Alternative titles; symbols
HGNC Approved Gene Symbol: SERPINB2
Cytogenetic location: 18q21.33-q22.1 Genomic coordinates (GRCh38): 18:63,887,705-63,903,888 (from NCBI)
The specific inhibitors of plasminogen activators (173370, 191840) have been classified into 4 immunologically distinct groups: PAI1 type PA inhibitor from endothelial cells (173360); PAI2 type PA inhibitor from placenta, monocytes, and macrophages; urinary inhibitor; and protease-nexin-I. Antalis et al. (1988) purified human monocyte-derived plasminogen activator inhibitor to homogeneity and partially sequenced it. They used oligonucleotide probes derived from this sequence to screen a cDNA library. By nucleotide sequence analysis, they showed that the PAI2 cDNA encodes a protein containing 450 amino acids with a predicted unglycosylated molecular mass of 46,543. Plasminogen activator inhibitor-2 is also known as monocyte arg-serpin because it belongs to the superfamily of serine proteases in which the target specificity of each is determined by the amino acid residue located at its reactive center; i.e., met or val for elastase, leu for kinase, and arg for thrombin.
Webb et al. (1987) isolated the cDNA encoding a monocyte-derived PAI.
Kruithof et al. (1995) concluded that although a large body of information has accumulated on the biology, biochemistry, and clinical aspects of PAI2, suggesting that it is involved in many physiologic and pathologic processes, its precise role in placenta, in pregnancy plasma, in skin, and in inflammatory conditions, as well as the diagnostic and therapeutic possibilities of PAI2, remained to be established.
Using gene expression microarrays, Woodruff et al. (2007) found that CLCA1 (603906), periostin (POSTN; 608777), and SERPINB2 were upregulated in airway epithelial cells of individuals with asthma (see 600807), but not smokers. Corticosteroid treatment downregulated expression of these 3 genes and upregulated expression of FKBP51 (602623). High baseline expression of CLCA1, POSTN, and SERPINB2 was associated with a good clinical response to corticosteroids, whereas high expression of FKBP51 was associated with a poor response. Treatment of airway epithelial cells with IL13 resulted in increased expression of CLCA1, POSTN, and SERPINB2, an effect that could be suppressed by corticosteroids.
Gastrin (GAS; 137250) regulates the expression of a variety of genes involved in the control of acid secretion. It also triggers tissue response to damage, infection, and inflammation in cells expressing gastrin receptor (CCKBR; 118445) and, indirectly, in nearby cells via a paracrine mechanism. Almeida-Vega et al. (2009) found that gastrin directly induced upregulation of PAI2 in CCKBR-positive cells. CCKBR-positive cells also released IL8 (146930) and prostaglandin E2 into the culture medium in response to gastrin, which resulted in elevated PAI2 expression in cocultured CCKBR-negative cells. IL8 signaling in CCKBR-negative cells upregulated PAI2 via binding of the ASC1 complex (see TRIP4; 604501) to the PAI2 promoter. Prostaglandin E2 independently upregulated PAI2 via RHOA (165390)-dependent signaling that induced binding of MAZ (600999) to the PAI2 promoter. Electrophoretic mobility shift assays and chromatin immunoprecipitation analysis revealed that MAZ and the p50 subunit of the ASC1 complex (ASCC1; 614215) bound directly to sites in the PAI2 promoter. Mutation of the putative MAZ site in the PAI2 promoter reduced responses to RHOA. Knockdown of the p50 or p65 (TRIP4) subunits of the ASC1 complex via small interfering RNA significantly reduced PAI2 upregulation in response to gastrin.
Samia et al. (1990) demonstrated that the intron-exon arrangement of PAI2 is identical to that of chicken ovalbumin and Y genes and distinct from that of other members of the serpin superfamily.
By Southern blot analysis of human-mouse somatic cell hybrid DNA, Webb et al. (1987) located the PAI2 gene, which they called PLANH2, to human chromosome 18. Oldenburg et al. (1989) also assigned PAI2 to chromosome 18 by Southern analysis of rodent-human somatic cell hybrid DNAs. By in situ hybridization, Webb et al. (1989) assigned the PLANH2 gene to 18q21.2-q22. By YAC cloning of a 2-Mb contig within chromosomal band 18q21, Silverman et al. (1991) established physical linkage of BCL2 (151430) with PLANH2. They concluded that PLANH2 is 600 kb telomeric to BCL2 and has an opposite transcriptional orientation.
Bartuski et al. (1997) identified 6 genes in a 500-kb region of 18q21.3. The order of the 6 genes from centromere to telomere was determined to be cen--PI5 (154790)--SCCA2 (600518)--SCCA1 (600517)--PAI2--PI10 (602058)--PI8 (601697)--tel.
PAI2 is thought to serve as a primary regulator of plasminogen activation in the extravascular compartment. High levels of PAI2 are found in keratinocytes, monocytes, and the human trophoblast, the latter suggesting a role in placental maintenance or in embryo development. The primarily intracellular distribution of PAI2 may also indicate a unique regulatory role in a protease-dependent cellular process such as apoptosis (Dickinson et al., 1995). To examine the potential functions of PAI2 in vivo, Dougherty et al. (1999) generated PAI2-deficient mice by gene targeting in embryonic stem cells. Homozygous PAI2-deficient mice exhibited normal development, survival, and fertility, and were also indistinguishable from normal controls in response to a bacterial infectious challenge or endotoxin infusion. No differences in monocyte recruitment into the peritoneum were observed after thioglycollate injection. Epidermal wound healing was equivalent among null and control mice. Finally, crossing PAI2 -/- with PAI1 -/- mice to generate animals deficient in both plasminogen activator inhibitors failed to uncover an overlap in function between these 2 related proteins.
Almeida-Vega, S., Catlow, K., Kenny, S., Dimaline, R., Varro, A. Gastrin activates paracrine networks leading to induction of PAI-2 via MAZ and ASC-1. Am. J. Physiol. Gastrointest. Liver Physiol. 296: G414-G423, 2009. [PubMed: 19074642] [Full Text: https://doi.org/10.1152/ajpgi.90340.2008]
Antalis, T. M., Clark, M. A., Barnes, T., Lehrbach, P. R., Devine, P. L., Schevzov, G., Goss, N. H., Stephens, R. W., Tolstoshev, P. Cloning and expression of a cDNA coding for a human monocyte-derived plasminogen activator inhibitor. Proc. Nat. Acad. Sci. 85: 985-989, 1988. [PubMed: 3257578] [Full Text: https://doi.org/10.1073/pnas.85.4.985]
Bartuski, A. J., Kamachi, Y., Schick, C., Overhauser, J., Silverman, G. A. Cytoplasmic antiproteinase 2 (PI8) and bomapin (PI10) map to the serpin cluster at 18q21.3. Genomics 43: 321-328, 1997. [PubMed: 9268635] [Full Text: https://doi.org/10.1006/geno.1997.4827]
Dickinson, J. L., Bates, E. J., Ferrante, A., Antalis, T. M. Plasminogen activator inhibitor type 2 inhibits tumor necrosis factor alpha-induced apoptosis: evidence for an alternate biological function. J. Biol. Chem. 270: 27894-27904, 1995. [PubMed: 7499264] [Full Text: https://doi.org/10.1074/jbc.270.46.27894]
Dougherty, K. M., Pearson, J. M., Yang, A. Y., Westrick, R. J., Baker, M. S., Ginsburg, D. The plasminogen activator inhibitor-2 gene is not required for normal murine development or survival. Proc. Nat. Acad. Sci. 96: 686-691, 1999. [PubMed: 9892694] [Full Text: https://doi.org/10.1073/pnas.96.2.686]
Kruithof, E. K. O., Baker, M. S., Bunn, C. L. Biological and clinical aspects of plasminogen activator inhibitor type 2. Blood 86: 4007-4024, 1995. [PubMed: 7492756]
Oldenburg, M., Wijnen, J. T., van den Berg, E. A., le Clercq, E., Kooistra, T., Meera Khan, P. Assignment of plasminogen activator-inhibitor type 2 (PAI2) to chromosome 18. (Abstract) Cytogenet. Cell Genet. 51: 1055, 1989.
Samia, J. A., Alexander, S. J., Horton, K. W., Auron, P. E., Byers, M. G., Shows, T. B., Webb, A. C. Chromosomal organization and localization of the human urokinase inhibitor gene: perfect structural conservation with ovalbumin. Genomics 6: 159-167, 1990. [PubMed: 2303256] [Full Text: https://doi.org/10.1016/0888-7543(90)90461-3]
Silverman, G. A., Jockel, J. I., Domer, P. H., Mohr, R. M., Taillon-Miller, P., Korsmeyer, S. J. Yeast artificial chromosome cloning of a two-megabase-size contig within chromosomal band 18q21 establishes physical linkage between BCL2 and plasminogen activator inhibitor type-2. Genomics 9: 219-228, 1991. [PubMed: 2004771] [Full Text: https://doi.org/10.1016/0888-7543(91)90245-a]
Webb, A. C., Alexander, S. J., Samia, J. A., Auron, P. E., Byers, M. G., Shows, T. B. Localization of the urokinase-type plasminogen activator inhibitor (PLANH2) gene to the long arm of chromosome 18 at 18q21.2-q22.(Abstract) Cytogenet. Cell Genet. 51: 1103, 1989.
Webb, A. C., Collins, K. L., Snyder, S. E., Alexander, S. J., Rosenwasser, L. J., Eddy, R. L., Shows, T. B., Auron, P. E. Human monocyte arg-serpin cDNA: sequence, chromosomal assignment, and homology to plasminogen activator-inhibitor. J. Exp. Med. 166: 77-94, 1987. [PubMed: 3496414] [Full Text: https://doi.org/10.1084/jem.166.1.77]
Woodruff, P. G., Boushey, H. A., Dolganov, G. M., Barker, C. S., Yang, Y. H., Donnelly, S., Ellwanger, A., Sidhu, S. S., Dao-Pick, T. P., Pantoja, C., Erle, D. J., Yamamoto, K. R., Fahy, J. V. Genome-wide profiling identifies epithelial cell genes associated with asthma and with treatment response to corticosteroids. Proc. Nat. Acad. Sci. 104: 15858-15863, 2007. [PubMed: 17898169] [Full Text: https://doi.org/10.1073/pnas.0707413104]