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Gene Review

Plat  -  plasminogen activator, tissue

Mus musculus

Synonyms: AU020998, AW212668, D8Ertd2e, Tissue-type plasminogen activator, t-PA, ...
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Disease relevance of Plat

  • Progeny studies using NZW x (NZW x BXSB) F1 male backcross mice showed that the BXSB Plat allele was significantly associated with high levels of both platelet-binding antibodies and thrombocytopenia [1].
  • Thus, the BXSB-type Plat may be one susceptibility allele for the multigenic antiphospholipid syndrome seen in (NZW x BXSB) F1 mice [1].
  • We also show that injection of tPA into the cerebrospinal fluid in the absence of ischemia results in a rapid dose-dependent increase in vascular permeability [2].
  • Tissue-type plasminogen activator (tPA) is one of the major components in the matrix proteolytic network whose role in the pathogenesis of renal interstitial fibrosis remains largely unknown [3].
  • Mice lacking tPA developed less morphological injury and displayed a reduced deposition of interstitial collagen III and fibronectin as well as total tissue collagen in the kidneys after sustained ureteral obstruction, when compared with their wild-type counterparts [3].

Psychiatry related information on Plat

  • This treatment regime had no effect on locomotor activity in either genotype. tPA-/- mice showed no spatial learning deficits, but were more sensitive to dizocilpine during acquisition (though not expression) of a DRL task [4].
  • Targeted disruption of tPA release or its upstream regulation by glutamic acid decarboxylase (GAD65) prevented MD-induced spine loss that was pharmacologically rescued concomitant with critical period plasticity [5].
  • The learning disability of tPA -/- was overcome by more intense training [6].
  • Consistently, in Alzheimer's disease (AD) patients' brains, high levels of tPA colocalize with amyloid-rich areas, activated Erk1/2 and phosphorylated tau [7].
  • These results support our hypothesis that tPA plays a role in long-lasting neuronal changes related to drug dependence [8].

High impact information on Plat

  • Excess excitatory amino acids can provoke neuronal death in the hippocampus, and the extracellular proteases tissue plasminogen activator (tPA) and plasmin (ogen) have been implicated in this death [9].
  • These results indicate that disruption of neuron-ECM interaction via tPA/plasmin catalyzed degradation of laminin sensitizes hippocampal neurons to cell death [9].
  • Therefore, the stage-specific regulation of poly(A) tail length accounts for the regulated synthesis of tPA in oocytes, and reversible deadenylation provides a mechanism for the translational control of dormant mRNAs [10].
  • Activated protein C (APC), a serine protease with anticoagulant, anti-inflammatory and antiapoptotic activities, which is neuroprotective during transient ischemia and promotes activation of antiapoptotic mechanisms in brain cells by acting directly on endothelium and neurons, blocked tPA vascular and neuronal toxicities in vitro and in vivo [11].
  • In human cerebral microvascular endothelial cells, MMP-9 was upregulated when recombinant tPA was added [12].

Chemical compound and disease context of Plat


Biological context of Plat


Anatomical context of Plat


Associations of Plat with chemical compounds

  • Tissue plasminogen activator (tPA) is a serine protease involved in the degradation of blood clots through the activation of plasminogen to plasmin [24].
  • These findings demonstrate that an additional plasminogen activator provides sufficient plasmin activity to sustain the healing process albeit at decreased speed in the absence of uPA, tPA and galardin-sensitive MMPs and suggest that pKal plays a role in plasmin generation [19].
  • Strikingly, the stress-induced decrease in NMDA receptors coincides spatially with sites of plasminogen activation, thereby predicting a role for tissue plasminogen activator (tPA) in this form of stress-induced plasticity [20].
  • Nitric oxide mediates neurodegeneration and breakdown of the blood-brain barrier in tPA-dependent excitotoxic injury in mice [25].
  • We examine here the potentially interrelated roles of tPA, NO and peroxynitrite (ONOO-), which is the toxic metabolite of NO, in BBB breakdown and neurodegeneration following intrahippocampal injection of the glutamate analog kainite (KA) [25].

Physical interactions of Plat

  • Furthermore, these two traits appeared to be regulated by a complementary effect of two BXSB alleles; one is linked to Plat and the other to the H-2 complex and the gene for plasminogen [1].

Enzymatic interactions of Plat


Co-localisations of Plat

  • Fibrin autography of storage granules revealed a prominent lytic zone at Mr 66 kD comigrating with free t-PA [27].

Regulatory relationships of Plat

  • This study investigated the mechanism by which tPA induces MMP-9 gene expression [23].
  • Here, we report that BDNF stimulates the expression of tissue-type plasminogen activator (tPA) in primary cultures of cortical neurons in a time- and concentration-dependent manner [28].
  • Our data highlight the complexities of PA function, and suggest that approaches either to target u-PA or to enhance local t-PA activity in joints may be of therapeutic benefit in rheumatoid arthritis [29].
  • Analysis of plasminogen activator inhibitor-1 (PAI-1) expression showed that PAI-1 antigen is upregulated by 24 hr and could account for the tPA activity downregulation seen at this time point [30].
  • In the embryonic spinal cord, PN-1 expression occurs in cells lining the neural canal that are different from the cells previously shown to express tPA [31].

Other interactions of Plat

  • The results revealed that tPA played the most important role in local regulation of fibrin deposition in the heart, with lesser contributions by TM and uPA (least significant) [32].
  • A marked decrease in matrix metalloproteinase-9 (MMP-9) induction was found in the obstructed kidneys of tPA(-/-) mice, which led to a dramatic preservation of the structural and functional integrity of tubular basement membrane (TBM) [3].
  • Moreover, a synergistic relationship in fibrin formation existed in mice with concomitant modifications of tPA and TM, resulting in myocardial necrosis and depressed cardiac function [32].
  • We further demonstrate that growth of primary fibroblasts in culture is dependent on a tPA-mediated cleavage of latent PDGF-CC, generating a growth stimulatory loop [24].
  • We report a comparative study of animals with individual and combined deficits in uPAR and tPA and show that these proteins are complementary fibrinolytic factors in mice [33].

Analytical, diagnostic and therapeutic context of Plat


  1. Genetic polymorphism of murine tissue plasminogen activator associated with antiphospholipid syndrome. Shirai, J., Ida, A., Jiang, Y., Sanokawa-Akakura, R., Miura, Y., Yan, K., Hamano, Y., Hirose, S., Shirai, T. Genes Immun. (1999) [Pubmed]
  2. Tissue-type plasminogen activator induces opening of the blood-brain barrier via the LDL receptor-related protein. Yepes, M., Sandkvist, M., Moore, E.G., Bugge, T.H., Strickland, D.K., Lawrence, D.A. J. Clin. Invest. (2003) [Pubmed]
  3. Disruption of tissue-type plasminogen activator gene in mice reduces renal interstitial fibrosis in obstructive nephropathy. Yang, J., Shultz, R.W., Mars, W.M., Wegner, R.E., Li, Y., Dai, C., Nejak, K., Liu, Y. J. Clin. Invest. (2002) [Pubmed]
  4. Evidence for disrupted NMDA receptor function in tissue plasminogen activator knockout mice. Horwood, J.M., Ripley, T.L., Stephens, D.N. Behav. Brain Res. (2004) [Pubmed]
  5. Experience-dependent pruning of dendritic spines in visual cortex by tissue plasminogen activator. Mataga, N., Mizuguchi, Y., Hensch, T.K. Neuron (2004) [Pubmed]
  6. Rapid, specific and active site-catalyzed effect of tissue-plasminogen activator on hippocampus-dependent learning in mice. Pawlak, R., Nagai, N., Urano, T., Napiorkowska-Pawlak, D., Ihara, H., Takada, Y., Collen, D., Takada, A. Neuroscience (2002) [Pubmed]
  7. Tissue plasminogen activator mediates amyloid-induced neurotoxicity via Erk1/2 activation. Medina, M.G., Ledesma, M.D., Domínguez, J.E., Medina, M., Zafra, D., Alameda, F., Dotti, C.G., Navarro, P. EMBO J. (2005) [Pubmed]
  8. Drug dependence, synaptic plasticity, and tissue plasminogen activator. Yamada, K., Nagai, T., Nabeshima, T. J. Pharmacol. Sci. (2005) [Pubmed]
  9. Neuronal death in the hippocampus is promoted by plasmin-catalyzed degradation of laminin. Chen, Z.L., Strickland, S. Cell (1997) [Pubmed]
  10. Transient translational silencing by reversible mRNA deadenylation. Huarte, J., Stutz, A., O'Connell, M.L., Gubler, P., Belin, D., Darrow, A.L., Strickland, S., Vassalli, J.D. Cell (1992) [Pubmed]
  11. Tissue plasminogen activator neurovascular toxicity is controlled by activated protein C. Liu, D., Cheng, T., Guo, H., Fernández, J.A., Griffin, J.H., Song, X., Zlokovic, B.V. Nat. Med. (2004) [Pubmed]
  12. Lipoprotein receptor-mediated induction of matrix metalloproteinase by tissue plasminogen activator. Wang, X., Lee, S.R., Arai, K., Lee, S.R., Tsuji, K., Rebeck, G.W., Lo, E.H. Nat. Med. (2003) [Pubmed]
  13. Different mechanisms of increased luminal stenosis after arterial injury in mice deficient for urokinase- or tissue-type plasminogen activator. Schäfer, K., Konstantinides, S., Riedel, C., Thinnes, T., Müller, K., Dellas, C., Hasenfuss, G., Loskutoff, D.J. Circulation (2002) [Pubmed]
  14. Essential role of endogenous tissue plasminogen activator through matrix metalloproteinase 9 induction and expression on heparin-produced cerebral hemorrhage after cerebral ischemia in mice. Zhao, B.Q., Ikeda, Y., Ihara, H., Urano, T., Fan, W., Mikawa, S., Suzuki, Y., Kondo, K., Sato, K., Nagai, N., Umemura, K. Blood (2004) [Pubmed]
  15. Endogenous tissue-type plasminogen activator is protective during Escherichia coli-induced abdominal sepsis in mice. Renckens, R., Roelofs, J.J., Florquin, S., de Vos, A.F., Pater, J.M., Lijnen, H.R., Carmeliet, P., van 't Veer, C., van der Poll, T. J. Immunol. (2006) [Pubmed]
  16. Endogenous tissue type plasminogen activator facilitates NMDA-induced retinal damage. Kumada, M., Niwa, M., Wang, X., Matsuno, H., Hara, A., Mori, H., Matsuo, O., Yamamoto, T., Kozawa, O. Toxicol. Appl. Pharmacol. (2004) [Pubmed]
  17. Increased sensitivity to cocaine, and over-responding during cocaine self-administration in tPA knockout mice. Ripley, T.L., Rocha, B.A., Oglesby, M.W., Stephens, D.N. Brain Res. (1999) [Pubmed]
  18. Chromosomal location and isoform analysis of mouse Fc epsilon RII/CD23. Conrad, D.H., Kozak, C.A., Vernachio, J., Squire, C.M., Rao, M., Eicher, E.M. Mol. Immunol. (1993) [Pubmed]
  19. Plasminogen activation independent of uPA and tPA maintains wound healing in gene-deficient mice. 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., Danø, K., Rømer, J. EMBO J. (2006) [Pubmed]
  20. Tissue plasminogen activator and plasminogen mediate stress-induced decline of neuronal and cognitive functions in the mouse hippocampus. Pawlak, R., Rao, B.S., Melchor, J.P., Chattarji, S., McEwen, B., Strickland, S. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  21. Urokinase-dependent plasminogen activation is required for efficient skeletal muscle regeneration in vivo. Lluís, F., Roma, J., Suelves, M., Parra, M., Aniorte, G., Gallardo, E., Illa, I., Rodríguez, L., Hughes, S.M., Carmeliet, P., Roig, M., Muñoz-Cánoves, P. Blood (2001) [Pubmed]
  22. Coordinated induction of extracellular proteolysis systems during experimental autoimmune encephalomyelitis in mice. Teesalu, T., Hinkkanen, A.E., Vaheri, A. Am. J. Pathol. (2001) [Pubmed]
  23. Tissue-type plasminogen activator acts as a cytokine that triggers intracellular signal transduction and induces matrix metalloproteinase-9 gene expression. Hu, K., Yang, J., Tanaka, S., Gonias, S.L., Mars, W.M., Liu, Y. J. Biol. Chem. (2006) [Pubmed]
  24. Tissue plasminogen activator is a potent activator of PDGF-CC. Fredriksson, L., Li, H., Fieber, C., Li, X., Eriksson, U. EMBO J. (2004) [Pubmed]
  25. Nitric oxide mediates neurodegeneration and breakdown of the blood-brain barrier in tPA-dependent excitotoxic injury in mice. Parathath, S.R., Parathath, S., Tsirka, S.E. J. Cell. Sci. (2006) [Pubmed]
  26. Modulation of murine B16F10 melanoma plasminogen activator production by a synthetic peptide derived from the laminin A chain. Stack, M.S., Gray, R.D., Pizzo, S.V. Cancer Res. (1993) [Pubmed]
  27. Adenovirus-mediated expression and packaging of tissue-type plasminogen activator in megakaryocytic cells. Chuang, J.L., Schleef, R.R. Thromb. Haemost. (2001) [Pubmed]
  28. BDNF stimulates expression, activity and release of tissue-type plasminogen activator in mouse cortical neurons. Fiumelli, H., Jabaudon, D., Magistretti, P.J., Martin, J.L. Eur. J. Neurosci. (1999) [Pubmed]
  29. Differing roles for urokinase and tissue-type plasminogen activator in collagen-induced arthritis. Cook, A.D., Braine, E.L., Campbell, I.K., Hamilton, J.A. Am. J. Pathol. (2002) [Pubmed]
  30. Localization and regulation of the tissue plasminogen activator-plasmin system in the hippocampus. Salles, F.J., Strickland, S. J. Neurosci. (2002) [Pubmed]
  31. Variable and multiple expression of Protease Nexin-1 during mouse organogenesis and nervous system development. Mansuy, I.M., van der Putten, H., Schmid, P., Meins, M., Botteri, F.M., Monard, D. Development (1993) [Pubmed]
  32. A murine model of myocardial microvascular thrombosis. Christie, P.D., Edelberg, J.M., Picard, M.H., Foulkes, A.S., Mamuya, W., Weiler-Guettler, H., Rubin, R.H., Gilbert, P., Rosenberg, R.D. J. Clin. Invest. (1999) [Pubmed]
  33. Urokinase-type plasminogen activator is effective in fibrin clearance in the absence of its receptor or tissue-type plasminogen activator. Bugge, T.H., Flick, M.J., Danton, M.J., Daugherty, C.C., Romer, J., Dano, K., Carmeliet, P., Collen, D., Degen, J.L. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  34. Biological effects of combined inactivation of plasminogen activator and plasminogen activator inhibitor-1 gene function in mice. Lijnen, H.R., Moons, L., Beelen, V., Carmelie, P., Collen, D. Thromb. Haemost. (1995) [Pubmed]
  35. Inhibition of plasminogen activation protects against ganglion cell loss in a mouse model of retinal damage. Zhang, X., Chaudhry, A., Chintala, S.K. Mol. Vis. (2003) [Pubmed]
  36. Aggravation of focal cerebral ischemia by tissue plasminogen activator is reversed by 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor but does not depend on endothelial NO synthase. Kilic, E., Kilic, U., Matter, C.M., Lüscher, T.F., Bassetti, C.L., Hermann, D.M. Stroke (2005) [Pubmed]
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