A10.

Keywords

S100A10 - annexin A2 - plasminogen - plasmin - tissue plasminogen activator - plasminogen regulation
 

  • References

  • 1 Plow EF, Herren T, Redlitz A. et al. The cell biology of the plasminogen system. FASEB J 1995; 9: 939-945.
    CrossrefPubMedGoogle Scholar
  • 2 Fleury V, Loyau S, Lijnen HR. et al. Molecular assembly of plasminogen and tissue-type plasminogen activator on an evolving fibrin surface. Eur J Biochem 1993; 216: 549-556.
    CrossrefPubMedGoogle Scholar
  • 3 Aisina RB, Mukhametova LI. Structure and function of plasminogen/plasmin system. Russ J Bioorg Chem 2014; 40: 590-605.
    CrossrefPubMedGoogle Scholar
  • 4 Miles LA, Parmer RJ. Plasminogen receptors: the first quarter century. Semin Thromb Hemost 2013; 39: 329-337.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Madureira PA, O’Connell PA, Surette AP. et al. The Biochemistry and Regulation of S100A10: A Multifunctional Plasminogen Receptor Involved in Onco-genesis. J Biomed Biotechnol 2012; 2012: 353687.
    PubMedGoogle Scholar
  • 6 Bharadwaj A, Bydoun M, Holloway R. et al. Annexin A2 heterotetramer: structure and function. Int J Mol Sci 2013; 14: 6259-6305.
    CrossrefPubMedGoogle Scholar
  • 7 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.
    CrossrefPubMedGoogle Scholar
  • 8 Kassam G, Choi KS, Ghuman J. et al. The role of annexin II tetramer in the activation of plasminogen. J Biol Chem 1998; 273: 4790-4799.
    CrossrefPubMedGoogle Scholar
  • 9 Kwon M, MacLeod TJ, Zhang Y. et al. S100A10, annexin A2, and annexin A2 heterotetramer as candidate plasminogen receptors. Front Biosci 2005; 10: 300-325.
    CrossrefPubMedGoogle Scholar
  • 10 Surette AP, Madureira PA, Phipps KD. et al. Regulation of fibrinolysis by S100A10 in vivo. Blood 2011; 118: 3172-3181.
    CrossrefPubMedGoogle Scholar
  • 11 MacLeod TJ, Kwon M, Filipenko NR. et al. Phospholipid-associated annexin A2-S100A10 heterotetramer and its subunits: characterization of the interaction with tissue plasminogen activator, plasminogen, and plasmin. J Biol Chem 2003; 278: 25577-25584.
    CrossrefPubMedGoogle Scholar
  • 12 Deutsch DG, Mertz ET. Plasminogen: purification from human plasma by affinity chromatography. Science 1970; 170: 1095-1096.
    CrossrefPubMedGoogle Scholar
  • 13 Ayala-Sanmartin J, Gouache P, Henry JP. N-Terminal domain of annexin 2 regulates Ca(2+)-dependent membrane aggregation by the core domain: a site directed mutagenesis study. Biochemistry 2000; 39: 15190-15198.
    CrossrefPubMedGoogle Scholar
  • 14 Khanna NC, Helwig ED, Ikebuchi NW. et al. Purification and characterization of annexin proteins from bovine lung. Biochemistry 1990; 29: 4852-4862.
    CrossrefPubMedGoogle Scholar
  • 15 Joshi KK, Nanda JS, Kumar P. et al. Substrate kringle-mediated catalysis by the streptokinase-plasmin activator complex: critical contribution of kringle-4 revealed by the mutagenesis approaches. Biochim Biophys Acta 2012; 1824: 326-333.
    CrossrefPubMedGoogle Scholar
  • 16 Longstaff C, Thelwell C, Williams SC. et al. The interplay between tissue plasminogen activator domains and fibrin structures in the regulation of fibrinolysis: kinetic and microscopic studies. Blood 2011; 117: 661-668.
    CrossrefPubMedGoogle Scholar
  • 17 Kassam G, Manro A, Braat CE. et al. Characterization of the heparin binding properties of annexin II tetramer. JBiolChem 1997; 272: 15093-15100.
    PubMedGoogle Scholar
  • 18 Fraczkiewicz R, Braun W. Exact and efficient analytical calculation of the accessible surface areas and their gradients for macromolecules. J Comput Chem 1998; 19: 319-333.
    CrossrefPubMedGoogle Scholar
  • 19 Felez J, Chanquia CJ, Fabregas P. et al. Competition between plasminogen and tissue plasminogen activator for cellular binding sites. Blood 1993; 82: 2433-2441.
    PubMedGoogle Scholar
  • 20 Hajjar KA, Mauri L, Jacovina AT. et al. Tissue plasminogen activator binding to the annexin II tail domain. Direct modulation by homocysteine. J Biol Chem 1998; 273: 9987-9993.
    PubMedGoogle Scholar
  • 21 Roda O, Valero ML, Peiró S. et al. New insights into the tPA-annexin A2 interaction. Is annexin A2 CYS8 the sole requirement for this association?. J Biol Chem 2003; 278: 5702-5709.
    CrossrefPubMedGoogle Scholar
  • 22 Jacovina AT, Deora AB, Ling Q. et al. Homocysteine inhibits neoangiogenesis in mice through blockade of annexin A2-dependent fibrinolysis. J Clin Invest 2009; 119: 3384-3394.
    PubMedGoogle Scholar
  • 23 Miles LA, Dahlberg CM, Plow EF. The cell-binding domains of plasminogen and their function in plasma. J Biol Chem 1988; 263: 11928-11934.
    PubMedGoogle Scholar
  • 24 Law RHP, Caradoc-Davies T, Cowieson N. et al. The X-ray crystal structure of full-length human plasminogen. Cell Rep 2012; 1: 185-190.
    CrossrefPubMedGoogle Scholar
  • 25 Fogg DK, Bridges D, Cheung KT. et al. The p11 subunit of annexin II heterotetramer is regulated by basic carboxypeptidase. Biochemistry 2002; 41: 4953-4961.
    CrossrefPubMedGoogle Scholar
  • 26 Galántai R, Módos K, Fidy J. et al. Structural basis of the cofactor function of denatured albumin in plasminogen activation by tissue-type plasminogen activator. Biochem Biophys Res Commun 2006; 341: 736-741.
    CrossrefPubMedGoogle Scholar
  • 27 Machovich R, Owen WG. Denatured proteins as cofactors for plasminogen activation. Arch Biochem Biophys 1997; 344: 343-349.
    CrossrefPubMedGoogle Scholar
  • 28 Kornblatt JA, Rajotte I, Heitz F. Reaction of canine plasminogen with 6-amino-hexanoate: a thermodynamic study combining fluorescence, circular dichroism, and isothermal titration calorimetry. Biochemistry 2001; 40: 3639-3647.
    CrossrefPubMedGoogle Scholar
  • 29 Angles-Cano E. A spectrophotometric solid-phase fibrin-tissue plasminogen activator activity assay (SOFIA-tPA) for high-fibrin-affinity tissue plasminogen activators. Anal Biochem 1986; 153: 201-210.
    CrossrefPubMedGoogle Scholar
  • 30 Choi KS, Fogg DK, Yoon CS. et al. P11 regulates extracellular plasmin production and invasiveness of HT1080 fibrosarcoma cells. FASEB J 2003; 17: 235-246.
    CrossrefPubMedGoogle Scholar
  • 31 Zhang L, Fogg DK, Waisman DM. RNA interference-mediated silencing of the S100A10 gene attenuates plasmin generation and invasiveness of Colo 222 colorectal cancer cells. J Biol Chem 2004; 279: 2053-2062.
    CrossrefPubMedGoogle Scholar
  • 32 O’Connell PA, Madureira PA, Berman JN. et al. Regulation of S100A10 by the PML-RAR- oncoprotein. Blood 2011; 117: 4095-4105.
    CrossrefPubMedGoogle Scholar
  • 33 Madureira PA, Bharadwaj AG, Bydoun M. et al. Cell surface protease activation during RAS transformation: Critical role of the plasminogen receptor, S100A10. Oncotarget 2016; 7: 47720-47737.
    CrossrefPubMedGoogle Scholar
  • 34 Yang X, Popescu NC, Zimonjic DB. DLC1 interaction with S100A10 mediates inhibition of in vitro cell invasion and tumorigenicity of lung cancer cells through a RhoGAP-independent mechanism. Cancer Res 2011; 71: 2916-2925.
    CrossrefPubMedGoogle Scholar
  • 35 Silva MMCG, Thelwell C, Williams SC. et al. Regulation of fibrinolysis by C-terminal lysines operates through plasminogen and plasmin but not tissue-type plasminogen activator. J Thromb Haemost 2012; 10: 2354-2360.
    CrossrefPubMedGoogle Scholar
  • 36 Samson AL, Nevin ST, Croucher D. et al. Tissue-type plasminogen activator requires a co-receptor to enhance NMDA receptor function. J Neurochem 2008; 107: 1091-1101.
    PubMedGoogle Scholar
  • 37 Fredriksson L, Li H, Fieber C. et al. Tissue plasminogen activator is a potent activator of PDGF-CC. EMBO J 2004; 23: 3793-3802.
    CrossrefPubMedGoogle Scholar
  • 38 Bydoun M, Waisman DM. On the contribution of S100A10 and annexin A2 to plasminogen activation and oncogenesis: an enduring ambiguity. Future Oncol 2014; 10: 2469-2479.
    CrossrefPubMedGoogle Scholar
  • 39 Madureira PA, Waisman DM. Annexin A2: the importance of being redox sensitive. Int J Mol Sci 2013; 14: 3568-3594.
    CrossrefPubMedGoogle Scholar
  • 40 Hajjar KA, Jacovina AT. Modulation of annexin II by homocysteine: implications for atherothrombosis. J Investig Med 1998; 46: 364-369.
    PubMedGoogle Scholar
  • 41 Becker T, Weber K, Johnsson N. Protein-protein recognition via short amphiphilic helices; a mutational analysis of the binding site of annexin II for p11. EMBO J 1990; 9: 4207-4213.
    PubMedGoogle Scholar
  • 42 Dayal S, Chauhan AK, Jensen M. et al. Paradoxical absence of a prothrombotic phenotype in a mouse model of severe hyperhomocysteinemia. Blood 2012; 119: 3176-3183.
    CrossrefPubMedGoogle Scholar
  • 43 Ho-Tin-Noé B, Rojas G, Vranckx R. et al. Functional hierarchy of plasminogen kringles 1 and 4 in fibrinolysis and plasmin-induced cell detachment and apoptosis. FEBS J 2005; 272: 3387-3400.
    CrossrefPubMedGoogle Scholar
  • 44 Uversky VN. Size-exclusion chromatography in structural analysis of intrinsically disordered proteins. Methods Mol Biol 2012; 896: 179-194.
    PubMedGoogle Scholar
  • 45 Samson AL, Borg RJ, Niego B. ’eri et al. A nonfibrin macromolecular cofactor for tPA-mediated plasmin generation following cellular injury. Blood 2009; 114: 1937-1946.
    CrossrefPubMedGoogle Scholar
  • 46 Maas C, Hermeling S, Bouma B. et al. A role for protein misfolding in immunogenicity of biopharmaceuticals. J Biol Chem 2007; 282: 2229-2236.
    CrossrefPubMedGoogle Scholar
  • 47 Bergmann S, Wild D, Diekmann O. et al. Identification of a novel plasmin(ogen)-binding motif in surface displayed alpha-enolase of Streptococcus pneumoniae. Mol Microbiol 2003; 49: 411-423.
    CrossrefPubMedGoogle Scholar
  • 48 Ehinger S, Schubert WD, Bergmann S. et al. Plasmin(ogen)-binding alpha-enolase from Streptococcus pneumoniae: crystal structure and evaluation of plasmin(ogen)-binding sites. J Mol Biol 2004; 343: 997-1005.
    CrossrefPubMedGoogle Scholar
  • 49 Felez J, Miles LA, Fabregas P. et al. Characterization of cellular binding sites and interactive regions within reactants required for enhancement of plasminogen activation by tPA on the surface of leukocytic cells. Thromb Haemost 1996; 76: 577-584.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 50 Longstaff C, Kolev K. Basic mechanisms and regulation of fibrinolysis. J Thromb Haemost 2015; 13 (Suppl. 01) S98-105.
    CrossrefPubMedGoogle Scholar