Genomes and Genes
plasminogen activator inhibitor 2
Summary: Member of the serpin family of proteins. It inhibits both the tissue-type and urokinase-type plasminogen activators.
- Jankova L, Harrop S, Saunders D, Andrews J, Bertram K, Gould A, et al. Crystal structure of the complex of plasminogen activator inhibitor 2 with a peptide mimicking the reactive center loop. J Biol Chem. 2001;276:43374-82 pubmed..This torsional change is due to the binding of the P14 threonine of the RCL to the open breach region of PAI-2. ..
- Dougherty K, Pearson J, Yang A, Westrick R, Baker M, Ginsburg D. The plasminogen activator inhibitor-2 gene is not required for normal murine development or survival. Proc Natl Acad Sci U S A. 1999;96:686-91 pubmed..Finally, crossing PAI-2 -/- with PAI-1 -/- mice to generate animals deficient in both plasminogen activator inhibitors failed to uncover an overlap in function between these two related proteins. ..
- Boncela J, Przygodzka P, Papiewska Pajak I, Wyroba E, Cierniewski C. Association of plasminogen activator inhibitor type 2 (PAI-2) with proteasome within endothelial cells activated with inflammatory stimuli. J Biol Chem. 2011;286:43164-71 pubmed publisher..This suggests that PAI-2, in endothelial cells induced with inflammatory stimuli, can inhibit proteasome and thus tilt the balance favoring proapoptotic signaling. ..
- Song Y, Qu C, Rizvi S, Li Y, Robertson G, Raja C, et al. Cytotoxicity of PAI2, C595 and Herceptin vectors labeled with the alpha-emitting radioisotope Bismuth-213 for ovarian cancer cell monolayers and clusters. Cancer Lett. 2006;234:176-83 pubmed..These ACs are potential candidates for the control of ovarian cancer at the minimum residual disease (MRD) stage...
- Croucher D, Saunders D, Stillfried G, Ranson M. A structural basis for differential cell signalling by PAI-1 and PAI-2 in breast cancer cells. Biochem J. 2007;408:203-10 pubmed..We thus propose a structurally based mechanism for these differences between PAI-1 and PAI-2 and suggest that PAI-2 is able to inhibit and clear uPA activity without initiating mitogenic signalling events through VLDLr. ..
- Wilczynska M, Lobov S, Ohlsson P, Ny T. A redox-sensitive loop regulates plasminogen activator inhibitor type 2 (PAI-2) polymerization. EMBO J. 2003;22:1753-61 pubmed..Taken together, our data suggest that the CD-loop functions as a redox-sensitive switch that converts PAI-2 between an active stable monomeric and a polymerogenic conformation, which is prone to form inactive polymers. ..
- Allen B, Tian Z, Rizvi S, Li Y, Ranson M. Preclinical studies of targeted alpha therapy for breast cancer using 213Bi-labelled-plasminogen activator inhibitor type 2. Br J Cancer. 2003;88:944-50 pubmed..Thus, (213)Bi-PAI2 is successful in targeting isolated breast cancer cells and preangiogenic cell clusters. These results indicate the promising potential of (213)Bi-PAI2 as a novel therapeutic agent for micrometastatic breast cancer. ..
- Dickinson J, Bates E, Ferrante A, Antalis T. Plasminogen activator inhibitor type 2 inhibits tumor necrosis factor alpha-induced apoptosis. Evidence for an alternate biological function. J Biol Chem. 1995;270:27894-904 pubmed..The results suggest that intracellular PAI-2 might be an important factor in regulating cell death in TNF-mediated inflammatory processes through inhibition of a proteinase involved in TNF-induced apoptosis. ..
- Varro A, Hemers E, Archer D, Pagliocca A, Haigh C, Ahmed S, et al. Identification of plasminogen activator inhibitor-2 as a gastrin-regulated gene: Role of Rho GTPase and menin. Gastroenterology. 2002;123:271-80 pubmed..Gene expression was studied using promoter-luciferase reporter constructs. Plasminogen activator inhibitor 2 (PAI-2) was identified as a major, previously unknown target of gastrin in the gastric cancer cell ..
- Lee J, Cochran B, Lobov S, Ranson M. Forty years later and the role of plasminogen activator inhibitor type 2/SERPINB2 is still an enigma. Semin Thromb Hemost. 2011;37:395-407 pubmed publisher..This review readdresses the evidence supporting a role for PAI-2 in fibrinolysis and proteolysis within extracellular environments and includes a review of the many potential intracellular functions attributed to PAI-2. ..
- Wilczynska M, Lobov S, Ny T. The spontaneous polymerization of plasminogen activator inhibitor type-2 and Z-antitrypsin are due to different molecular aberrations. FEBS Lett. 2003;537:11-6 pubmed..Rather, PAI-2 exists in a highly polymerogenic conformation and does not require conformational rearrangements before polymerization can take place. ..
- Nicholl S, Roztocil E, Davies M. Plasminogen activator system and vascular disease. Curr Vasc Pharmacol. 2006;4:101-16 pubmed
- Xiao G, Liu Y, Gentz R, Sang Q, Ni J, Goldberg I, et al. Suppression of breast cancer growth and metastasis by a serpin myoepithelium-derived serine proteinase inhibitor expressed in the mammary myoepithelial cells. Proc Natl Acad Sci U S A. 1999;96:3700-5 pubmed..The expression of MEPI in myoepithelial cells may prevent breast cancer malignant progression leading to metastasis. ..
- Ritchie H, Robbie L, Kinghorn S, Exley R, Booth N. 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 pubmedb>Plasminogen activator inhibitor 2 (PAI-2) is a major product of activated human monocytes. Here we show that monocytes inhibited u-PA- but not t-PA-mediated fibrinolysis, by secreting PAI-2 into an overlying fibrin clot...
- Palafox Sánchez C, Vazquez Del Mercado M, Orozco Barocio G, Garcia de la Torre I, Torres Carrillo N, Torres Carrillo N, et al. 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. 2009;15:233-8 pubmed publisher..Besides, PAI-2 polymorphism could be related with thrombotic phenomena in systemic lupus erythematosus. ..
- Ohba K, Miyata Y, Kanda S, Koga S, Hayashi T, Kanetake H. Expression of urokinase-type plasminogen activator, urokinase-type plasminogen activator receptor and plasminogen activator inhibitors in patients with renal cell carcinoma: correlation with tumor associated macrophage and prognosis. J Urol. 2005;174:461-5 pubmed..On the other hand, PAI-2 has a minimum role in survival. Our results may help discussions of treatment strategy in patients with RCC. ..
- Lian X, Yang T. Plasminogen activator inhibitor 2: expression and role in differentiation of epidermal keratinocyte. Biol Cell. 2004;96:109-16 pubmedb>Plasminogen activator inhibitor 2 (PAI-2) is an enzyme inhibitor which is involved in cell differentiation, tissue growth and regeneration...
- Al Ejeh F, Croucher D, Ranson M. Kinetic analysis of plasminogen activator inhibitor type-2: urokinase complex formation and subsequent internalisation by carcinoma cell lines. Exp Cell Res. 2004;297:259-71 pubmed..PAI-2 was subsequently degraded, presumably within lysosomes. This study is the first to provide definitive evidence for uPA/uPAR-mediated PAI-2 endocytosis. ..
- Lobov S, Wilczynska M, Bergström F, Johansson L, Ny T. Structural bases of the redox-dependent conformational switch in the serpin PAI-2. J Mol Biol. 2004;344:1359-68 pubmed
- Abbas Rizvi S, Li Y, Song E, Qu C, Raja C, Morgenstern A, et al. Preclinical studies of bismuth-213 labeled plasminogen activator inhibitor type 2 (PAI2) in a prostate cancer nude mouse xenograft model. Cancer Biol Ther. 2006;5:386-93 pubmed..The efficacy of single and multiple dose TAT in mice was demonstrated within tolerance limits, the multiple dose regime being no more toxic than the single dose. Either of the two chelators could be used for 213Bi studies. ..
- Robbie L, Dummer S, Booth N, Adey G, Bennett B. Plasminogen activator inhibitor 2 and urokinase-type plasminogen activator in plasma and leucocytes in patients with severe sepsis. Br J Haematol. 2000;109:342-8 pubmed..Leucocyte release of these agents within fibrin deposits may influence the persistence of fibrin and thus the development of multiple organ failure. ..
- Duffy M, Duggan C. The urokinase plasminogen activator system: a rich source of tumour markers for the individualised management of patients with cancer. Clin Biochem. 2004;37:541-8 pubmed..The measurement of uPA components, especially in breast cancer, thus has the potential to help with individualised patient management. ..
- Nordengren J, Fredstorp Lidebring M, Bendahl P, Brunner N, Fernö M, Hogberg T, et al. 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. 2002;97:379-85 pubmed..including various tumor types have shown different associations between tumor tissue levels of plasminogen activator inhibitor 2 (PAI-2) and patient survival...
- Yu H, Maurer F, Medcalf R. Plasminogen activator inhibitor type 2: a regulator of monocyte proliferation and differentiation. Blood. 2002;99:2810-8 pubmed..These results implicate endogenous PAI-2 as a modulator of monocyte adhesion, proliferation, and differentiation. ..
- Myöhänen H, Vaheri A. Regulation and interactions in the activation of cell-associated plasminogen. Cell Mol Life Sci. 2004;61:2840-58 pubmed..The functional role of the PAIs is no longer simply to inhibit overexpressed plasminogen activators, and PAI-2 has an unidentified role in the regulation of cell death. ..
- Brenner B. Haemostatic changes in pregnancy. Thromb Res. 2004;114:409-14 pubmed..Disruption of anticoagulant mechanisms, for example, autoantibodies, to annexin V may increase pregnancy complications in patients with antiphospholipid antibodies (APLA). ..
- Foekens J, Peters H, Look M, Portengen H, Schmitt M, Kramer M, et al. The urokinase system of plasminogen activation and prognosis in 2780 breast cancer patients. Cancer Res. 2000;60:636-43 pubmed..Knowledge of these factors could be helpful to assess the individual risk of patients, to select various types of adjuvant treatment and to identify patients who may benefit from targeted therapies that are currently being developed. ..
- Yoshino H, Endo Y, Watanabe Y, Sasaki T. Significance of plasminogen activator inhibitor 2 as a prognostic marker in primary lung cancer: association of decreased plasminogen activator inhibitor 2 with lymph node metastasis. Br J Cancer. 1998;78:833-9 pubmed
- Schroder W, Gardner J, Le T, Duke M, Burke M, Jones M, et al. SerpinB2 deficiency modulates Th1?Th2 responses after schistosome infection. Parasite Immunol. 2010;32:764-8 pubmed..SerpinB2-/- mice immunized with soluble egg antigen (SEA) also showed reduced levels of SEA-specific IgG1. SerpinB2 deficiency thus promoted certain Th1 and reduced certain Th2 responses in response to this Th2 immunogen. ..
- Humphries J, Burnand K, Cunningham P, Brock A, Westwood N, Smith A. Identification of potentially effective antisense oligodeoxyribonucleotide (ODN) sequences for inhibiting plasminogen activator inhibitor-2 (PAI-2) production by monocytes. Thromb Haemost. 2002;88:131-6 pubmed..3 ng/ml, sem 4.5, p = 0.0112) and baseline (mean 51.4 ng/ml, sem 6.7, p = 0.0009). Use of the RRL screening system allowed the selection of a novel antisense sequence, which significantly reduced PAI-2 production in monocytes. ..
- Mikus P, Urano T, Liljestrom P, Ny T. Plasminogen-activator inhibitor type 2 (PAI-2) is a spontaneously polymerising SERPIN. Biochemical characterisation of the recombinant intracellular and extracellular forms. Eur J Biochem. 1993;218:1071-82 pubmed..Instead, this treatment enhanced the formation of PAI-2 polymers, possibly by the loop-sheet polymerisation mechanism described for alpha 1-antitrypsin. ..
- Jensen P, Cressey L, Gjertsen B, Madsen P, Mellgren G, Hokland P, et al. Cleaved intracellular plasminogen activator inhibitor 2 in human myeloleukaemia cells is a marker of apoptosis. Br J Cancer. 1994;70:834-40 pubmedThe proteolytic modification of plasminogen activator inhibitor 2 (PAI-2) was studied during apoptosis in the human promyelocytic leukaemic NB4 cell line during treatment with the phosphatase inhibitors okadaic acid and calyculin A as ..
- Li Y, Rizvi S, Ranson M, Allen B. 213Bi-PAI2 conjugate selectively induces apoptosis in PC3 metastatic prostate cancer cell line and shows anti-cancer activity in a xenograft animal model. Br J Cancer. 2002;86:1197-203 pubmed
- Park J, Greten F, Wong A, Westrick R, Arthur J, Otsu K, et al. Signaling pathways and genes that inhibit pathogen-induced macrophage apoptosis--CREB and NF-kappaB as key regulators. Immunity. 2005;23:319-29 pubmed..Here we describe key roles for transcription factor CREB, a target for p38 signaling, and the plasminogen activator 2 (PAI-2) gene, a target for CREB, in maintenance of macrophage survival. ..
- Croucher D, Saunders D, 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;281:10206-13 pubmed..Furthermore, lack of a direct interaction between PAI-2 and LRP implies that downstream signaling events initiated by PAI-1 may not be activated by PAI-2. ..
- Darnell G, Antalis T, Johnstone R, Stringer B, Ogbourne S, Harrich D, et al. Inhibition of retinoblastoma protein degradation by interaction with the serpin plasminogen activator inhibitor 2 via a novel consensus motif. Mol Cell Biol. 2003;23:6520-32 pubmed..These results indicate that PAI-2 may enhance Rb's tumor suppressor activity and suggest a potential therapeutic role for PAI-2 against HPV-transformed lesions. ..
- Stasinopoulos S, Mariasegaram M, Gafforini C, Nagamine Y, Medcalf R. The plasminogen activator inhibitor 2 transcript is destabilized via a multi-component 3' UTR localized adenylate and uridylate-rich instability element in an analogous manner to cytokines and oncogenes. FEBS J. 2010;277:1331-44 pubmed publisher..Hence, post-transcriptional regulation of the PAI-2 mRNA transcript involves an interaction between closely spaced adenylate-uridylate elements in a manner analogous to the post-transcriptional regulation of oncogenes and cytokines. ..
- Duffy M. The urokinase plasminogen activator system: role in malignancy. Curr Pharm Des. 2004;10:39-49 pubmed..Finally, preclinical studies show that either inhibition of uPA catalytic activity or prevention of uPA binding to its receptor reduces tumor growth, angiogenesis and metastasis. ..
- Di Giusto D, Sutherland A, Jankova L, Harrop S, Curmi P, King G. Plasminogen activator inhibitor-2 is highly tolerant to P8 residue substitution--implications for serpin mechanistic model and prediction of nsSNP activities. J Mol Biol. 2005;353:1069-80 pubmed
- Darnell G, Schroder W, Gardner J, Harrich D, Yu H, Medcalf R, et al. SerpinB2 is an inducible host factor involved in enhancing HIV-1 transcription and replication. J Biol Chem. 2006;281:31348-58 pubmed..This is the first report associating HIV-1 replication with SerpinB2 expression and illustrates that SerpinB2 is a potentially important inducible host factor that significantly promotes HIV-1 replication. ..
- Qu C, Song E, Li Y, Rizvi S, Raja C, Smith R, et al. Pre-clinical study of 213Bi labeled PAI2 for the control of micrometastatic pancreatic cancer. Clin Exp Metastasis. 2005;22:575-86 pubmed..213)Bi-PAI2 can specifically target pancreatic cancer cells in vitro and inhibit tumor growth in vivo. (213)Bi-PAI2 may be a useful agent for the treatment of post-surgical pancreatic cancer patients with minimum residual disease. ..
- Unlu A, Leake R. Transforming growth factor beta1 stimulates urokinase plasminogen activator system on prostate cancer cells. Int J Biol Markers. 2003;18:147-51 pubmed..In conclusion, the potential contribution of TGFbeta1 to tumor invasion may be considered as positive, based on both loss of growth inhibition and stimulation of components of the invasive system of prostate carcinoma...
- Ahn N, Hu H, Park J, Park J, Kim J, An S, et al. Molecular mechanisms of the 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced inverted U-shaped dose responsiveness in anchorage independent growth and cell proliferation of human breast epithelial cells with stem cell characteristics. Mutat Res. 2005;579:189-99 pubmed..The fact that these genes are intrinsically related to breast epithelial cell proliferation and survival clearly suggests that they may be involved in the TCDD-induced breast tumorigenesis. ..
- Macaluso M, Montanari M, Marshall C, Gambone A, Tosi G, Giordano A, et al. Cytoplasmic and nuclear interaction between Rb family proteins and PAI-2: a physiological crosstalk in human corneal and conjunctival epithelial cells. Cell Death Differ. 2006;13:1515-22 pubmed
- Ulisse S, Baldini E, Mottolese M, Sentinelli S, Gargiulo P, Valentina B, et al. Increased expression of urokinase plasminogen activator and its cognate receptor in human seminomas. BMC Cancer. 2010;10:151 pubmed publisher..We demonstrated the increased expression of uPA and uPAR in human seminomas with respect to normal testis tissues, which may be relevant in testicular cancer progression. ..
- Vazquez Del Mercado M, García Cobián T, Muñoz Valle J, Torres Carrillo N, Martin Marquez B, Arana Argaez V, et al. 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. 2007;36:206-10 pubmed..The Ser(413)/Ser genotype demonstrated in 60% of the affected members (3/5) of this family might increase the risk for autoimmune syndromes such as APS or SLE. ..
- Wang X, Li P, Zhang Y, Hou M, Sun X, Tan L, et al. [Biological function of fusion protein ATF-PAI2CD]. Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai). 2003;35:624-8 pubmed..The results indicate that the biological characteristics of ATF-PAI2CD were very similar to those of the wide type PAI-2 (or mutants PAI-2, PAI-2CD) and to pro-uPA in binding to uPAR-bearing cells. ..
- Chappell L, Seed P, Kelly F, Briley A, Hunt B, Charnock Jones D, et al. Vitamin C and E supplementation in women at risk of preeclampsia is associated with changes in indices of oxidative stress and placental function. Am J Obstet Gynecol. 2002;187:777-84 pubmed..Antioxidant supplementation in women who were at risk of preeclampsia was associated with improvement in biochemical indices of the disease. ..
- Peters M, Mekonnen Z, Yuan S, Bhakta N, Woodruff P, Fahy J. Measures of gene expression in sputum cells can identify TH2-high and TH2-low subtypes of asthma. J Allergy Clin Immunol. 2014;133:388-94 pubmed publisher..IL-4, IL-5, and IL-13 transcripts are easily detected in sputum cells from asthmatic patients, and their expression levels can be used to classify asthma into T(H)2-high and T(H)2-low endotypes. ..