Alternative titles; symbols
HGNC Approved Gene Symbol: SERPINE2
Cytogenetic location: 2q36.1 Genomic coordinates (GRCh38): 2:223,975,045-224,039,286 (from NCBI)
Protease nexin I is a 44-kD thrombin and urokinase inhibitor released by human foreskin fibroblasts. PN I shares several features with antithrombin III (107300), an abundant plasma thrombin inhibitor. Both PN I and AT III have high affinities for heparin, and heparin accelerates their rate of thrombin inhibition. In addition, the published sequence of 28 amino acids at the N terminus of PN I is identical to the N-terminal amino acid sequence of a glial-derived neurite-promoting factor. McGrogan et al. (1988) described the isolation, sequence, and expression of a PN1 cDNA clone from a human foreskin fibroblast cDNA library. Two forms, designated alpha and beta, were identified. These differed only by the insertion of 3 nucleotides into the coding sequence, and apparently arose by use of an alternative splice acceptor site in the PN1 gene. In the resulting proteins, alpha-PN I contains an arginine residue at position 310, whereas beta-PN I contains threonine-lysine residues. Both forms are expressed in mammalian cells and inhibit thrombin and urokinase. The amino acid sequence of beta-PN I is identical to that of glial-derived neurite-promoting factor (Gloor et al., 1986; Sommer et al., 1987).
Protease nexin I is the most important physiologic regulator of alpha-thrombin in tissues (Carter et al., 1995). PN1 is highly expressed and developmentally regulated in the nervous system where it is concentrated at neuromuscular junctions and also central synapses in the hippocampus and striatum. Approximately 10% of identified proteins at mammalian neuromuscular junctions are serine protease inhibitors, consistent with their central role in balancing serine protease activity to develop, maintain, and remodel synapses.
The mammalian sex-determining pathway is controlled by the presence or absence of SRY (480000) expression in the embryonic gonad. In order to identify additional sex-determining or gonadal differentiation genes, Grimmond et al. (2000) screened for genes exhibiting sexually dimorphic patterns of expression in the mouse gonad at 12.5 and 13.5 days postcoitum, after overt gonad differentiation, by comparing complex cDNA probes derived from male and female gonadal tissue at these stages on microarrays constructed from a normalized urogenital ridge library. Using in situ hybridization analysis, they determined that mouse Pn1 and vanin-1 (603570) exhibit male-specific expression prior to overt gonadal differentiation and are detected in the somatic portion of the developing gonad, suggesting to the authors a possible direct link to the testis-determining pathway for both genes.
Following platelet activation, PAI1 (SERPINE1; 173360) stabilizes a thrombus by inhibiting endogenous fibrinolysis. However, Boulaftali et al. (2011) showed that PN1 contributes to control of fibrinolysis in a PAI1-independent manner. Using human and mouse platelets, they found that platelet PN1 inhibited activation of plasminogen (PLG; 173350) by fibrin (see 134820)-bound TPA (PLAT; 173370) and also directly inhibited fibrin-bound plasmin. Antibody-mediated blockade of PN1 in human platelets or knockout of Pn1 in Pn1 -/- mouse platelets resulted in increased clot lysis and acceleration of the lysis front. In addition, Tpa-induced thrombolysis and vascular recanalization following occlusive injury was significantly increased in Pn1 -/- mice. Boulaftali et al. (2011) concluded that PN1 is a major determinant of lysis resistance in platelet-rich clots.
Wagenblast et al. (2015) developed a polyclonal mouse model of breast tumor heterogeneity and showed that distinct clones within a mixed population display specialization, for example, by dominating the primary tumor, contributing to metastatic populations, or showing tropism for entering the lymphatic or vasculature systems. The authors correlated these stable properties to distinct gene expression profiles. Those clones that efficiently enter the vasculature express 2 secreted proteins, SERPINE2 and SLPI (107285), which are necessary and sufficient to program these cells for vascular mimicry. The data indicated that these proteins not only drive the formation of extravascular networks but also ensure their perfusion by acting as anticoagulants. Wagenblast et al. (2015) proposed that vascular mimicry drives the ability of some breast tumor cells to contribute to distant metastases while simultaneously satisfying a critical need of the primary tumor to be fed by the vasculature. Enforced expression of SERPINE2 and SLPI in human breast cancer cell lines also programmed them for vascular mimicry, and SERPINE2 and SLPI were overexpressed preferentially in human patients who had lung-metastatic relapse. Wagenblast et al. (2015) proposed that these 2 secreted proteins, and the phenotype they promote, may be broadly relevant as drivers of metastatic progression in human cancer.
DeMeo et al. (2006) stated that the SERPINE2 gene consists of 9 exons.
By Southern blot hybridization of PN1 cDNA to somatic cell hybrid DNAs, Carter et al. (1995) mapped the PN1 gene, also known as PI7, to 2q33-q35. The regional localization was achieved by studying microcell hybrids that retained fragments of chromosome 2. The gene was located between the markers CRYGA (123660) and MYL1 (160780), both of which are located in the 2q33-q35 region. Further observations indicated that PN1 is close to MYL1 and farther removed from CRYGA. By hybrid cell methods, Carter et al. (1995) mapped the homologous gene to mouse chromosome 1 and sheep 2q, which are known to have regions of homology of synteny to human 2q.
Chronic obstructive pulmonary disease (COPD; 606963) is a complex disorder of the lungs, probably influenced by multiple genes, cigarette smoking, and gene-by-smoking interactions. Alpha-1-antitrypsin deficiency (613490), caused by mutation in the SERPINA1 gene (107400), is a cause of COPD. The SERPINE2 gene is a fellow member of the serpin protein family. DeMeo et al. (2006) integrated results from microarray studies of murine lung development and human COPD gene expression with human COPD linkage results on chromosome 2q to prioritize candidate gene selection, thus identifying SERPINE2 as a positional candidate susceptibility gene for COPD. Immunohistochemistry demonstrated expression of SERPINE2 protein in mouse and human adult lung tissue. In family-based association testing of 127 severe, early-onset COPD pedigrees from the Boston Early-Onset COPD Study, they observed significant association with COPD phenotypes and 18 single-nucleotide polymorphisms (SNPs) in the SERPINE2 gene. Association of 5 of these SNPs with COPD was replicated in a case-control analysis with cases from the National Emphysema Treatment Trial and controls from the Normative Aging Study. Family-based and case-control haplotype analyses supported similar regions of association within the SERPINE2 gene. When significantly associated SNPs in these haplotypic regions were included as covariates in linkage models, lod score attenuation was observed most markedly in a smokers-only linkage model (lod 4.41, attenuated to 1.74). After the integration of murine and human microarray data to inform candidate-gene selection, DeMeo et al. (2006) observed significant family-based association and independent replication of association in a case-control study, suggesting that SERPINE2 is a COPD susceptibility gene and is likely influenced by gene-by-smoking interaction.
Chappell et al. (2006) were unable to replicate the observations of DeMeo et al. (2006) in a more highly powered case-control study. They suggested that differences in the disease phenotype of the patients studied may account for this, as the study by Chappell et al. (2006) included patients with and without emphysema.
Boulaftali, Y., Ho-Tin-Noe, B., Pena, A., Loyau, S., Venisse, L., Francois, D., Richard, B., Arocas, V., Collet, J.-P., Jandrot-Perrus, M., Bouton, M.-C. Platelet protease nexin-1, a serpin that strongly influences fibrinolysis and thrombolysis. Circulation 123: 1326-1334, 2011. [PubMed: 21403095] [Full Text: https://doi.org/10.1161/CIRCULATIONAHA.110.000885]
Carter, R. E., Cerosaletti, K. M., Burkin, D. J., Fournier, R. E. K., Jones, C., Greenberg, B. D., Citron, B. A., Festoff, B. W. The gene for the serpin thrombin inhibitor (P17), protease nexin 1, is located on human chromosome 2q33-q35 and on syntenic regions in the mouse and sheep genomes. Genomics 27: 196-199, 1995. [PubMed: 7665170] [Full Text: https://doi.org/10.1006/geno.1995.1025]
Chappell, S., Daly, L., Morgan, K., Baranes, T. G., Roca, J., Rabinovich, R., Millar, A., Donnelly, S. C., Keatings, V., MacNee, W., Stolk, J., Hiemstra, P. S., Miniati, M., Monti, S., O'Connor, C. M., Kalsheker, N. The SERPINE2 gene and chronic obstructive pulmonary disease. (Letter) Am. J. Hum. Genet. 79: 184-186, 2006. [PubMed: 16773582] [Full Text: https://doi.org/10.1086/505268]
DeMeo, D. L., Mariani, T. J., Lange, C., Srisuma, S., Litonjua, A. A., Celedon, J. C., Lake, S. L., Reilly, J. J., Chapman, H. A., Mecham, B. H., Haley, K. J., Sylvia, J. S., Sparrow, D., Spira, A. E., Beane, J., Pinto-Plata, V., Speizer, F. E., Shapiro, S. D., Weiss, S. T., Silverman, E. K. The SERPINE2 gene is associated with chronic obstructive pulmonary disease. Am. J. Hum. Genet. 78: 253-264, 2006. [PubMed: 16358219] [Full Text: https://doi.org/10.1086/499828]
Gloor, S., Odink, K., Guenther, J., Nick, H., Monard, D. A glia-derived neurite promoting factor with protease inhibitory activity belongs to the protease nexins. Cell 47: 687-693, 1986. [PubMed: 2877744] [Full Text: https://doi.org/10.1016/0092-8674(86)90511-8]
Grimmond, S., Van Hateren, N., Siggers, P., Arkell, R., Larder, R., Soares, M. B., de Fatima Bonaldo, M., Smith, L., Tymowska-Lalanne, Z., Wells, C., Greenfield, A. Sexually dimorphic expression of protease nexin-1 and vanin-1 in the developing mouse gonad prior to overt differentiation suggests a role in mammalian sexual development. Hum. Molec. Genet. 9: 1553-1560, 2000. [PubMed: 10888606] [Full Text: https://doi.org/10.1093/hmg/9.10.1553]
McGrogan, M., Kennedy, J., Li, M. P., Hsu, C., Scott, R. W., Simonsen, C. C., Baker, J. B. Molecular cloning and expression of two forms of human protease nexin I. Nature Biotech. 6: 172-177, 1988.
Sommer, J., Gloor, S., Rovelli, G. F., Hofsteenge, J., Nick, H., Meier, R., Monard, D. cDNA sequence coding for a rat glia-derived nexin and its homology to members of the serpin family. Biochemistry 26: 6407-6410, 1987. [PubMed: 3427015] [Full Text: https://doi.org/10.1021/bi00394a016]
Wagenblast, E., Soto, M., Gutierrez-Angel, S., Hartl, C. A., Gable, A. L., Maceli, A. R., Erard, N., Williams, A. M., Kim, S. Y., Dickopf, S., Harrell, J. C., Smith, A. D., Perou, C. M., Wilkinson, J. E., Hannon, G. J., Knott, S. R. V. A model of breast cancer heterogeneity reveals vascular mimicry as a driver of metastasis. Nature 520: 358-362, 2015. [PubMed: 25855289] [Full Text: https://doi.org/10.1038/nature14403]