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Gene Review

Plat  -  plasminogen activator, tissue

Rattus norvegicus

Synonyms: PATISS, Tissue-type plasminogen activator, t-PA, t-plasminogen activator, tPA
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Disease relevance of Plat

  • Using chemical crosslinking, we have recently identified a plasminogen-activator inhibitor type 1 (PAI-1)-independent t-PA clearance receptor on rat hepatoma MH1C1 cells with a relative molecular mass of approximately 500 kDa [1].
  • To investigate this question, we overexpressed plasminogen activator inhibitor-1 (PAI-1), an inhibitor of t-PA and u-PA, in a rat model of aortic aneurysm [2].
  • In the context of ICH, our results suggest that the use of tPA or uPA to lyse clotted blood in brain parenchyma may promote edema formation in surrounding tissue [3].
  • These data demonstrate that t-PA and PAI-1 production is strongly upregulated in the liver in rats with mild cirrhosis [4].
  • After 12 hours through 10 days of unilateral ureteral obstruction, t-PA mRNA in obstructed and contralateral kidneys was significantly elevated compared with in control kidneys (p <0.05) [5].

High impact information on Plat

  • Exposure of granule cells in culture to forskolin results in secretion of tPA, elongation of mossy fiber axons, and formation of new, active presynaptic varicosities contiguous to dendritic clusters of the glutamate receptor R1 [6].
  • We have found that inhibitors of tPA inhibit the late phase of long-term potentiation (L-LTP) induced by either forskolin or tetanic stimulation in the hippocampal mossy fiber and Schaffer collateral pathways [6].
  • Moreover, application of tPA enhances L-LTP induced by a single tetanus [6].
  • We immunocytochemically stained rat pituitary glands using antibodies against plasminogen activators of the tissue type (t-PA) and the urokinase type (u-PA) [7].
  • These findings represent the first direct evidence for the presence of t-PA in cell types other than endothelial cells in the intact normal organism [7].

Chemical compound and disease context of Plat

  • We have reported previously that incubation of HTC rat hepatoma cells with the synthetic glucocorticoid dexamethasone causes a 90% decrease in tissue-type plasminogen activator (tPA) activity secondary to a 4-fold increase in plasminogen activator inhibitor-1 (PAI-1) mRNA accumulation [8].
  • Retinoic acid enhances fibrinolytic activity in-vivo by enhancing tissue type plasminogen activator (t-PA) activity and inhibits venous thrombosis [9].
  • Tissue plasminogen activator (tPA), an arginine-specific serine protease, is an oestrogen-regulated protein in uterine and breast cancer tissue [10].
  • That heparin could prevent the arterial occlusion and that tPA could reperfuse the occluded artery are observations consistent with the histopathological ones that the primary lesion of endothelium injured photochemically activates the platelet aggregation to form platelet-rich thrombus with extensions of erythrocyte-rich lesions [11].
  • These data indicate that cyclic AMP mediates the actions of PTH, prostaglandin E2 and calcitonin in increasing tPA activity in the clonal osteogenic sarcoma cells [12].

Biological context of Plat


Anatomical context of Plat

  • In vitro, supernatants, cytosols, and membranes of renal proximal tubular cells in primary cultures had no detectable uPA activity, and lovastatin (0.1 to 10 microM) induced an increase in tPA and a decrease in PAI-1 activities and antigens [17].
  • In contrast, oocyte-free granulosa cells in these preantral follicles contained uPA, but not tPA [13].
  • Culturing of denuded oocytes for 24 h increased the cellular content of tPA, but the enzyme activity was not further enhanced by treatment with FSH or forskolin [13].
  • We have recently described a PAI-1-independent pathway of tissue-type plasminogen activator (t-PA) uptake and degradation on the rat MH1C1 hepatoma cell line [18].
  • Although tPA and uPA protein could not be measured, these results suggest that glucocorticoids suppress PA activity predominantly by increasing PAI-1 synthesis in rat osteoblasts [19].

Associations of Plat with chemical compounds

  • Tissue-type plasminogen activator (t-PA), a serine protease that catalyzes the initial and rate-limiting step in the fibrinolytic cascade, is cleared rapidly in vivo by the liver [1].
  • Proximal tubules freshly isolated from rats treated for 2 d with lovastatin (4 mg/kg per d) showed increased tissue-type plasminogen activator (tPA) and urokinase (uPA) activities and antigens [17].
  • Dexamethasone had no effect on tPA or uPA mRNA in either cell type [19].
  • The mRNA and activities of both urokinase-type PA (uPA) and tissue-type PA (tPA) were enhanced by PGE2 treatment [20].
  • Denuded oocytes collected from ovaries of hypophysectomized, estrogen-treated immature rats contained a tissue-type plasminogen activator (tPA), but not urokinase (uPA) [13].

Physical interactions of Plat

  • In addition to the free pool of tPA, a large portion of tPA is complexed to PAI-1 and is therefore functionally inactive [21].

Enzymatic interactions of Plat

  • At 12 hours, tPA-treated rats showed significantly higher levels of pro-MMP-9 and cleaved MMP-9 than untreated controls [22].

Regulatory relationships of Plat


Other interactions of Plat

  • Plasminogen zymography showed a 39% reduction of u-PA in the basal ganglia (p < 0.0001); t-PA expression was reduced by 26% in the cortex and by 33% in the basal ganglia (p < 0.0001) [27].
  • These results indicate that in the FN remodeling process, occurring during FRT epithelium maturation, both plasmin-dependent (tPA activated) and plasmin-independent proteolytic activities are involved [28].
  • Reciprocal actions of NCAM and tPA via a Ras-dependent MAPK activation in rat hippocampal neurons [29].
  • Although tissue-type PA (tPA) protein was not measured, TGF beta did not influence production of mRNA for tPA [30].
  • Elastin was preserved in the LPSN group. t-PA, the major PA expressed in the model, was decreased in the LPSN group compared with the other groups, as determined by zymography [2].

Analytical, diagnostic and therapeutic context of Plat

  • When analyzed by SDS/PAGE, we found the t-PA receptor identified on MH1C1 cells comigrated with the large subunit of LRP/alpha 2MR [1].
  • Zymography and Northern blot analysis of purified astroglial, microglial, and mixed glial cell cultures demonstrated that astroglial cells produce tPA and a plasminogen activator inhibitor (PAI-1) and are thereby responsible for the production of plasmin which may activate the inactive TGF in these cultures [31].
  • Immunohistochemical study of paraffin-embedded liver sections and fibrin autography of frozen sections showed that the normal rat liver produces very little t-PA or PAI-1 [4].
  • The identity of tPA and uPA in the cumulus-oocyte complexes was further confirmed by immunoprecipitation with specific antibodies [13].
  • Meanwhile, slight polymerase chain reaction products of t-PA were observed in control kidneys [5].


  1. Low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor is an hepatic receptor for tissue-type plasminogen activator. Bu, G., Williams, S., Strickland, D.K., Schwartz, A.L. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  2. Prevention of aneurysm development and rupture by local overexpression of plasminogen activator inhibitor-1. Allaire, E., Hasenstab, D., Kenagy, R.D., Starcher, B., Clowes, M.M., Clowes, A.W. Circulation (1998) [Pubmed]
  3. Plasminogen activators potentiate thrombin-induced brain injury. Figueroa, B.E., Keep, R.F., Betz, A.L., Hoff, J.T. Stroke (1998) [Pubmed]
  4. Production of tissue-type plasminogen activator (t-PA) and type-1 plasminogen activator inhibitor (PAI-1) in mildly cirrhotic rat liver. Seki, T., Imai, H., Uno, S., Ariga, T., Gelehrter, T.D. Thromb. Haemost. (1996) [Pubmed]
  5. Plasminogen activator inhibitor-1 and tissue-type plasminogen activator are up-regulated during unilateral ureteral obstruction in adult rats. Ishidoya, S., Ogata, Y., Fukuzaki, A., Kaneto, H., Takeda, A., Orikasa, S. J. Urol. (2002) [Pubmed]
  6. Tissue plasminogen activator contributes to the late phase of LTP and to synaptic growth in the hippocampal mossy fiber pathway. Baranes, D., Lederfein, D., Huang, Y.Y., Chen, M., Bailey, C.H., Kandel, E.R. Neuron (1998) [Pubmed]
  7. Immunocytochemical demonstration of tissue-type plasminogen activator in endocrine cells of the rat pituitary gland. Kristensen, P., Nielsen, L.S., Grøndahl-Hansen, J., Andresen, P.B., Larsson, L.I., Danø, K. J. Cell Biol. (1985) [Pubmed]
  8. Transcriptional and posttranscriptional regulation of type 1 plasminogen activator inhibitor and tissue-type plasminogen activator gene expression in HTC rat hepatoma cells by glucocorticoids and cyclic nucleotides. Heaton, J.H., Kathju, S., Gelehrter, T.D. Mol. Endocrinol. (1992) [Pubmed]
  9. Retinoic acid enhances fibrinolytic activity in-vivo by enhancing tissue type plasminogen activator (t-PA) activity and inhibits venous thrombosis. van Giezen, J.J., Boon, G.I., Jansen, J.W., Bouma, B.N. Thromb. Haemost. (1993) [Pubmed]
  10. Absence of specific cell-surface binding of tissue plasminogen activator in uterine cells. Ayub, M., Jenkins, N., White, J.O. J. Mol. Endocrinol. (1990) [Pubmed]
  11. Photochemically induced thrombosis model in rat femoral artery and evaluation of effects of heparin and tissue-type plasminogen activator with use of this model. Matsuno, H., Uematsu, T., Nagashima, S., Nakashima, M. Journal of pharmacological methods. (1991) [Pubmed]
  12. Cyclic AMP-dependent and -independent effects on tissue-type plasminogen activator activity in osteogenic sarcoma cells; evidence from phosphodiesterase inhibition and parathyroid hormone antagonists. Allan, E.H., Hamilton, J.A., Medcalf, R.L., Kubota, M., Martin, T.J. Biochim. Biophys. Acta (1986) [Pubmed]
  13. Identification and regulation of tissue plasminogen activator activity in rat cumulus-oocyte complexes. Liu, Y.X., NY, T., Sarkar, D., Loskutoff, D., Hsueh, A.J. Endocrinology (1986) [Pubmed]
  14. Plasminogen activator activity in vitamin A-deficient rat corneas. Hayashi, K., Frangieh, G., Kenyon, K.R., Berman, M., Wolf, G. Invest. Ophthalmol. Vis. Sci. (1988) [Pubmed]
  15. Enhanced tissue plasminogen activator synthesis by the sympathetic neurons that innervate aging vessels. Jiang, X., Hand, A.R., Shen, S., Cone, R.E., O'Rourke, J. J. Neurosci. Res. (2003) [Pubmed]
  16. Plasminogen activator-plasmin system potentiates the proliferation of hepatocytes in primary culture. Akao, M., Hasebe, Y., Okumura, N., Hagiwara, H., Seki, T., Ariga, T. Thromb. Res. (2002) [Pubmed]
  17. Lovastatin modulates in vivo and in vitro the plasminogen activator/plasmin system of rat proximal tubular cells: role of geranylgeranylation and Rho proteins. Essig, M., Vrtovsnik, F., Nguyen, G., Sraer, J.D., Friedlander, G. J. Am. Soc. Nephrol. (1998) [Pubmed]
  18. Interaction of a 39 kDa protein with the low-density-lipoprotein-receptor-related protein (LRP) on rat hepatoma cells. Iadonato, S.P., Bu, G., Maksymovitch, E.A., Schwartz, A.L. Biochem. J. (1993) [Pubmed]
  19. Glucocorticoid regulation of plasminogen activator inhibitor-1 messenger ribonucleic acid and protein in normal and malignant rat osteoblasts. Fukumoto, S., Allan, E.H., Zeheb, R., Gelehrter, T.D., Martin, T.J. Endocrinology (1992) [Pubmed]
  20. Prostaglandin E2 regulates production of plasminogen activator isoenzymes, urokinase receptor, and plasminogen activator inhibitor-1 in primary cultures of rat calvarial osteoblasts. Allan, E.H., Martin, T.J. J. Cell. Physiol. (1995) [Pubmed]
  21. Immunohistochemical localization of tissue plasminogen activator in vascular endothelium of stroke-prone regions of the rat brain. Schreiber, S.S., Tan, Z., Sun, N., Wang, L., Zlokovic, B.V. Neurosurgery (1998) [Pubmed]
  22. Involvement of matrix metalloproteinase in thrombolysis-associated hemorrhagic transformation after embolic focal ischemia in rats. Sumii, T., Lo, E.H. Stroke (2002) [Pubmed]
  23. Tissue plasminogen activator in primary afferents induces dorsal horn excitability and pain response after peripheral nerve injury. Yamanaka, H., Obata, K., Fukuoka, T., Dai, Y., Kobayashi, K., Tokunaga, A., Noguchi, K. Eur. J. Neurosci. (2004) [Pubmed]
  24. Cytokine-induced expression of tPA is differentially modulated by NO and ROS in rat mesangial cells. Eberhardt, W., Beck, K.F., Pfeilschifter, J. Kidney Int. (2002) [Pubmed]
  25. Follicular stage-dependent regulation of rat granulosa cell plasminogen activator system by transforming growth factor-alpha in vitro. Karakji, E.G., Tsang, B.K. Biol. Reprod. (1995) [Pubmed]
  26. Real-time imaging of the axonal transport of granules containing a tissue plasminogen activator/green fluorescent protein hybrid. Lochner, J.E., Kingma, M., Kuhn, S., Meliza, C.D., Cutler, B., Scalettar, B.A. Mol. Biol. Cell (1998) [Pubmed]
  27. ACE inhibition reduces activity of the plasminogen/plasmin and MMP systems in the brain of spontaneous hypertensive stroke-prone rats. Liebetrau, M., Burggraf, D., Wunderlich, N., Jäger, G., Linz, W., Hamann, G.F. Neurosci. Lett. (2005) [Pubmed]
  28. The role of proteases in fibronectin matrix remodeling in thyroid epithelial cell monolayer cultures. Nezi, L., Greco, D., Nitsch, L., Garbi, C. Biol. Chem. (2002) [Pubmed]
  29. Reciprocal actions of NCAM and tPA via a Ras-dependent MAPK activation in rat hippocampal neurons. Son, H., Seuk Kim, J., Mogg Kim, J., Lee, S.H., Lee, Y.S. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  30. Transforming growth factor beta inhibits plasminogen activator (PA) activity and stimulates production of urokinase-type PA, PA inhibitor-1 mRNA, and protein in rat osteoblast-like cells. Allan, E.H., Zeheb, R., Gelehrter, T.D., Heaton, J.H., Fukumoto, S., Yee, J.A., Martin, T.J. J. Cell. Physiol. (1991) [Pubmed]
  31. Role of astrocyte-derived tissue-type plasminogen activator in the regulation of endotoxin-stimulated nitric oxide production by microglial cells. Vincent, V.A., Löwik, C.W., Verheijen, J.H., de Bart, A.C., Tilders, F.J., Van Dam, A.M. Glia (1998) [Pubmed]
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