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Link to original content: https://omim.org/entry/173391
Alternative titles; symbols
HGNC Approved Gene Symbol: PLAUR
Cytogenetic location: 19q13.31 Genomic coordinates (GRCh38) : 19:43,646,095-43,670,169 (from NCBI)
The urokinase-type plasminogen activator receptor is a key molecule in the regulation of cell surface plasminogen activation and, as such, plays an important role in many normal as well as pathologic processes (summary by Huai et al., 2006).
Min et al. (1992) cloned the cDNA for Mo3, an activation antigen expressed by human monocytes and myelomonocytic cell lines after stimulation by a variety of agents. Mo3 expression in vivo is associated predominantly with macrophages in inflammatory sites. It is a highly glycosylated protein of about 50 kD in monocytes where it is anchored to the plasma membrane by glycosyl-phosphatidylinositol linkage. The complete coding sequence of the cDNA was found to encode 335 amino acids including a predicted signal peptide of 22 residues and a hydrophobic C-terminal portion. A database search revealed that Mo3 is identical to the human receptor for the urokinase plasminogen activator (UPA, or PLAU; 191840).
Using fluorescence resonance energy transfer and biochemical analysis, Sitrin et al. (2001) demonstrated that PLAUR is directly associated with the carbohydrate-binding domain of SELL (153240) in the membrane of neutrophils, an association analogous to that between PLAUR and beta-2 integrins (see 600065). Spectrofluorometric analysis indicated that PLAUR-mediated calcium mobilization is SELL dependent.
Foca et al. (2000) demonstrated that UPAR mRNA levels correlated with the invasive potential of endometrial carcinomas and showed a 33-fold increase in UPAR mRNA levels in advanced clinical stage endometrial tumors compared with normal endometrial tissue. Furthermore, the increase in UPAR mRNA levels correlated linearly with the progression of disease stage. Memarzadeh et al. (2002) examined whether UPAR protein expression correlated with (1) the grade and stage of endometrial cancer and (2) recurrence and mortality rate in patients with endometrial cancer. Their ultimate goal was to determine whether UPAR protein could be used as a prognostic marker in patients with endometrial cancer. They found no expression of UPAR protein in 7 patients with benign neoplasia of the endometrium. On the other hand, UPAR protein expression highly correlated with stage of disease in endometrial cancer. Moreover, high UPAR expression positively correlated with grade of disease. It also correlated positively with rate of recurrence and mortality in patients with endometrial cancer. Memarzadeh et al. (2002) concluded that UPAR is a useful prognostic marker for biologically aggressive forms of endometrial cancer.
In human coronary artery vascular smooth muscle cells, UPA stimulates cell migration via a UPAR 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.
Wang et al. (2004) found that both Klf4 (602253) and Upar were predominantly expressed in luminal surface epithelial cells of the colonic crypt in mice. Colon cells from Klf4-null mice showed a dramatic reduction in Upar protein compared with wildtype mice. Conversely, KLF4 expression in human colon cancer cells increased the amount of UPAR protein and mRNA. Mobility shift experiments and chromatin immunoprecipitation showed that KLF4 bound multiple regions of the UPAR promoter.
Park et al. (2009) found that macrophages from Upar -/- mice had enhanced ability to engulf wildtype neutrophils, but not Upar -/- neutrophils. The enhanced phagocytic activity of Upar -/- macrophages could be abrogated by incubation with soluble Upar, arg-gly-asp peptides, or anti-integrin antibodies. Similarly, wildtype macrophages showed increased uptake of Upar -/- neutrophils, except in the presence of soluble Upar or anti-integrin antibodies. Incubation of either Upar -/- neutrophils or Upar -/- macrophages, but not both, with soluble Upar enhanced the uptake of Upar -/- neutrophils by Upar -/- macrophages. Upar expression was reduced on the surface of apoptotic neutrophils compared with viable neutrophils. Park et al. (2009) concluded that UPAR is involved in the recognition and clearance of neutrophils.
Using gel retardation, quantitative RT-PCR, and reporter gene assays, Roll et al. (2010) found that human FOXP2 (605317) bound the promoter regions of SRPX2 (300642) and its binding partner UPAR and downregulated their expression. Foxp2-binding sites were conserved in the promoter regions of chimpanzee and mouse Srpx2 and in chimpanzee Upar, but Foxp2-binding sites were not conserved in mouse Upar.
Role in Focal Segmental Glomerulosclerosis
Using quantitative RT-PCR with glomeruli isolated from human kidney biopsies, Wei et al. (2008) found that expression of UPAR was low in healthy glomeruli, but it was induced in glomeruli from individuals with focal segmental glomerulosclerosis (FSGS; see 603278) and highly induced in glomeruli from individuals with diabetic nephropathy. In all rat and mouse models of proteinuria, Upar protein expression was increased in glomerular cells, including podocytes, compared with controls. Immunoelectron microscopy detected homogeneous distribution of Upar in normal rat podocytes and mesangial and endothelial cells. However, diabetic rats showed increased Upar labeling in all cells of the glomerular tuft and increased podocyte Upar expression in basal membranes of the foot process. Mice lacking Upar were protected from lipopolysaccharide (LPS)-mediated proteinuria, but they developed disease after expression of constitutively active beta-3 integrin (ITGB3; 173470). Gene transfer studies revealed a prerequisite for Upar expression in podocytes, but not in endothelial cells, for development of LPS-mediated proteinuria. Upar was required to activate alpha-V (ITGAV; 193210)/beta-3 integrin in podocytes, promoting cell motility and activation of the small GTPases Cdc42 (116952) and Rac1 (602048). Blockade of alpha-5/beta-3 integrin reduced podocyte motility in vitro and lowered proteinuria in mice. Wei et al. (2008) concluded that UPAR has a role in regulating renal permeability.
Wei et al. (2011) identified secreted PLAUR as a circulating factor responsible for the development of FSGS. Levels of serum soluble PLAUR were increased in two-thirds of patients with FSGS, but not in patients with other glomerular disease. A higher serum concentration of PLAUR before kidney transplantation was associated with an increased risk for recurrence of FSGS after transplantation. Immunohistochemical studies on human kidney samples derived from patients with FSGS demonstrated that soluble PLAUR binds to and activates beta-3 integrin. In mouse models, Plaur activated podocyte beta-3 integrin in both native and grafted kidneys, causing foot process effacement, proteinuria, and FSGS-like glomerulopathy. The findings suggested that renal disease only develops when Plaur sufficiently activates podocyte beta-3-integrin. Inhibition of PLAUR resulted in a reduction of beta-integrin activity in podocytes, and plasmapheresis in humans reduced serum PLAUR concentrations in some patients with increased levels. Wei et al. (2011) concluded that pharmacologic modulation of excessive podocyte beta-3 integrin activation may be a target for management of this form of renal disease.
Crystal Structure
Huai et al. (2006) reported the crystal structure at 1.9 angstroms of the urokinase receptor 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.
By hybridization of a cDNA probe to DNAs from a panel of somatic cell hybrids, Borglum et al. (1991, 1992) mapped the gene for the urokinase-type plasminogen activator receptor to 19q13-qter. Using RFLPs related to the clone, they did linkage studies in 40 CEPH families and demonstrated localization in the 19q13.1-q13.2 region. By in situ hybridization, Vagnarelli et al. (1992) localized the PLAUR gene to 19q13.
Powell et al. (2001) reported that Plaur knockout mice (Dewerchin et al. (1996)) exhibit deficient scatter activity in the forebrain, abnormal interneuron migration from the ganglionic eminence, and reduced interneurons in the frontal and parietal cortex. Using immunoblots and scatter assays, they concluded that the forebrain of Plaur knockout mice has reduced levels of biologically active HGF (142409).
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 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.
Borglum, A., Anette, B., Roldan, A. L., Blasi, F., Bolund, L., Kruse, T. A. Assignment of the gene for urokinase-type plasminogen activator receptor to chromosome 19q13. (Abstract) Cytogenet. Cell Genet. 58: 2016-2017, 1991.
Borglum, A. D., Byskov, A., Ragno, P., Roldan, A. L., Tripputi, P., Cassani, G., Dano, K., Blasi, F., Bolund, L., Kruse, T. A. Assignment of the urokinase-type plasminogen activator receptor gene (PLAUR) to chromosome 19q13.1-q13.2. Am. J. Hum. Genet. 50: 492-497, 1992. [PubMed: 1311495]
Dewerchin, M., Van Nuffelen, A., Wallays, G., Bouche, A., Moons, L., Carmeliet, P., Mulligan, R. C., Collen, D. Generation and characterization of urokinase receptor-deficient mice. J. Clin. Invest. 97: 870-878, 1996. [PubMed: 8609247] [Full Text: https://doi.org/10.1172/JCI118489]
Foca, C., Moses, E. K., Quinn, M. A., Rice, G. E. Differential mRNA expression of urokinase-type plasminogen activator, plasminogen activator receptor and plasminogen activator inhibitor type-2 in normal human endometria and endometrial carcinomas. Gynec. Oncol. 79: 244-250, 2000. [PubMed: 11063652] [Full Text: https://doi.org/10.1006/gyno.2000.5959]
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]
Memarzadeh, S., Kozak, K. R., Chang, L., Natarajan, S., Shintaku, P., Reddy, S. T., Farias-Eisner, R. Urokinase plasminogen activator receptor: prognostic biomarker for endometrial cancer. Proc. Nat. Acad. Sci. 99: 10647-10652, 2002. Note: Erratum: Proc. Nat. Acad. Sci. 99: 12501 only, 2002. [PubMed: 12130664] [Full Text: https://doi.org/10.1073/pnas.152127499]
Min, H. Y., Semnani, R., Mizukami, I. F., Watt, K., Todd, R. F., III, Liu, D. Y. cDNA for Mo3, a monocyte activation antigen, encodes the human receptor for urokinase plasminogen activator. J. Immun. 148: 3636-3642, 1992. [PubMed: 1316922]
Park, Y.-J., Liu, G., Tsuruta, Y., Lorne, E., Abraham, E. Participation of the urokinase receptor in neutrophil efferocytosis. Blood 114: 860-870, 2009. [PubMed: 19398720] [Full Text: https://doi.org/10.1182/blood-2008-12-193524]
Powell, E. M., Mars, W. M., Levitt, P. Hepatocyte growth factor/scatter factor is a motogen for interneurons migrating from the ventral to dorsal telencephalon. Neuron 30: 79-89, 2001. [PubMed: 11343646] [Full Text: https://doi.org/10.1016/s0896-6273(01)00264-1]
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]
Roll, P., Vernes, S. C., Bruneau, N., Cillario, J., Ponsole-Lenfant, M., Massacrier, A., Rudolf, G., Khalife, M., Hirsch, E., Fisher, S. E., Szepetowski, P. Molecular networks implicated in speech-related disorders: FOXP2 regulates the SRPX2/uPAR complex. Hum. Molec. Genet. 19: 4848-4860, 2010. [PubMed: 20858596] [Full Text: https://doi.org/10.1093/hmg/ddq415]
Sitrin, R. G., Pan, P. M., Blackwood, R. A., Huang, J., Petty, H. R. Cutting edge: evidence for a signaling partnership between urokinase receptors (CD87) and L-selectin (CD62L) in human polymorphonuclear neutrophils. J. Immun. 166: 4822-4825, 2001. [PubMed: 11290756] [Full Text: https://doi.org/10.4049/jimmunol.166.8.4822]
Vagnarelli, P., Raimondi, E., Mazzieri, R., De Carli, L., Mignatti, P. Assignment of the human urokinase receptor gene (PLAUR) to 19q13. Cytogenet. Cell Genet. 60: 197-199, 1992. [PubMed: 1324136] [Full Text: https://doi.org/10.1159/000133335]
Wang, H., Yang, L., Jamaluddin, M. S., Boyd, D. D. The Kruppel-like KLF4 transcription factor, a novel regulator of urokinase receptor expression, drives synthesis of this binding site in colonic crypt luminal surface epithelial cells. J. Biol. Chem. 279: 22674-22683, 2004. [PubMed: 15031282] [Full Text: https://doi.org/10.1074/jbc.M401257200]
Wei, C., El Hindi, S., Li, J., Fornoni, A., Goes, N., Sageshima, J., Maiguel, D., Karumanchi, S. A., Yap, H.-K., Saleem, M., Zhang, Q., Nikolic, B., and 16 others. Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis. Nature Med. 17: 952-960, 2011. [PubMed: 21804539] [Full Text: https://doi.org/10.1038/nm.2411]
Wei, C., Moller, C. C., Altintas, M. M., Li, J., Schwarz, K., Zacchigna, S., Xie, L., Henger, A., Schmid, H., Rastaldi, M. P., Cowan, P., Kretzler, M., Parrilla, R., Bendayan, M., Gupta, V., Nikolic, B., Kalluri, R., Carmeliet, P., Mundel, P., Reiser, J. Modification of kidney barrier function by the urokinase receptor. Nature Med. 14: 55-63, 2008. [PubMed: 18084301] [Full Text: https://doi.org/10.1038/nm1696]