Alternative titles; symbols
HGNC Approved Gene Symbol: PLAU
Cytogenetic location: 10q22.2 Genomic coordinates (GRCh38): 10:73,909,164-73,917,494 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q22.2 | {Alzheimer disease, late-onset, susceptibility to} | 104300 | Autosomal dominant | 3 |
| Quebec platelet disorder | 601709 | Autosomal dominant | 3 |
Urinary plasminogen activator (uPA, PLAU; EC 3.4.21.73) converts plasminogen (173350) to plasmin.
Urokinase has a molecular mass of about 54 kD and is composed of 2 disulfide-linked chains, A and B, of molecular masses 18 kD and 33 kD, respectively. Salerno et al. (1984) developed separate monoclonal antibodies for the A and B chains and by using them identified a single-chain biosynthetic precursor in a rabbit reticulocyte cell-free protein-synthesizing system directed by human kidney total polyadenylated RNA. Thus, the precursor must be cleaved in a way that the insulin precursor is cleaved.
Urokinase may occur as a single-chain form or as a 2-chain derivative, which is generated by cleavage of the peptide bond between lys(158) and ile(159) in the single-chain form by plasmin. Lijnen et al. (1988) produced site-specific mutation in position 158 (lys to glu). Studies of the enzymatic properties of the mutant form, which was resistant to plasmin, indicated that the amino acid in position 158 is a main determinant of the functional properties of the single-chain form, but not of the 2-chain form.
Crystal Structure
Huai et al. (2006) reported the crystal structure at 1.9 angstroms of the urokinase receptor (PLAUR; 173391) complexed with the urokinase amino-terminal fragment and antibody against the receptor. The 3 domains of the urokinase receptor form a concave shape with a central cone-shaped cavity where the urokinase fragment inserts. Huai et al. (2006) concluded that the structure provides insight into the flexibility of the urokinase receptor that enables its interaction with a wide variety of ligands and a basis for the design of urokinase-urokinase receptor antagonists.
In human coronary artery vascular smooth muscle cells, UPA stimulates cell migration via a UPA receptor (UPAR, or PLAUR) signaling complex containing TYK2 (176941) and phosphatidylinositol 3-kinase (PI3K; see 601232). Kiian et al. (2003) showed that association of TYK2 and PI3K with active GTP-bound forms of both RHOA (ARHA; 165390) and RAC1 (602048), but not CDC42 (116952), as well as phosphorylation of myosin light chain (see 160781), are downstream events required for UPA/UPAR-directed migration.
Using a yeast 1-hybrid screen and EMSA, Tong et al. (2005) found that PBK1 (RSL1D1; 615874) bound an enhancer region in the UPA promoter between 2 AP1 (see 165160) sites. Overexpression and knockdown experiments with 95D human lung cancer cell lines confirmed that PBK1 upregulated UPA expression by binding to the enhancer element.
By combined somatic cell genetics, in situ hybridization, and Southern hybridization, Tripputi et al. (1985) localized the human urokinase gene to 10q24-qter. By use of specific cDNA probes in the study of human-mouse somatic cell hybrids, Rajput et al. (1985) mapped the human tissue plasminogen activator and urokinase genes to chromosomes 8 and 10, respectively. By Southern blot analysis of DNA from mouse-Chinese hamster and mouse-rat somatic cell hybrids, Rajput et al. (1987) assigned the mouse equivalent (Plau) to mouse chromosome 14.
Ahmed et al. (2001) stated that PLAU is 1 of 3 genes that are nested in the introns of PCDH15 (605514), which maps to 10q21-q22.
Quebec Platelet Disorder
In 38 patients with Quebec platelet disorder (QPD; 601709), Paterson et al. (2010) identified a heterozygous 78-kb tandem duplication of the PLAU gene (191840.0002). The authors postulated that the duplication resulted in increased PLAU expression, which has been found in patients with the disorder (Diamandis et al., 2009).
Possible Association With Alzheimer Disease
Finckh et al. (2003) noted that plasmin is involved in the processing of amyloid precursor protein (104760) and degrades secreted and aggregated amyloid-beta, a hallmark of Alzheimer disease (104300). They also noted that the PLAU gene maps between 2 regions showing linkage to late-onset Alzheimer disease (LOAD) (see AD6; 605526). They genotyped a frequent C/T SNP of the PLAU gene, which results in a pro141-to-leu (P141L) mutation (rs2227564; 191840.0001), in 347 patients with LOAD and 291 control subjects. LOAD was associated with a CC genotype in the whole sample as well as in all subsamples stratified by gender or APOE4 (107741) carrier status. The odds ratio for LOAD due to a CC genotype was 1.89. Finckh et al. (2003) suggested that PLAU is a susceptibility gene for LOAD, with allele C (P141) being a recessive risk allele and allele T (L141) conferring protection.
Ertekin-Taner et al. (2005) found significant association between PLAU 5-SNP haplotypes and LOAD in 3 independent series of 204, 148, and 113 AD patients with matched controls. Plasma A-beta-42 levels among individuals over 50 years old in 10 extended LOAD families were also significantly associated with PLAU haplotypes (p = 0.005). The CT and TT genotypes of rs2227564 were associated with LOAD (p = 0.05) and with age-dependent elevation of plasma A-beta-42 in 24 extended LOAD families (p = 0.0006). In Plau-knockout mice, plasma A-beta-42 and A-beta-40 levels, but not levels in brain, were significantly elevated in an age-dependent manner.
Bagnoli et al. (2005) found no association between 238 Italian patients with sporadic late-onset Alzheimer disease and the CC genotype of the P141L polymorphism.
Blomqvist et al. (2006) found no association between 4 variants in the PLAU gene, including the P141L polymorphism, and risk for AD among 940 Scottish and Swedish individuals with AD.
Stimulation with either gram-negative or gram-positive bacteria induces upregulation of UPAR on monocytes and neutrophils. In general, gram-negative bacterial stimuli require the beta-2 integrin CD11B/CD18B (600065) for neutrophil emigration, whereas gram-positive bacteria do not. Rijneveld et al. (2002) generated mice deficient in Upa or Upar. Intranasal exposure to a beta-2 integrin-dependent pathogen, Streptococcus pneumoniae, resulted in locally elevated levels of Upa in wildtype mouse lungs. In Upar -/- mice, there was less granulocyte accumulation but more bacteria in lungs, as well as reduced survival, compared with wildtype mice. In contrast, Upa -/- mice manifested increased neutrophil influx and fewer pneumococci in the lungs. Rijneveld et al. (2002) concluded that UPAR is necessary for adequate neutrophil recruitment into alveoli and lungs during pneumonia caused by S. pneumoniae.
Falkenberg et al. (2002) investigated whether elevated uPA expression accelerates atherogenesis by cloning a rabbit uPA cDNA and expressing it in carotid arteries of cholesterol-fed rabbits. One week after gene transfer, uPA-transduced arteries were constricted, with significantly smaller lumens and thicker walls, but no difference in intimal or medial mass. By 4 weeks, uPA-transduced arteries had 70% larger intimas than control-transduced arteries and smaller lumens. Falkenberg et al. (2002) interpreted the data as suggesting that elevated uPA expression in atherosclerotic arteries contributes to intimal growth and constrictive remodeling leading to lumen loss. They suggested that overexpression of uPA in endothelial cells to prevent intravascular thrombosis be reconsidered, because this intervention could worsen underlying disease.
Lund et al. (2006) observed that wound healing in Plat-null or Plau-null mice was similar to that in wildtype mice, but wound healing in mice deficient for both Plat and Plau was significantly delayed. These findings suggested functional overlap between the 2 plasminogen activators. However, wound healing in the Plat/Plau-deficient mice was not as impaired as in plasminogen-null mice, suggesting the presence of an additional plasminogen activator. Pharmacologic inhibition of kallikrein (KLK1; 147910) in Plat/Plau-null mice resulted in delayed wound healing similar to that in Plg-null mice. Lund et al. (2006) concluded that kallikrein may play a role in plasmin generation.
Finckh et al. (2003) found an association between late-onset Alzheimer disease (see 104300) and a CC genotype of a C/T polymorphism of the PLAU gene, resulting in a pro141-to-leu (P141L) mutation, in a sample of 347 patients with late-onset Alzheimer disease and in subsamples stratified by gender or APOE4 (107741) carrier status. The odds ratio for late-onset Alzheimer disease due to a CC genotype was 1.89. They suggested that PLAU is a susceptibility gene for late-onset Alzheimer disease, with allele C (P141) being a recessive risk allele and allele T (L141) conferring protection.
Ertekin-Taner et al. (2005) found that the CT and TT genotypes were associated with LOAD (p = 0.05) and with age-dependent elevation of plasma A-beta-42 in 24 extended LOAD families (p = 0.0006).
Bagnoli et al. (2005) found no association between 238 Italian patients with sporadic late-onset Alzheimer disease and the CC genotype of the P141L polymorphism.
Blomqvist et al. (2006) found no association between 4 variants in the PLAU gene, including the P141L polymorphism, and risk for AD among 940 Scottish and Swedish individuals with AD.
In 38 patients with Quebec platelet disorder (601709), Paterson et al. (2010) identified a heterozygous 78-kb tandem duplication of the PLAU gene. The duplication was not observed in unaffected family members or in 311 controls. The breakpoint junction endpoints occurred 11.87 kb 5-prime of the PLAU transcription start site, including all regulatory units of the gene, and 59.69 kb 3-prime of PLAU. Sequence alignment analysis indicated that it was a direct tandem repeat containing PLAU and C10ORF55, a gene of unknown function on the antisense strand, mediated by nonhomologous recombination. Southern blotting confirmed the local duplication. Paterson et al. (2010) postulated that the duplication resulted in increased PLAU expression, which has been found in patients with the disorder (Diamandis et al., 2009).
Ahmed, Z. M., Riazuddin, S., Bernstein, S. L., Ahmed, Z., Khan, S., Griffith, A. J., Morell, R. J., Friedman, T. B., Riazuddin, S., Wilcox, E. R. Mutations of the protocadherin gene PCDH15 cause Usher syndrome type 1F. Am. J. Hum. Genet. 69: 25-34, 2001. [PubMed: 11398101] [Full Text: https://doi.org/10.1086/321277]
Bagnoli, S., Tedde, A., Cellini, E., Rotondi, M., Nacmias, B., Sorbi, S. The urokinase-plasminogen activator (PLAU) gene is not associated with late onset Alzheimer's disease. Neurogenetics 6: 53-54, 2005. Note: Erratum: Neurogenetics 6: 105 only, 2005. [PubMed: 15616835] [Full Text: https://doi.org/10.1007/s10048-004-0203-2]
Blomqvist, M. E.-L., Reynolds, C., Katzov, H., Feuk, L., Andreasen, N., Bogdanovic, N., Blennow, K., Brookes, A. J., Prince, J. A. Towards compendia of negative genetic association studies: an example for Alzheimer disease. Hum. Genet. 119: 29-37, 2006. [PubMed: 16341549] [Full Text: https://doi.org/10.1007/s00439-005-0078-9]
Diamandis, M., Paterson, A. D., Rommens, J. M., Veljkovic, D. K., Blavignac, J., Bulman, D. E., Waye, J. S., Derome, F., Rivard, G. E., Hayward, C. P. Quebec platelet disorder is linked to the urokinase plasminogen activator gene (PLAU) and increases expression of the linked allele in megakaryocytes. Blood 113: 1543-1546, 2009. [PubMed: 18988861] [Full Text: https://doi.org/10.1182/blood-2008-08-175216]
Ertekin-Taner, N., Ronald, J., Feuk, L., Prince, J., Tucker, M., Younkin, L., Hella, M., Jain, S., Hackett, A., Scanlin, L., Kelly, J., Kihiko-Ehman, M., and 11 others. Elevated amyloid beta protein (A-beta-42) and late onset Alzheimer's disease are associated with single nucleotide polymorphisms in the urokinase-type plasminogen activator gene. Hum. Molec. Genet. 14: 447-460, 2005. [PubMed: 15615772] [Full Text: https://doi.org/10.1093/hmg/ddi041]
Falkenberg, M., Tom, C., DeYoung, M. B., Wen, S., Linnemann, R., Dichek, D. A. Increased expression of urokinase during atherosclerotic lesion development causes arterial constriction and lumen loss, and accelerates lesion growth. Proc. Nat. Acad. Sci. 99: 10665-10670, 2002. [PubMed: 12149463] [Full Text: https://doi.org/10.1073/pnas.162236599]
Finckh, U., van Hadeln, K., Muller-Thomsen, T., Alberici, A., Binetti, G., Hock, C., Nitsch, R. M., Stoppe, G., Reiss, J., Gal, A. Association of late-onset Alzheimer disease with a genotype of PLAU, the gene encoding urokinase-type plasminogen activator on chromosome 10q22.2. Neurogenetics 4: 213-217, 2003. [PubMed: 12898287] [Full Text: https://doi.org/10.1007/s10048-003-0157-9]
Huai, Q., Mazar, A. P., Kuo, A., Parry, G. C., Shaw, D. E., Callahan, J., Li, Y., Yuan, C., Bian, C., Chen, L., Furie, B., Furie, B. C., Cines, D. B., Huang, M. Structure of human urokinase plasminogen activator in complex with its receptor. Science 311: 656-659, 2006. [PubMed: 16456079] [Full Text: https://doi.org/10.1126/science.1121143]
Kiian, I., Tkachuk, N., Haller, H., Dumler, I. Urokinase-induced migration of human vascular smooth muscle cells requires coupling of the small GTPase RhoA and Rac1 to the Tyk2/PI3-K signalling pathway. Thromb. Haemost. 89: 904-914, 2003. [PubMed: 12719789]
Lijnen, H. R., Van Hoef, B., Nelles, L., Holmes, W. E., Collen, D. Enzymatic properties of single-chain and two-chain forms of a lys(158)-to-glu(158) mutant of urokinase-type plasminogen activator. Europ. J. Biochem. 172: 185-188, 1988. [PubMed: 2894309] [Full Text: https://doi.org/10.1111/j.1432-1033.1988.tb13871.x]
Lund, L. R., Green, K. A., Stoop, A. A., Ploug, M., Almholt, K., Lilla, J., Nielsen, B. S., Christensen, I. J., Craik, C. S., Werb, Z., Dano, K., Romer, J. Plasminogen activation independent of uPA and tPA maintains wound healing in gene-deficient mice. EMBO J. 25: 2686-2697, 2006. [PubMed: 16763560] [Full Text: https://doi.org/10.1038/sj.emboj.7601173]
Nagai, M., Hiramatsu, R., Kaneda, T., Hayasuke, N., Arimura, H., Nishida, M., Suyama, T. Molecular cloning of cDNA coding for human preprourokinase. Gene 36: 183-188, 1985. [PubMed: 2415429] [Full Text: https://doi.org/10.1016/0378-1119(85)90084-8]
Nelles, L., Lijnen, H. R., Collen, D., Holmes, W. E. Characterization of recombinant human single chain urokinase-type plasminogen activator mutants produced by site-specific mutagenesis of lysine 158. J. Biol. Chem. 262: 5682-5689, 1987. [PubMed: 3106341]
Paterson, A. D., Rommens, J. M., Bharaj, B., Blavignac, J., Wong, I., Diamandis, M., Waye, J. S., Rivard, G. E., Hayward, C. P. Persons with Quebec platelet disorder have a tandem duplication of PLAU, the urokinase plasminogen activator gene. Blood 115: 1264-1266, 2010. [PubMed: 20007542] [Full Text: https://doi.org/10.1182/blood-2009-07-233965]
Rajput, B., Degen, S. F., Reich, E., Waller, E. K., Axelrod, J., Eddy, R. L., Shows, T. B. Chromosomal locations of human tissue plasminogen activator and urokinase genes. Science 230: 672-674, 1985. [PubMed: 3840278] [Full Text: https://doi.org/10.1126/science.3840278]
Rajput, B., Marshall, A., Killary, A. M., Lalley, P. A., Naylor, S. L., Belin, D., Rickles, R. J., Strickland, S. Chromosomal assignments of genes for tissue plasminogen activator and urokinase in mouse. Somat. Cell Molec. Genet. 13: 581-586, 1987. [PubMed: 2821634] [Full Text: https://doi.org/10.1007/BF01534500]
Riccio, A., Grimaldi, G., Verde, P., Sebastio, G., Boast, S., Blasi, F. The human urokinase-plasminogen activator gene and its promoter. Nucleic Acids Res. 13: 2759-2771, 1985. [PubMed: 2987867] [Full Text: https://doi.org/10.1093/nar/13.8.2759]
Rijneveld, A. W., Levi, M., Florquin, S., Speelman, P., Carmeliet, P., van der Poll, T. Urokinase receptor is necessary for adequate host defense against pneumococcal pneumonia. J. Immun. 168: 3507-3511, 2002. [PubMed: 11907112] [Full Text: https://doi.org/10.4049/jimmunol.168.7.3507]
Salerno, G., Verde, P., Nolli, M. L., Corti, A., Szots, H., Meo, T., Johnson, J., Bullock, S., Cassani, G., Blasi, F. Monoclonal antibodies to human urokinase identify the single-chain pro-urokinase precursor. Proc. Nat. Acad. Sci. 81: 110-114, 1984. [PubMed: 6364130] [Full Text: https://doi.org/10.1073/pnas.81.1.110]
Tong, C., Tan, L., Li, P., Zhu, Y.-S. Identification of a novel nucleus protein involved in the regulation of urokinase in 95D cells. Acta Biochim. Biophys. Sin. (Shanghai) 37: 303-309, 2005. [PubMed: 15880258] [Full Text: https://doi.org/10.1111/j.1745-7270.2005.00041.x]
Tripputi, P., Blasi, F., Verde, P., Cannizzaro, L. A., Emanuel, B. S., Croce, C. M. Human urokinase gene is located on the long arm of chromosome 10. Proc. Nat. Acad. Sci. 82: 4448-4452, 1985. [PubMed: 2989821] [Full Text: https://doi.org/10.1073/pnas.82.13.4448]