Skip to main content
SpringerLink
Log in

Plasminogen Activator Inhibitor Type-2 (PAI-2)/SerpinB2: A Unique Multifunctional Serpin

  • Chapter
The Serpin Family

  • 634 Accesses

Abstract

Plasminogen activator inhibitor type-2 (PAI-2) or SerpinB2 is a clade B serine protease inhibitor (serpin) with unique properties that was originally identified as an inhibitor of the secreted serine protease, urokinase-plasminogen activator (uPA). The plasminogen activating cascade is well recognized to play an important fibrinolytic role in maintaining vascular patency and for remodeling of the extracellular matrix. On the other hand, PAI-2 is present predominantly as a nucleocytoplasmic protein, and it has been shown to have a number of pleiotropic activities associated with its intracellular localization. Upregulation of PAI-2 is a major stress response in multiple cell types and recent data have started to illuminate PAI-2 functions in the cell, having immunomodulatory, cytoprotective, and anti-inflammatory activities.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Akira S, Takeda K (2004) Toll-like receptor signalling. Nat Rev Immunol 4:499–511

    CAS  PubMed  Google Scholar 

  • Al Ejeh F, Croucher D, Ranson M (2004) Kinetic analysis of plasminogen activator inhibitor type-2: urokinase complex formation and subsequent internalisation by carcinoma cell lines. Exp Cell Res 297:259–271

    CAS  PubMed  Google Scholar 

  • Andreasen PA, Kjoller L, Christensen L, Duffy MJ (1997) The urokinase-type plasminogen activator system in cancer metastasis: a review. Int J Cancer 72:1–22

    CAS  PubMed  Google Scholar 

  • Annand RR, Dahlen JR, Sprecher CA, De Dreu P, Foster DC, Mankovich JA, Talanian RV, Kisiel W, Giegel DA (1999) Caspase-1 (interleukin-1beta-converting enzyme) is inhibited by the human serpin analogue proteinase inhibitor 9. Biochem J 342(Pt 3):655–665

    PubMed Central  CAS  PubMed  Google Scholar 

  • Antalis TM, Clark MA, Barnes T, Lehrbach PR, Devine PL, Schevzov G, Goss NH, Stephens RW, Tolstoshev P (1988) Cloning and expression of a cDNA coding for a human monocyte-derived plasminogen activator inhibitor. Proc Natl Acad Sci USA 85:985–989

    PubMed Central  CAS  PubMed  Google Scholar 

  • Antalis TM, La Linn M, Donnan K, Mateo L, Gardner J, Dickinson JL, Buttigieg K, Suhrbier A (1998) The serine proteinase inhibitor (serpin) plasminogen activation inhibitor type 2 protects against viral cytopathic effects by constitutive interferon alpha/beta priming. J Exp Med 187:1799–1811

    PubMed Central  CAS  PubMed  Google Scholar 

  • Ashton JM, Balys M, Neering SJ, Hassane DC, Cowley G, Root DE, Miller PG, Ebert BL, McMurray HR, Land H, Jordan CT (2012) Gene sets identified with oncogene cooperativity analysis regulate in vivo growth and survival of leukemia stem cells. Cell Stem Cell 11:359–372

    PubMed Central  CAS  PubMed  Google Scholar 

  • Askew DJ, Askew YS, Kato Y, Turner RF, Dewar K, Lehoczky J, Silverman GA (2004) Comparative genomic analysis of the clade B serpin cluster at human chromosome 18q21: amplification within the mouse squamous cell carcinoma antigen gene locus. Genomics 84:176–184

    CAS  PubMed  Google Scholar 

  • Astedt B, Lindoff C, Lecander I (1998) Significance of the plasminogen activator inhibitor of placental type (PAI-2) in pregnancy. Semin Thromb Hemost 24:431–435

    CAS  PubMed  Google Scholar 

  • Baker MS, Bleakley P, Woodrow GC, Doe WF (1990) Inhibition of cancer cell urokinase plasminogen activator by its specific inhibitor PAI-2 and subsequent effects on extracellular matrix degradation. Cancer Res 50:4676–4684

    CAS  PubMed  Google Scholar 

  • Bodenstine TM, Welch DR (2008) Metastasis suppressors and the tumor microenvironment. Cancer Microenviron 1:1–11

    PubMed Central  PubMed  Google Scholar 

  • Boncela J, Przygodzka P, Papiewska-Pajak I, Wyroba E, Cierniewski CS (2011) Association of plasminogen activator inhibitor type 2 (PAI-2) with proteasome within endothelial cells activated with inflammatory stimuli. J Biol Chem 286:43164–43171

    PubMed Central  CAS  PubMed  Google Scholar 

  • Boncela J, Przygodzka P, Wyroba E, Papiewska-Pajak I, Cierniewski CS (2013) Secretion of SerpinB2 from endothelial cells activated with inflammatory stimuli. Exp Cell Res 319:1213–1219

    CAS  PubMed  Google Scholar 

  • Braungart E, Magdolen V, Degitz K (2001) Retinoic acid upregulates the plasminogen activator system in human epidermal keratinocytes. J Invest Dermatol 116:778–784

    CAS  PubMed  Google Scholar 

  • Bystrom J, Wynn TA, Domachowske JB, Rosenberg HF (2004) Gene microarray analysis reveals interleukin-5-dependent transcriptional targets in mouse bone marrow. Blood 103:868–877

    PubMed  Google Scholar 

  • Casslen B, Bossmar T, Lecander I, Astedt B (1994) Plasminogen activators and plasminogen activator inhibitors in blood and tumour fluids of patients with ovarian cancer. Eur J Cancer 30A:1302–1309

    CAS  PubMed  Google Scholar 

  • Chambers SK, Gertz RE Jr, Ivins CM, Kacinski BM (1995) The significance of urokinase- type plasminogen activator, its inhibitors, and its receptor in ascites of patients with epithelial ovarian cancer. Cancer 75:1627–1633

    CAS  PubMed  Google Scholar 

  • Chambers SK, Ivins CM, Carcangiu ML (1997) Expression of plasminogen activator inhibitor-2 in epithelial ovarian cancer: a favorable prognostic factor related to the actions of CSF-1. Int J Cancer 74:571–575

    CAS  PubMed  Google Scholar 

  • Champelovier P, Boucard N, Levacher G, Simon A, Seigneurin D, Praloran V (2002) Plasminogen- and colony-stimulating factor-1-associated markers in bladder carcinoma: diagnostic value of urokinase plasminogen activator receptor and plasminogen activator inhibitor type-2 using immunocytochemical analysis. Urol Res 30:301–309

    CAS  PubMed  Google Scholar 

  • Chen X, He J, Chang LJ (2004) Alteration of T cell immunity by lentiviral transduction of human monocyte-derived dendritic cells. Retrovirology 1:37

    PubMed Central  PubMed  Google Scholar 

  • Chuang SY, Yang CH, Chou CC, Chiang YP, Chuang TH, Hsu LC (2013) TLR-induced PAI-2 expression suppresses IL-1beta processing via increasing autophagy and NLRP3 degradation. Proc Natl Acad Sci USA 110:16079–16084

    PubMed Central  CAS  PubMed  Google Scholar 

  • Coolman M, Timmermans S, de Groot CJ, Russcher H, Lindemans J, Hofman A, Geurts-Moespot AJ, Sweep FC, Jaddoe VV, Steegers EA (2012) Angiogenic and fibrinolytic factors in blood during the first half of pregnancy and adverse pregnancy outcomes. Obstet Gynecol 119:1190–1200

    PubMed  Google Scholar 

  • Copple BL, Bai S, Burgoon LD, Moon JO (2011) Hypoxia-inducible factor-1alpha regulates the expression of genes in hypoxic hepatic stellate cells important for collagen deposition and angiogenesis. Liver Int 31:230–244

    PubMed Central  CAS  PubMed  Google Scholar 

  • Corsetti JP, Salzman P, Ryan D, Moss AJ, Zareba W, Sparks CE (2013) Plasminogen activator inhibitor-2 polymorphism associates with recurrent coronary event risk in patients with high HDL and C-reactive protein levels. PLoS One 8, e68920

    PubMed Central  CAS  PubMed  Google Scholar 

  • Cousin E, Medcalf RL, Bergonzelli GE, Kruithof EK (1991) Regulatory elements involved in constitutive and phorbol ester-inducible expression of the plasminogen activator inhibitor type 2 gene promoter. Nucleic Acids Res 19:3881–3886

    PubMed Central  CAS  PubMed  Google Scholar 

  • Croucher D, Saunders DN, Ranson M (2006) The urokinase/PAI-2 complex: a new high affinity ligand for the endocytosis receptor low density lipoprotein receptor-related protein. J Biol Chem 281:10206–10213

    CAS  PubMed  Google Scholar 

  • Croucher DR, Saunders DN, Lobov S, Ranson M (2008) Revisiting the biological roles of PAI2 (SERPINB2) in cancer. Nat Rev Cancer 8:535–545

    CAS  PubMed  Google Scholar 

  • Darnell GA, Antalis TM, Johnstone RW, Stringer BW, Ogbourne SM, Harrich D, Suhrbier A (2003) Inhibition of retinoblastoma protein degradation by interaction with the serpin plasminogen activator inhibitor 2 via a novel consensus motif. Mol Cell Biol 23:6520–6532

    PubMed Central  CAS  PubMed  Google Scholar 

  • Darnell GA, Schroder WA, Gardner J, Harrich D, Yu H, Medcalf RL, Warrilow D, Antalis TM, Sonza S, Suhrbier A (2006) SerpinB2 is an inducible host factor involved in enhancing HIV-1 transcription and replication. J Biol Chem 281:31348–31358

    CAS  PubMed  Google Scholar 

  • Delhase M, Kim SY, Lee H, Naiki-Ito A, Chen Y, Ahn ER, Murata K, Kim SJ, Lautsch N, Kobayashi KS, Shirai T, Karin M, Nakanishi M (2012) TANK-binding kinase 1 (TBK1) controls cell survival through PAI-2/serpinB2 and transglutaminase 2. Proc Natl Acad Sci USA 109:E177–E186

    PubMed Central  CAS  PubMed  Google Scholar 

  • Dickinson JL, Bates EJ, Ferrante A, Antalis TM (1995) Plasminogen activator inhibitor type 2 inhibits tumor necrosis factor alpha-induced apoptosis. Evidence for an alternate biological function. J Biol Chem 270:27894–27904

    CAS  PubMed  Google Scholar 

  • Dickinson JL, Norris BJ, Jensen PH, Antalis TM (1998) The C-D interhelical domain of the serpin plasminogen activator inhibitor-type 2 is required for protection from TNF-alpha induced apoptosis. Cell Death Differ 5:163–171

    CAS  PubMed  Google Scholar 

  • Dougherty KM, Pearson JM, Yang AY, Westrick RJ, Baker MS, Ginsburg D (1999) The plasminogen activator inhibitor-2 gene is not required for normal murine development or survival. Proc Natl Acad Sci USA 96:686–691

    PubMed Central  CAS  PubMed  Google Scholar 

  • Eaton A, Nagy E, Pacault M, Fauconnier J, Back M (2012) Cysteinyl leukotriene signaling through perinuclear CysLT(1) receptors on vascular smooth muscle cells transduces nuclear calcium signaling and alterations of gene expression. J Mol Med (Berl) 90:1223–1231

    CAS  Google Scholar 

  • Erler JT (2014) Cancer: disabling defences in the brain. Nature 508:46–47

    CAS  PubMed  Google Scholar 

  • Fan J, Zhang YQ, Li P, Hou M, Tan L, Wang X, Zhu YS (2004) Interaction of plasminogen activator inhibitor-2 and proteasome subunit, beta type 1. Acta Biochim Biophys Sin (Shanghai) 36:42–46

    CAS  Google Scholar 

  • Fish RJ, Kruithof EK (2006) Evidence for serpinB2-independent protection from TNF-alpha-induced apoptosis. Exp Cell Res 312:350–361

    CAS  PubMed  Google Scholar 

  • Gan H, Newman GW, Remold HG (1995) Plasminogen activator inhibitor type 2 prevents programmed cell death of human macrophages infected with Mycobacterium avium, serovar 4. J Immunol 155:1304–1315

    CAS  PubMed  Google Scholar 

  • Gan H, Lee J, Ren F, Chen M, Kornfeld H, Remold HG (2008) Mycobacterium tuberculosis blocks crosslinking of annexin-1 and apoptotic envelope formation on infected macrophages to maintain virulence. Nat Immunol 9:1189–1197

    CAS  PubMed  Google Scholar 

  • Ganesh S, Sier CF, Griffioen G, Vloedgraven HJ, de Boer A, Welvaart K, van de Velde CJ, van Krieken JH, Verheijen JH, Lamers CB (1994) Prognostic relevance of plasminogen activators and their inhibitors in colorectal cancer. Cancer Res 54:4065–4071

    CAS  PubMed  Google Scholar 

  • Genton C, Kruithof EK, Schleuning WD (1987) Phorbol ester induces the biosynthesis of glycosylated and nonglycosylated plasminogen activator inhibitor 2 in high excess over urokinase-type plasminogen activator in human U-937 lymphoma cells. J Cell Biol 104:705–712

    CAS  PubMed  Google Scholar 

  • Gettins PG (2002) Serpin structure, mechanism, and function. Chem Rev 102:4751–4804

    CAS  PubMed  Google Scholar 

  • Gossage JA, Humphries J, Modarai B, Burnand KG, Smith A (2006) Adenoviral urokinase-type plasminogen activator (uPA) gene transfer enhances venous thrombus resolution. J Vasc Surg 44:1085–1090

    PubMed  Google Scholar 

  • Greten FR, Arkan MC, Bollrath J, Hsu LC, Goode J, Miething C, Goktuna SI, Neuenhahn M, Fierer J, Paxian S, van Rooijen N, Xu Y, O’Cain T, Jaffee BB, Busch DH, Duyster J, Schmid RM, Eckmann L, Karin M (2007) NF-kappaB is a negative regulator of IL-1beta secretion as revealed by genetic and pharmacological inhibition of IKKbeta. Cell 130:918–931

    PubMed Central  CAS  PubMed  Google Scholar 

  • Guha M, Mackman N (2001) LPS induction of gene expression in human monocytes. Cell Signal 13:85–94

    CAS  PubMed  Google Scholar 

  • Hahne JC, Okuducu AF, Fuchs T, Florin A, Wernert N (2011) Identification of ETS-1 target genes in human fibroblasts. Int J Oncol 38:1645–1652

    CAS  PubMed  Google Scholar 

  • Harrop SJ, Jankova L, Coles M, Jardine D, Whittaker JS, Gould AR, Meister A, King GC, Mabbutt BC, Curmi PM (1999) The crystal structure of plasminogen activator inhibitor 2 at 2.0 A resolution: implications for serpin function. Struct Fold Des 7:43–54

    CAS  Google Scholar 

  • Hsu LC, Ali SR, McGillivray S, Tseng PH, Mariathasan S, Humke EW, Eckmann L, Powell JJ, Nizet V, Dixit VM, Karin M (2008) A NOD2-NALP1 complex mediates caspase-1-dependent IL-1beta secretion in response to Bacillus anthracis infection and muramyl dipeptide. Proc Natl Acad Sci USA 105:7803–7808

    PubMed Central  CAS  PubMed  Google Scholar 

  • Huang Z, Li H, Huang Q, Chen D, Han J, Wang L, Pan C, Chen W, House MG, Nephew KP, Guo Z (2014) SERPINB2 down-regulation contributes to chemoresistance in head and neck cancer. Mol Carcinog 53:777–786

    CAS  PubMed  Google Scholar 

  • Hui C, Lili M, Libin C, Rui Z, Fang G, Ling G, Jianping Z (2012) Changes in coagulation and hemodynamics during pregnancy: a prospective longitudinal study of 58 cases. Arch Gynecol Obstet 285:1231–1236

    PubMed  Google Scholar 

  • Jang S, Yang TH, An EJ, Yoon HK, Sohn KC, Cho AY, Ryu EK, Park YS, Yoon TY, Lee JH, Kim CD (2010) Role of plasminogen activator inhibitor-2 (PAI-2) in keratinocyte differentiation. J Dermatol Sci 59:25–30

    CAS  PubMed  Google Scholar 

  • Jensen PH (1987) Structure and function of plasminogen activator inhibitor-2: an intracellular serine proteinase inhibitor modulating apoptosis. Int J Oncol 11:557–570

    Google Scholar 

  • Jensen PH, Lorand L, Ebbesen P, Gliemann J (1993) Type-2 plasminogen-activator inhibitor is a substrate for trophoblast transglutaminase and factor XIIIa. Transglutaminase-catalyzed cross-linking to cellular and extracellular structures. Eur J Biochem 214:141–146

    CAS  PubMed  Google Scholar 

  • Jensen PH, Schuler E, Woodrow G, Richardson M, Goss N, Hojrup P, Petersen TE, Rasmussen LK (1994) A unique interhelical insertion in plasminogen activator inhibitor-2 contains three glutamines, Gln83, Gln84, Gln86, essential for transglutaminase-mediated cross-linking. J Biol Chem 269:15394–15398

    CAS  PubMed  Google Scholar 

  • Jensen PH, Jensen TG, Laug WE, Hager H, Gliemann J, Pepinsky B (1996) The exon 3 encoded sequence of the intracellular serine proteinase inhibitor plasminogen activator inhibitor 2 is a protein binding domain. J Biol Chem 271:26892–26899

    CAS  PubMed  Google Scholar 

  • Kaiserman D, Bird PI (2005) Analysis of vertebrate genomes suggests a new model for clade B serpin evolution. BMC Genomics 6:167

    PubMed Central  PubMed  Google Scholar 

  • Kasyapa CS, Kunapuli P, Hawthorn L, Cowell JK (2006) Induction of the plasminogen activator inhibitor-2 in cells expressing the ZNF198/FGFR1 fusion kinase that is involved in atypical myeloproliferative disease. Blood 107:3693–3699

    PubMed Central  CAS  PubMed  Google Scholar 

  • Katic J, Loers G, Kleene R, Karl N, Schmidt C, Buck F, Zmijewski JW, Jakovcevski I, Preissner KT, Schachner M (2014) Interaction of the cell adhesion molecule CHL1 with vitronectin, integrins, and the plasminogen activator inhibitor-2 promotes CHL1-induced neurite outgrowth and neuronal migration. J Neurosci 34:14606–14623

    PubMed  Google Scholar 

  • Kawano T, Morimoto K, Uemura Y (1970) Partial purification and properties of urokinase inhibitor from human placenta. J Biochem 67:333–342

    CAS  PubMed  Google Scholar 

  • Krishnamurti C, Wahl LM, Alving BM (1989) Stimulation of plasminogen activator inhibitor activity in human monocytes infected with dengue virus. Am J Trop Med Hyg 40:102–107

    CAS  PubMed  Google Scholar 

  • Kruithof EK, Baker MS, Bunn CL (1995) Biological and clinical aspects of plasminogen activator inhibitor type 2. Blood 86:4007–4024

    CAS  PubMed  Google Scholar 

  • Ksiazek K, Mikula-Pietrasik J, Catar R, Dworacki G, Winckiewicz M, Frydrychowicz M, Dragun D, Staniszewski R, Jorres A, Witowski J (2010) Oxidative stress-dependent increase in ICAM-1 expression promotes adhesion of colorectal and pancreatic cancers to the senescent peritoneal mesothelium. Int J Cancer 127:293–303

    CAS  PubMed  Google Scholar 

  • Kumar S, Baglioni C (1991) Protection from tumor necrosis factor-mediated cytolysis by overexpression of plasminogen activator inhibitor type-2. J Biol Chem 266:20960–20964

    CAS  PubMed  Google Scholar 

  • Laug WE, Cao XR, Yu YB, Shimada H, Kruithof EK (1993) Inhibition of invasion of HT1080 sarcoma cells expressing recombinant plasminogen activator inhibitor 2. Cancer Res 53:6051–6057

    CAS  PubMed  Google Scholar 

  • Lavker RM, Risse B, Brown H, Ginsburg D, Pearson J, Baker MS, Jensen PJ (1998) Localization of plasminogen activator inhibitor type 2 (PAI-2) in hair and nail: implications for terminal differentiation. J Invest Dermatol 110:917–922

    CAS  PubMed  Google Scholar 

  • Law RH, Zhang Q, McGowan S, Buckle AM, Silverman GA, Wong W, Rosado CJ, Langendorf CG, Pike RN, Bird PI, Whisstock JC (2006) An overview of the serpin superfamily. Genome Biol 7:216

    PubMed Central  PubMed  Google Scholar 

  • Leszczyniecka M, Roberts T, Dent P, Grant S, Fisher PB (2001) Differentiation therapy of human cancer: basic science and clinical applications. Pharmacol Ther 90:105–156

    CAS  PubMed  Google Scholar 

  • Levine B, Mizushima N, Virgin HW (2011) Autophagy in immunity and inflammation. Nature 469:323–335

    PubMed Central  CAS  PubMed  Google Scholar 

  • Li W, Ai N, Wang S, Bhattacharya N, Vrbanac V, Collins M, Signoretti S, Hu Y, Boyce FM, Gravdal K, Halvorsen OJ, Nalwoga H, Akslen LA, Harlow E, Watnick RS (2014) GRK3 is essential for metastatic cells and promotes prostate tumor progression. Proc Natl Acad Sci USA 111:1521–1526

    PubMed Central  CAS  PubMed  Google Scholar 

  • Lijnen HR, Frederix L, Scroyen I (2007) Deficiency of plasminogen activator inhibitor-2 impairs nutritionally induced murine adipose tissue development. J Thromb Haemost 5:2259–2265

    CAS  PubMed  Google Scholar 

  • Lin BT, Wang JY (1992) Cell cycle regulation of retinoblastoma protein phosphorylation. Ciba Found Symp 170:227–241

    CAS  PubMed  Google Scholar 

  • Losick VP, Isberg RR (2006) NF-kappaB translocation prevents host cell death after low-dose challenge by Legionella pneumophila. J Exp Med 203:2177–2189

    PubMed Central  CAS  PubMed  Google Scholar 

  • Major LD, Partridge TS, Gardner J, Kent SJ, de Rose R, Suhrbier A, Schroder WA (2013) Induction of SerpinB2 and Th1/Th2 modulation by SerpinB2 during lentiviral infections in vivo. PLoS One 8, e57343

    PubMed Central  CAS  PubMed  Google Scholar 

  • Medcalf RL (2007) Fibrinolysis, inflammation, and regulation of the plasminogen activating system. J Thromb Haemost 5(Suppl 1):132–142

    CAS  PubMed  Google Scholar 

  • Medcalf RL (2011) Plasminogen activator inhibitor type 2: still an enigmatic serpin but a model for gene regulation. Methods Enzymol 499:105–134

    CAS  PubMed  Google Scholar 

  • Medcalf RL, Stasinopoulos SJ (2005) The undecided serpin. The ins and outs of plasminogen activator inhibitor type 2. FEBS J 272:4858–4867

    CAS  PubMed  Google Scholar 

  • Medcalf RL, Kruithof EK, Schleuning WD (1988) Plasminogen activator inhibitor 1 and 2 are tumor necrosis factor/cachectin-responsive genes. J Exp Med 168:751–759

    CAS  PubMed  Google Scholar 

  • Mirlashari MR, Hoiby EA, Holst J, Lyberg T (2001) Outer membrane vesicles from Neisseria meningitidis: effects on tissue factor and plasminogen activator inhibitor-2 production in human monocytes. Thromb Res 102:375–380

    CAS  PubMed  Google Scholar 

  • Montemurro P, Barbuti G, Conese M, Gabriele S, Petio M, Colucci M, Semeraro N (1999) Retinoic acid stimulates plasminogen activator inhibitor 2 production by blood mononuclear cells and inhibits urokinase-induced extracellular proteolysis. Br J Haematol 107:294–299

    CAS  PubMed  Google Scholar 

  • Montemurro P, Barbuti G, Dundon WG, Del Giudice G, Rappuoli R, Colucci M, De Rinaldis P, Montecucco C, Semeraro N, Papini E (2001) Helicobacter pylori neutrophil-activating protein stimulates tissue factor and plasminogen activator inhibitor-2 production by human blood mononuclear cells. J Infect Dis 183:1055–1062

    CAS  PubMed  Google Scholar 

  • Mosser DM, Edwards JP (2008) Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8:958–969

    PubMed Central  CAS  PubMed  Google Scholar 

  • Mueller BM, Yu YB, Laug WE (1995) Overexpression of plasminogen activator inhibitor 2 in human melanoma cells inhibits spontaneous metastasis in scid/scid mice. Proc Natl Acad Sci USA 92:205–209

    PubMed Central  CAS  PubMed  Google Scholar 

  • Nordengren J, Fredstorp LM, Bendahl PO, Brunner N, Ferno M, Hogberg T, Stephens RW, Willen R, Casslen B (2002) High tumor tissue concentration of plasminogen activator inhibitor 2 (PAI-2) is an independent marker for shorter progression-free survival in patients with early stage endometrial cancer. Int J Cancer 97:379–385

    CAS  PubMed  Google Scholar 

  • O’Hara A, Howarth A, Varro A, Dimaline R (2013) The role of proteasome beta subunits in gastrin-mediated transcription of plasminogen activator inhibitor-2 and regenerating protein1. PLoS One 8, e59913

    PubMed Central  PubMed  Google Scholar 

  • Palafox-Sanchez CA, Vazquez-Del Mercado M, Orozco-Barocio G, Garcia-De la Torre I, Torres-Carrillo N, Torres-Carrillo NM, Illades-Aguiar B, Munoz-Valle JF (2009) A functional Ser(413)/Ser(413) PAI-2 polymorphism is associated with susceptibility and damage index score in systemic lupus erythematosus. Clin Appl Thromb Hemost 15:233–238

    CAS  PubMed  Google Scholar 

  • Park JM, Greten FR, Wong A, Westrick RJ, Arthur JS, Otsu K, Hoffmann A, Montminy M, Karin M (2005) Signaling pathways and genes that inhibit pathogen-induced macrophage apoptosis--CREB and NF-kappaB as key regulators. Immunity 23:319–329

    CAS  PubMed  Google Scholar 

  • Platini F, Perez-Tomas R, Ambrosio S, Tessitore L (2010) Understanding autophagy in cell death control. Curr Pharm Des 16:101–113

    CAS  PubMed  Google Scholar 

  • Plow EF, Herren T, Redlitz A, Miles LA, Hoover-Plow JL (1995) The cell biology of the plasminogen system. FASEB J 9:939–945

    CAS  PubMed  Google Scholar 

  • Praus M, Wauterickx K, Collen D, Gerard RD (1999) Reduction of tumor cell migration and metastasis by adenoviral gene transfer of plasminogen activator inhibitors. Gene Ther 6:227–236

    CAS  PubMed  Google Scholar 

  • Ranson M, Berghofer P, Vine KL, Greguric I, Shepherd R, Katsifis A (2012) Different radiolabelling methods alter the pharmacokinetic and biodistribution properties of plasminogen activator inhibitor type 2 (PAI-2) forms. Nucl Med Biol 39:833–839

    CAS  PubMed  Google Scholar 

  • Remold-O’Donnell E (1993) The ovalbumin family of serpin proteins. FEBS Lett 315:105–108

    PubMed  Google Scholar 

  • Rinker-Schaeffer CW, O’Keefe JP, Welch DR, Theodorescu D (2006) Metastasis suppressor proteins: discovery, molecular mechanisms, and clinical application. Clin Cancer Res 12:3882–3889

    PubMed Central  CAS  PubMed  Google Scholar 

  • Rushworth LK, Kidger AM, Delavaine L, Stewart G, van Schelven S, Davidson J, Bryant CJ, Caddye E, East P, Caunt CJ, Keyse SM (2014) Dual-specificity phosphatase 5 regulates nuclear ERK activity and suppresses skin cancer by inhibiting mutant Harvey-Ras (HRasQ61L)-driven SerpinB2 expression. Proc Natl Acad Sci USA 111:18267–18272

    PubMed Central  CAS  PubMed  Google Scholar 

  • Schleuning WD, Medcalf RL, Hession C, Rothenbuhler R, Shaw A, Kruithof EK (1987) Plasminogen activator inhibitor 2: regulation of gene transcription during phorbol ester-mediated differentiation of U-937 human histiocytic lymphoma cells. Mol Cell Biol 7:4564–4567

    PubMed Central  CAS  PubMed  Google Scholar 

  • Schroder WA, Le TT, Major L, Street S, Gardner J, Lambley E, Markey K, MacDonald KP, Fish RJ, Thomas R, Suhrbier A (2010a) A physiological function of inflammation-associated SerpinB2 is regulation of adaptive immunity. J Immunol 184:2663–2670

    CAS  PubMed  Google Scholar 

  • Schroder WA, Gardner J, Le TT, Duke M, Burke ML, Jones MK, McManus DP, Suhrbier A (2010b) SerpinB2 deficiency modulates Th1Th2 responses after schistosome infection. Parasite Immunol 32:764–768

    CAS  PubMed  Google Scholar 

  • Schroder WA, Major L, Suhrbier A (2011) The role of SerpinB2 in immunity. Crit Rev Immunol 31:15–30

    CAS  PubMed  Google Scholar 

  • Schroder WA, Major LD, Le TT, Gardner J, Sweet MJ, Janciauskiene S, Suhrbier A (2014) Tumor cell-expressed SerpinB2 is present on microparticles and inhibits metastasis. Cancer Med 3:500–513

    PubMed Central  CAS  PubMed  Google Scholar 

  • Schuster WA, Medcalf RL, Kruithof EK (1993) Retinoic acid potentiates phorbol ester-mediated induction of urokinase and plasminogen activator inhibitor type 2 in human myeloid leukemic cell lines. Endocrinology 133:1724–1730

    CAS  PubMed  Google Scholar 

  • Schuster WA, Medcalf RL, Kruithof EKO (1994) Localization and characterization of a retinoic acid response-like element in the plasminogen activator inhibitor-2 gene promoter. Fibrinolysis 8:113–9

    CAS  Google Scholar 

  • Shafren DR, Gardner J, Mann VH, Antalis TM, Suhrbier A (1999) Picornavirus receptor down-regulation by plasminogen activator inhibitor type 2. J Virol 73:7193–7198

    PubMed Central  CAS  PubMed  Google Scholar 

  • Sharon R, Abramovitz R, Miskin R (2002) Plasminogen mRNA induction in the mouse brain after kainate excitation: codistribution with plasminogen activator inhibitor-2 (PAI-2) mRNA. Brain Res Mol Brain Res 104:170–175

    CAS  PubMed  Google Scholar 

  • Shimizu T, Sato K, Suzuki T, Tachibana K, Takeda K (2003) Induction of plasminogen activator inhibitor-2 is associated with suppression of invasive activity in TPA-mediated differentiation of human prostate cancer cells. Biochem Biophys Res Commun 309:267–271

    CAS  PubMed  Google Scholar 

  • Siefert SA, Chabasse C, Mukhopadhyay S, Hoofnagle MH, Strickland DK, Sarkar R, Antalis TM (2014) Enhanced venous thrombus resolution in plasminogen activator inhibitor type-2 deficient mice. J Thromb Haemost 12:1706–1716

    PubMed Central  CAS  PubMed  Google Scholar 

  • Silverman GA, Bird PI, Carrell RW, Church FC, Coughlin PB, Gettins PG, Irving JA, Lomas DA, Luke CJ, Moyer RW, Pemberton PA, Remold-O’Donnell E, Salvesen GS, Travis J, Whisstock JC (2001) The serpins are an expanding superfamily of structurally similar but functionally diverse proteins. Evolution, mechanism of inhibition, novel functions, and a revised nomenclature. J Biol Chem 276:33293–33296

    CAS  PubMed  Google Scholar 

  • Singh I, Burnand KG, Collins M, Luttun A, Collen D, Boelhouwer B, Smith A (2003) Failure of thrombus to resolve in urokinase-type plasminogen activator gene-knockout mice: rescue by normal bone marrow-derived cells. Circulation 107:869–875

    CAS  PubMed  Google Scholar 

  • Stringer B, Udofa EA, Antalis TM (2012) Regulation of the human plasminogen activator inhibitor type 2 gene: cooperation of an upstream silencer and transactivator. J Biol Chem 287:10579–10589

    PubMed Central  CAS  PubMed  Google Scholar 

  • Swartz JM, Bystrom J, Dyer KD, Nitto T, Wynn TA, Rosenberg HF (2004) Plasminogen activator inhibitor-2 (PAI-2) in eosinophilic leukocytes. J Leukoc Biol 76:812–819

    CAS  PubMed  Google Scholar 

  • Tan PH, Xue SA, Manunta M, Beutelspacher SC, Fazekasova H, Alam AK, McClure MO, George AJ (2006) Effect of vectors on human endothelial cell signal transduction: implications for cardiovascular gene therapy. Arterioscler Thromb Vasc Biol 26:462–467

    CAS  PubMed  Google Scholar 

  • Tapiovaara H, Matikainen S, Hurme M, Vaheri A (1994) Induction of differentiation of promyelocytic NB4 cells by retinoic acid is associated with rapid increase in urokinase activity subsequently downregulated by production of inhibitors. Blood 83:1883–1891

    CAS  PubMed  Google Scholar 

  • Tarcic G, Avraham R, Pines G, Amit I, Shay T, Lu Y, Zwang Y, Katz M, Ben-Chetrit N, Jacob-Hirsch J, Virgilio L, Rechavi G, Mavrothalassitis G, Mills GB, Domany E, Yarden Y (2012) EGR1 and the ERK-ERF axis drive mammary cell migration in response to EGF. FASEB J 26:1582–1592

    PubMed Central  CAS  PubMed  Google Scholar 

  • Tonnetti L, Netzel-Arnett S, Darnell GA, Hayes T, Buzza MS, Anglin IE, Suhrbier A, Antalis TM (2008) SerpinB2 protection of retinoblastoma protein from calpain enhances tumor cell survival. Cancer Res 68:5648–5657

    PubMed Central  CAS  PubMed  Google Scholar 

  • Toyman U, Tuter G, Kurtis B, Kivrak E, Bozkurt S, Yucel AA, Serdar M (2015) Evaluation of gingival crevicular fluid levels of tissue plasminogen activator, plasminogen activator inhibitor 2, matrix metalloproteinase-3 and interleukin 1-beta in patients with different periodontal diseases. J Periodontal Res 50:44–51

    CAS  PubMed  Google Scholar 

  • Tyner JW, Uchida O, Kajiwara N, Kim EY, Patel AC, O’Sullivan MP, Walter MJ, Schwendener RA, Cook DN, Danoff TM, Holtzman MJ (2005) CCL5-CCR5 interaction provides antiapoptotic signals for macrophage survival during viral infection. Nat Med 11:1180–1187

    CAS  PubMed  Google Scholar 

  • Udofa EA, Stringer BW, Gade P, Mahony D, Buzza MS, Kalvakolanu DV, Antalis TM (2013) The transcription factor C/EBP-beta mediates constitutive and LPS-inducible transcription of murine SerpinB2. PLoS One 8, e57855

    PubMed Central  CAS  PubMed  Google Scholar 

  • Valiente M, Obenauf AC, Jin X, Chen Q, Zhang XH, Lee DJ, Chaft JE, Kris MG, Huse JT, Brogi E, Massague J (2014) Serpins promote cancer cell survival and vascular co-option in brain metastasis. Cell 156:1002–1016

    PubMed Central  CAS  PubMed  Google Scholar 

  • van den Akker J, van Weert A, Afink G, Bakker EN, van der Pol E, Boing AN, Nieuwland R, Van Bavel E (2012) Transglutaminase 2 is secreted from smooth muscle cells by transamidation-dependent microparticle formation. Amino Acids 42:961–973

    PubMed Central  PubMed  Google Scholar 

  • Varro A, Noble PJ, Pritchard DM, Kennedy S, Hart CA, Dimaline R, Dockray GJ (2004) Helicobacter pylori induces plasminogen activator inhibitor 2 in gastric epithelial cells through nuclear factor-kappaB and RhoA: implications for invasion and apoptosis. Cancer Res 64:1695–1702

    CAS  PubMed  Google Scholar 

  • Vassalli JD, Sappino AP, Belin D (1991) The plasminogen activator/plasmin system. J Clin Invest 88:1067–1072

    PubMed Central  CAS  PubMed  Google Scholar 

  • Vazquez-Del Mercado M, Garcia-Cobian TA, Munoz Valle JF, Torres-Carrillo N, Martin-Marquez BT, Arana-Argaez VE, Best-Aguilera CR, Martinez-Garcia EA, Petri MH, Nunez-Atahualpa L, Delgado-Rizo V (2007) Genotype Ser413/Ser of PAI-2 polymorphism Ser413/Cys is associated with anti-phospholipid syndrome and systemic lupus erythematosus in a familial case: comparison with healthy controls. Scand J Rheumatol 36:206–210

    CAS  PubMed  Google Scholar 

  • Vine KL, Indira CV, Locke JM, Matesic L, Lee J, Skropeta D, Bremner JB, Ranson M (2012) Targeting urokinase and the transferrin receptor with novel, anti-mitotic N-alkylisatin cytotoxin conjugates causes selective cancer cell death and reduces tumor growth. Curr Cancer Drug Targets 12:64–73

    CAS  PubMed  Google Scholar 

  • Vine KL, Lobov S, Chandran VI, Harris NL, Ranson M (2015) Improved pharmacokinetic and biodistribution properties of the selective urokinase inhibitor PAI-2 (SerpinB2) by site-specific PEGylation: implications for drug delivery. Pharm Res 32(3):1045–54

    CAS  PubMed  Google Scholar 

  • von Heijne G, Liljestrom P, Mikus P, Andersson H, Ny T (1991) The efficiency of the uncleaved secretion signal in the plasminogen activator inhibitor type 2 protein can be enhanced by point mutations that increase its hydrophobicity. J Biol Chem 266:15240–15243

    Google Scholar 

  • Webb AC, Collins KL, Snyder SE, Alexander SJ, Rosenwasser LJ, Eddy RL, Shows TB, Auron PE (1987) Human monocyte Arg-Serpin cDNA. Sequence, chromosomal assignment, and homology to plasminogen activator-inhibitor. J Exp Med 166:77–94

    CAS  PubMed  Google Scholar 

  • White E (2012) Deconvoluting the context-dependent role for autophagy in cancer. Nat Rev Cancer 12:401–410

    PubMed Central  CAS  PubMed  Google Scholar 

  • Wilczynska M, Lobov S, Ohlsson PI, Ny T (2003) A redox-sensitive loop regulates plasminogen activator inhibitor type 2 (PAI-2) polymerization. EMBO J 22:1753–1761

    PubMed Central  CAS  PubMed  Google Scholar 

  • Woodruff PG, Boushey HA, Dolganov GM, Barker CS, Yang YH, Donnelly S, Ellwanger A, Sidhu SS, Dao-Pick TP, Pantoja C, Erle DJ, Yamamoto KR, Fahy JV (2007) Genome-wide profiling identifies epithelial cell genes associated with asthma and with treatment response to corticosteroids. Proc Natl Acad Sci USA 104:15858–15863

    PubMed Central  CAS  PubMed  Google Scholar 

  • Wun TC, Reich E (1987) An inhibitor of plasminogen activation from human placenta. Purification and characterization. J Biol Chem 262:3646–3653

    CAS  PubMed  Google Scholar 

  • Wygrecka M, Markart P, Ruppert C, Kuchenbuch T, Fink L, Bohle RM, Grimminger F, Seeger W, Gunther A (2004) Compartment- and cell-specific expression of coagulation and fibrinolysis factors in the murine lung undergoing inhalational versus intravenous endotoxin application. Thromb Haemost 92:529–540

    CAS  PubMed  Google Scholar 

  • Xiao Y, Li H, Bunn C, Bartold PM (2001) The expression of plasminogen activator system in a rat model of periodontal wound healing. J Periodontol 72:849–857

    CAS  PubMed  Google Scholar 

  • Ye RD, Wun TC, Sadler JE (1987) cDNA cloning and expression in Escherichia coli of a plasminogen activator inhibitor from human placenta. J Biol Chem 262:3718–3725

    CAS  PubMed  Google Scholar 

  • Ye RD, Ahern SM, Le Beau MM, Lebo RV, Sadler JE (1989) Structure of the gene for human plasminogen activator inhibitor-2. The nearest mammalian homologue of chicken ovalbumin. J Biol Chem 264:5495–5502

    CAS  PubMed  Google Scholar 

  • Yu H, Maurer F, Medcalf RL (2002) Plasminogen activator inhibitor type 2: a regulator of monocyte proliferation and differentiation. Blood 99:2810–2818

    CAS  PubMed  Google Scholar 

  • Zhang SJ, Zou M, Lu L, Lau D, Ditzel DA, Delucinge-Vivier C, Aso Y, Descombes P, Bading H (2009) Nuclear calcium signaling controls expression of a large gene pool: identification of a gene program for acquired neuroprotection induced by synaptic activity. PLoS Genet 5, e1000604

    PubMed Central  PubMed  Google Scholar 

  • Zhang Y, Morgan MJ, Chen K, Choksi S, Liu ZG (2012) Induction of autophagy is essential for monocyte-macrophage differentiation. Blood 119:2895–2905

    PubMed Central  CAS  PubMed  Google Scholar 

  • Zhao A, Yang Z, Sun R, Grinchuk V, Netzel-Arnett S, Anglin IE, Driesbaugh KH, Notari L, Bohl JA, Madden KB, Urban JF Jr, Antalis TM, Shea-Donohue T (2013) SerpinB2 is critical to Th2 immunity against enteric nematode infection. J Immunol 190:5779–5787

    PubMed Central  CAS  PubMed  Google Scholar 

  • Zhou HM, Bolon I, Nichols A, Wohlwend A, Vassalli JD (2001) Overexpression of plasminogen activator inhibitor type 2 in basal keratinocytes enhances papilloma formation in transgenic mice. Cancer Res 61:970–976

    CAS  PubMed  Google Scholar 

  • Zou Z, Zeng F, Xu W, Wang C, Ke Z, Wang QJ, Deng F (2012) PKD2 and PKD3 promote prostate cancer cell invasion by modulating NF-kappaB- and HDAC1-mediated expression and activation of uPA. J Cell Sci 125:4800–4811

    PubMed Central  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Physiology, Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Biopark Building One, Room 235, 800 West Baltimore Street, Baltimore, MD, 21201, USA

    Tierra A. Johnson, Marguerite S. Buzza Ph.D. & Ekemini A. U. Riley Ph.D.

  2. Department of Physiology, Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Biopark Building One, Room 220, 800 West Baltimore Street, Baltimore, MD, 21201, USA

    Toni M. Antalis Ph.D.

Authors
  1. Tierra A. Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marguerite S. Buzza Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ekemini A. U. Riley Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Toni M. Antalis Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Toni M. Antalis Ph.D. .

Editor information

Editors and Affiliations

  1. Department of Vascular Biology and Thrombosis Research, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria

    Margarethe Geiger

  2. Department of Vascular Biology and Thrombosis Research, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria

    Felix Wahlmüller

  3. Department of Vascular Biology and Thrombosis Research, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria

    Margareta Furtmüller

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Johnson, T.A., Buzza, M.S., Riley, E.A.U., Antalis, T.M. (2015). Plasminogen Activator Inhibitor Type-2 (PAI-2)/SerpinB2: A Unique Multifunctional Serpin. In: Geiger, M., Wahlmüller, F., Furtmüller, M. (eds) The Serpin Family. Springer, Cham. https://doi.org/10.1007/978-3-319-22711-5_8

Download citation

Publish with us

Policies and ethics

Search

Navigation