Alternative titles; symbols
HGNC Approved Gene Symbol: PLAT
Cytogenetic location: 8p11.21 Genomic coordinates (GRCh38): 8:42,174,718-42,207,565 (from NCBI)
Tissue plasminogen activator (tPA; PLAT; EC 3.4.21.68) is a serine protease. One of the main functions of tPA is to cleave and activate the proenzyme plasminogen to plasmin (PLG; 173350), which in turn is responsible for fibrinolytic activity.
PLAT is synthesized in vascular endothelial cells as a single polypeptide chain that undergoes proteolytic cleavage by plasmin or trypsin (PRSS1; 276000) at a centrally located arginine-isoleucine bond, resulting in a 2-chain disulfide-linked form composed of the N-terminally derived heavy chain and the C-terminal light chain. The light chain contains the active site (Ny et al., 1984).
Edlund et al. (1983) cloned a 370-bp cDNA segment that codes for part of human tissue PLAT. They used synthetic oligonucleotides based on the amino acid sequence of PLAT to isolate the corresponding gene. They pointed out that tissue PLAT is probably identical to the vascular activator, which is assumed to be synthesized by endothelial cells and released into the blood by certain stimuli. Edlund et al. (1983) also noted that urokinase (PLAU; 191840), an immunologically unrelated protein, is also a plasminogen activator.
Browne et al. (1985) isolated a genomic clone for tissue-type plasminogen activator (tPA).
MacDonald et al. (1986) concluded that the light chain cDNA contains the complete genetic information for the plasminogen activator activity.
Ny et al. (1984) determined that the PLAT gene contains 14 exons. The structural domains of the protein correlated well with the exon/intron boundaries. The signal peptide, the propeptide, and the domains of the heavy chain, including the regions homologous to growth factors, were all encoded by separate exons. Two kringle regions of tPA were both coded for by 2 exons. The region coding for the light chain, comprising the serine protease part of the molecule was split by 4 introns, revealing a gene organization similar to other serine proteases.
Although Kucherlapati et al. (1978) mapped the PLAT gene to chromosome 6 by studying mouse-human hybrid cells, Benham et al. (1985), Rajput et al. (1985), Visse et al. (1985), and Yang-Feng et al. (1985) corrected the assignment to chromosome 8 using various DNA probes for somatic cell hybrids analysis. Verheijen et al. (1986) provided the definitive report on the work reported in abstract by Visse et al. (1985).
Tripputi et al. (1986) assigned PLAT to the pericentromeric area of chromosome 8 by in situ hybridization. The ideogram showing location of grains appeared to have more in 8q11 than in 8p11. By in situ hybridization and Southern blot analysis of somatic cell hybrid DNA, Yang-Feng et al. (1985, 1986) assigned the PLAT gene to 8p12-q11.2. They described a common EcoRI RFLP in the PLAT gene that could be useful for genetic linkage studies.
By Southern blot analysis of DNA from mouse-Chinese hamster and mouse-rat somatic cell hybrids, Rajput et al. (1987) assigned the mouse Plat gene to chromosome 8.
Loscalzo and Braunwald (1988) reviewed the biology and therapeutic use of tissue plasminogen activator.
Bell et al. (1988) chemically synthesized a 1,610-bp DNA duplex coding for tissue-type plasminogen activator, using the phosphoramidite procedure adapted for a custom-built gene synthesizer. The synthesized gene was expressed in mammalian cells and shown to produce authentic protein by an immunoactivity assay.
Ludwig et al. (1992) described an insertion/deletion polymorphism of a 311-bp Alu sequence in intron 8 of the PLAT gene. In all populations studied, the frequency of each of 2 alleles varied between 0.40 and 0.60. The similar frequencies among different ethnic groups suggested that the insertion or subsequent deletion of this Alu sequence occurred early in human evolution.
Tishkoff et al. (2000) typed 2 dinucleotide short tandem repeat polymorphisms (STRPs) and a polymorphic Alu element spanning a 22-kb region of the PLAT locus in 1,287 to 1,420 individuals originating from 30 geographically diverse human populations, as well as in 29 great apes. The data were analyzed as haplotypes consisting of each of the dinucleotide repeats and the flanking Alu insertion/deletion polymorphism. The global pattern of STRP/Alu haplotype variation and linkage disequilibrium (LD) was informative for the reconstruction of human evolutionary history. Sub-Saharan African populations had high levels of haplotype diversity within and between populations, relative to non-Africans, and had highly divergent patterns of LD. Non-African populations had both a subset of the haplotype diversity present in Africa and a distinct pattern of LD. The pattern of haplotype variation and LD observed at the PLAT locus suggested a recent common ancestry of non-African populations, from a small population originating in eastern Africa. These data indicated that throughout much of modern human history sub-Saharan Africa has maintained both a large effective population size and a high level of population substructure. Additionally, Papua New Guinean and Micronesian populations were found to have rare haplotypes observed otherwise only in African populations, suggesting ancient gene flow from Africa into Papua New Guinea, as well as gene flow between the Melanesian and Micronesian populations.
Associations Pending Confirmation
For discussion of an association between variation in the PLAT gene and defective release of tPA resulting in thrombophilia or hyperfibrinolysis, see 612348.
For discussion of a possible association between mutation in the PLAT gene and hydranencephaly, diaphragmatic hernia, and postnatal lethality, see 173370.0001.
Tissue plasminogen activator is the primary plasminogen activator in the brain and is present at high levels in regions undergoing extensive cell migration during embryonic and neonatal development. Seeds et al. (1996) demonstrated induction of tPA mRNA protein in cerebellar Purkinje cells of rats being trained for a complex motor task. They hypothesized that induction of PLAT may play a role in synaptic plasticity.
In the developing cerebellum, granule neurons turn on the gene for tissue plasminogen activator as they begin their migration into the cerebellar molecular layer. Granule neurons both secrete PLAT, an extracellular serine protease that converts the proenzyme plasminogen into the active protease plasmin, and bind PLAT to their cell surface. In the nervous system, PALT activity is correlated with neurite outgrowth, neuronal migration, learning, and excitotoxic death. Seeds et al. (1999) showed that compared with their normal counterparts, mice lacking the tPA gene, Plat -/-, have greater than 2-fold more migrating granule neurons in the cerebellar molecular layer during the most active phase of granule cell migration. A real-time analysis of granule cell migration in cerebellar slices of the null mice showed that granule neurons are migrating 51% as fast as granule neurons in slices from wildtype mice. These findings established a direct role for PLAT in facilitating neuronal migration, and they raised the possibility that late arriving neurons may have altered synaptic interactions.
Madani et al. (1999) showed that transgenic mice overexpressing tPA in postnatal neurons had increased and prolonged long-term potentiation in the hippocampus and showed improved performance in spatial orientation learning tasks. The findings suggested that tPA plays an important role in synaptic plasticity and learning, perhaps through extracellular proteolysis and synaptic remodeling.
Wang et al. (2003) demonstrated that PLAT upregulates MMP9 (120361) in cell culture and in vivo. Mmp9 levels were lower in Plat knockout compared with wildtype mice after focal cerebral ischemia. In human cerebral microvascular endothelial cells, MMP9 was upregulated when recombinant PLAT was added. RNA interference suggested that this response was mediated by the LDL receptor-related protein (LRP1; 107770), which avidly binds tPA and possesses signaling properties.
Pang et al. (2004) showed that by activating the extracellular protease plasmin, tPA converts the precursor proBdnf to the mature Bdnf (113505), and that such conversion is critical for late-phase long-term potentiation expression in mouse hippocampus. Moreover, Pang et al. (2004) found that application of mature Bdnf is sufficient to rescue late-phase long-term potentiation when protein synthesis is inhibited, which suggests that mature BDNF is a key protein synthesis product for late-phase long-term potentiation expression.
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.
Norris and Strickland (2007) showed that tPA is a key regulator of contextual fear conditioning in the hippocampus via interactions with the NR2B (138252) subunit of the NMDA receptor. Acute stress in wildtype mice resulted in decreased tPA activity in the hippocampus via increased expression of tPA inhibitor Pai1 (173360). Acute stress in wildtype mice also increased Nr2b expression and related phosphorylation in the hippocampus, representing postsynaptic plasticity. Further studies showed that tPA formed a complex with Nr2b and was necessary for Nr2b binding to postsynaptic proteins. Plat-null mice showed a decrease in contextual fear conditioning compared to wildtype mice. Overall, the findings indicated that tPA is an important factor in NMDA signaling and plasticity in the hippocampus and is a modulator in stabilizing the NMDA receptor complex during stress, which can result in behavioral changes.
Maiya et al. (2009) found that cocaine enhanced tPA activity in the amygdala of mice in a manner dependent on Crf (122560) factor and Crfr1 (122561). Enhanced tPA activity increased 30 minutes after exposure and returned to baseline after 6 hours. After cocaine exposure, Tpa-null mice displayed attenuated neuronal signaling, as indicated by decreased phosphorylation of ERK (176948), CREB (123810), and DARPP32 (604399), and blunted induction of immediate early genes in the amygdala and the nucleus accumbens compared to wildtype mice. Tpa-null mice also had significantly higher basal preprodynorphin (PDYN; 131340) mRNA levels in the nucleus accumbens compared to wildtype mice, and cocaine decreased pre-Pdyn mRNA levels in tPA-null mice only. Cocaine exposure had an anxiolytic effect in tPA-null but not in wildtype mice. Maiya et al. (2009) noted that cocaine exposure induces long-lasting molecular and structural adaptations in the brain, and concluded that tPA is an important modulator of cocaine-induced chances via its role as an extracellular protease involved in neuronal plasticity.
This variant is classified as a variant of unknown significance because its contribution to a lethal syndrome involving hydranencephaly and diaphragmatic hernia has not been confirmed.
In a Saudi Arabian male infant who died at 26 days of life with multiple congenital anomalies including hydranencephaly, diaphragmatic hernia, patent ductus arteriosus, ventricular septal defect, tricuspid regurgitation, dilated right atrium and left ventricle, and pulmonary hypertension, Shamseldin et al. (2016) performed exome sequencing and identified homozygosity for a 2-bp deletion (c.102delCA) in exon 3 of the PLAT gene, causing a frameshift predicted to result in a premature termination codon (Arg35IlefsTer39). Western blot analysis using lymphoblastoid cells from the proband revealed complete deficiency of tPA. The consanguineous parents were each heterozygous for the mutation, as was 1 unaffected sister, and the mutation was not found among more than 1,500 Saudi exomes or in the ExAC database. DNA was not available from an affected male sib born 9 years earlier, who died at 12 hours of life with similar features, including hydranencephaly and left diaphragmatic hernia. Both infants experienced respiratory distress at birth, and died of severe hypoxia despite ventilatory and circulatory support.
Bell, L. D., Smith, J. C., Derbyshire, R., Finlay, M., Johnson, I., Gilbert, R., Slocombe, P., Cook, E., Richards, H., Clissold, P., Meredith, D., Powell-Jones, C. H., Dawson, K. M., Carter, B. L., McCullagh, K. G. Chemical synthesis, cloning and expression in mammalian cells of a gene coding for human tissue-type plasminogen activator. Gene 63: 155-163, 1988. [PubMed: 2838384] [Full Text: https://doi.org/10.1016/0378-1119(88)90521-5]
Benham, F. J., Spurr, N., Povey, S., Brinton, B. T., Solomon, E., Goodfellow, P. N., Harris, T. J. R. Tissue-type plasminogen activator (PLAT) maps to chromosome 8 and there is a common restriction fragment length polymorphism within the gene. (Abstract) Cytogenet. Cell Genet. 40: 581 only, 1985.
Browne, M. J., Tyrrell, A. W. R., Chapman, C. G., Carey, J. E., Glover, D. M., Grosveld, F. G., Dodd, I., Robinson, J. H. Isolation of a human tissue-type plasminogen-activator genomic DNA clone and its expression in mouse L cells. Gene 33: 279-284, 1985. [PubMed: 3839198] [Full Text: https://doi.org/10.1016/0378-1119(85)90235-5]
Edlund, T., Ny, T., Ranby, M., Heden, L.-O., Palm, G., Holmgren, E., Josephson, S. Isolation of cDNA sequences coding for a part of human tissue plasminogen activator. Proc. Nat. Acad. Sci. 80: 349-352, 1983. [PubMed: 6572897] [Full Text: https://doi.org/10.1073/pnas.80.2.349]
Kucherlapati, R., Tepper, R., Granelli-Piperno, A., Reich, E. W. Modulation and mapping of a human plasminogen activator by cell fusion. Cell 15: 1331-1340, 1978. [PubMed: 569557] [Full Text: https://doi.org/10.1016/0092-8674(78)90058-2]
Loscalzo, J., Braunwald, E. Tissue plasminogen activator. New Eng. J. Med. 319: 925-931, 1988. Note: Erratum: New Eng. J. Med. 319: 1428 only, 1988. [PubMed: 3138537] [Full Text: https://doi.org/10.1056/NEJM198810063191407]
Ludwig, M., Wohn, K.-D., Schleuning, W.-D., Olek, K. Allelic dimorphism in the human tissue-type plasminogen activator (TPA) gene as a result of an Alu insertion/deletion event. Hum. Genet. 88: 388-392, 1992. [PubMed: 1346771] [Full Text: https://doi.org/10.1007/BF00215671]
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]
MacDonald, M. E., van Zonneveld, A.-J., Pannekoek, H. Functional analysis of the human tissue-type plasminogen activator protein: the light chain. Gene 42: 59-67, 1986. [PubMed: 3087818] [Full Text: https://doi.org/10.1016/0378-1119(86)90150-2]
Madani, R., Hulo, S., Toni, N., Madani, H., Steimer, T., Muller, D., Vassalli, J.-D. Enhanced hippocampal long-term potentiation and learning by increased neuronal expression of tissue-type plasminogen activator in transgenic mice. EMBO J. 18: 3007-3012, 1999. [PubMed: 10357813] [Full Text: https://doi.org/10.1093/emboj/18.11.3007]
Maiya, R., Zhou, Y., Norris, E. H., Kreek, M. J., Strickland, S. Tissue plasminogen activator modulates the cellular and behavioral response to cocaine. Proc. Nat. Acad. Sci. 106: 1983-1988, 2009. [PubMed: 19181855] [Full Text: https://doi.org/10.1073/pnas.0812491106]
Norris, E. H., Strickland, S. Modulation of NR2B-regulated contextual fear in the hippocampus by the tissue plasminogen activator system. Proc. Nat. Acad. Sci. 104: 13473-13487, 2007. [PubMed: 17673549] [Full Text: https://doi.org/10.1073/pnas.0705848104]
Ny, T., Elgh, F., Lund, B. The structure of the human tissue-type plasminogen activator gene: correlation of intron and exon structures to functional and structural domains. Proc. Nat. Acad. Sci. 81: 5355-5359, 1984. [PubMed: 6089198] [Full Text: https://doi.org/10.1073/pnas.81.17.5355]
Pang, P. T., Teng, H. K., Zaitsev, E., Woo, N. T., Sakata, K., Zhen, S., Teng, K. K., Yung, W.-H., Hempstead, B. L., Lu, B. Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity. Science 306: 487-491, 2004. [PubMed: 15486301] [Full Text: https://doi.org/10.1126/science.1100135]
Pennica, D., Holmes, W. E., Kohr, W. J., Harkins, R. N., Vehar, G. A., Ward, C. A., Bennett, W. F., Yelverton, E., Seeburg, P. H., Heyneker, H. L., Goeddel, D. V., Collen, D. Cloning and expression of human tissue-type plasminogen activator cDNA in E. coli. Nature 301: 214-221, 1983. [PubMed: 6337343] [Full Text: https://doi.org/10.1038/301214a0]
Rajput, B., Degen, S. F., Reich, E., Eddy, R. L., Shows, T. B. Mapping of tissue plasminogen activator (PLAT) to chromosome 8 and urokinase (PLAU) to chromosome 10 in humans. (Abstract) Cytogenet. Cell Genet. 40: 728-729, 1985.
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]
Seeds, N. W., Basham, M. E., Haffke, S. P. Neuronal migration is retarded in mice lacking the tissue plasminogen activator gene. Proc. Nat. Acad. Sci. 96: 14118-14123, 1999. [PubMed: 10570208] [Full Text: https://doi.org/10.1073/pnas.96.24.14118]
Seeds, N. W., Williams, B. L., Bickford, P. C. Tissue plasminogen activator induction in Purkinje neurons after cerebellar motor learning. Science 270: 1992-1994, 1996.
Shamseldin, H. E., Aldeeri, A., Babay, Z., Alsultan, A., Hashem, M., Alkuraya, F. S. A lethal phenotype associated with tissue plasminogen deficiency in humans. Hum. Genet. 135: 1209-1211, 2016. [PubMed: 27417437] [Full Text: https://doi.org/10.1007/s00439-016-1711-5]
Tishkoff, S. A., Pakstis, A. J., Stoneking, M., Kidd, J. R., Destro-Bisol, G., Sanjantila, A., Lu, R., Deinard, A. S., Sirugo, G., Jenkins, T., Kidd, K. K., Clark, A. G. Short tandem-repeat polymorphism/Alu haplotype variation at the PLAT locus: implications for modern human origins. Am. J. Hum. Genet. 67: 901-925, 2000. [PubMed: 10986042] [Full Text: https://doi.org/10.1086/303068]
Tripputi, P., Blasi, F., Emanuel, B. S., Letofsky, J., Croce, C. M. Tissue-type plasminogen activator gene is on chromosome 8. Cytogenet. Cell Genet. 42: 24-28, 1986. [PubMed: 3087707] [Full Text: https://doi.org/10.1159/000132245]
Verheijen, J. H., Visse, R., Wijnen, J. T., Chang, G. T. G., Kluft, C., Meera Khan, P. Assignment of the human tissue-type plasminogen activator gene (PLAT) to chromosome 8. Hum. Genet. 72: 153-156, 1986. [PubMed: 3002960] [Full Text: https://doi.org/10.1007/BF00283935]
Visse, R., Chang, G. T. G., Wijnen, J. T., Verheijen, J. H., Kluft, C., Meera Khan, P. Provisional assignment of human tissue-type plasminogen activator (PLAT) to chromosome 8. (Abstract) Cytogenet. Cell Genet. 40: 771 only, 1985.
Wang, X., Lee, S.-R., Arai, K., Lee, S.-R., Tsuji, K., Rebeck, G. W., Lo, E. H. Lipoprotein receptor-mediated induction of matrix metalloproteinase by tissue plasminogen activator. Nature Med. 9: 1313-1317, 2003. [PubMed: 12960961] [Full Text: https://doi.org/10.1038/nm926]
Yang-Feng, T. L., Opdenakker, G., Volckaert, G., Francke, U. Mapping of the human tissue-type plasminogen activator (PLAT) gene to chromosome 8 (8p12-q11.2). (Abstract) Cytogenet. Cell Genet. 40: 784 only, 1985.
Yang-Feng, T. L., Opdenakker, G., Volckaert, G., Francke, U. Human tissue-type plasminogen activator gene located near chromosomal breakpoint in myeloproliferative disorder. Am. J. Hum. Genet. 39: 79-87, 1986. [PubMed: 3092643]