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Gene Review

PLAT  -  plasminogen activator, tissue

Bos taurus

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Disease relevance of PLAT

  • OBJECTIVE: To determine if clopidogrel enhanced the thrombolytic rate of tissue-plasminogen activator (t-PA) on an in vitro feline whole blood thrombosis model [1].
  • The main plasma fibrinolytic enzyme which increased in anaphylaxis was proved by zymography to be t-PA with a molecular weight (MW) of 69,000 [2].

High impact information on PLAT

  • Alanine substitutions at the distal P4' (Glu-350) and P5' (Glu-351) residues of PAI-1 reduced the rates of Michaelis complex formation (k(a)) and overall inhibition (k(app)) with tPA by 13.4- and 4.7-fold, respectively, whereas the rate of loop insertion or final acyl-enzyme formation (k(lim)) increased by 3.3-fold [3].
  • We provide the first kinetic evidence that the removal of exosite interactions significantly alters the formation of the noncovalent Michaelis complex, facilitating the release of the primed side of the distal loop from the active-site pocket of tPA and the subsequent insertion of the cleaved reactive center loop into beta-sheet A [3].
  • Surprisingly, t-PA cleaves this engineered protein substrate with a Km that is reduced 950-fold relative to the Km for hydrolysis of the same target sequence within a peptide [4].
  • Since heparin suppresses the induction of the tPA gene by phorbol esters, these results suggest that heparin may interfere with the protein kinase C pathway [5].
  • In an in vitro mitogenesis model, tissue-type plasminogen activator (tPA) mRNA and protein increase in baboon smooth muscle cells stimulated with fetal bovine serum or phorbol esters [5].

Biological context of PLAT


Anatomical context of PLAT

  • In cultures of granulosa cells from large follicles, tPA activity increased significantly with time of culture, whereas SerpinE2 levels decreased [7].
  • In contrast, fibroblast growth factor-2 inhibited tPA secretion and SERPINE2 secretion and expression [6].
  • During ovarian follicle growth, there is expansion of the basal lamina and changes in the follicular extracellular matrix (ECM) that are mediated in part by proteolytic enzyme cascades regulated by tissue-type plasminogen activator (tPA) and urokinase plasminogen activator (uPA) [6].
  • These results suggest that uPA, tPA, and tPA-PAI are all produced by bovine COCs, but only uPA by oocytes, during maturation in vitro [9].
  • Activity for tPA was increased in follicular fluid and the preovulatory follicle apex and base within 12 h after the gonadotropin surge [10].

Associations of PLAT with chemical compounds

  • The serine proteinase plasmin is, together with tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA), involved in the dissolution of blood clots in a fibrin-dependent manner [11].
  • The stimulation of tPA activity by fibrin, however, is diminished by heparin [12].
  • RESULTS: All tested NSAIDs dose dependently inhibited the IL-1 induced mRNA expression of tPA, whereas only indomethacin and tiaprofenic acid were also able to reduce the expression of uPA [13].
  • BCEs at a subconfluent density showed a higher intensity of specific immunofluorescence for uPA than when they were at a confluent density. tPA was observed over the dorsal surface of cultured BCEs and accentuated at their margins, suggesting that tPA was diffusely distributed on the luminal surface of BCEs in vivo [14].
  • Previous studies have shown that tissue-type plasminogen activator (t-PA) in blood is cleared by the liver partially through a mannose-specific uptake system [15].

Other interactions of PLAT

  • Casein zymography revealed that the cells secreted predominantly tissue-type PA (tPA) with urokinase (uPA) being associated mainly with cell lysates, and Western blot demonstrated that the cells secreted SerpinE2 [7].
  • Epidermal growth factor inhibited SERPINE2 secretion and expression, but increased secreted tPA activity [6].
  • Bone morphogenetic protein-7 increased SERPINE2 secretion and expression and tPA secretion [6].
  • Messenger RNAs for tPA, uPA, and uPAR were increased in a temporally specific fashion within 24 h of the gonadotropin surge [10].
  • The amidolytic plasmin activity of a mixture of tissue plasminogen activator (tPA) and plasminogen is enhanced by heparin at therapeutic concentrations [12].

Analytical, diagnostic and therapeutic context of PLAT

  • The levels of MMPs, TIMPs, uPA, tPA, and PAI-1 expression were estimated by determining the mRNA levels using real-time RT-PCR and by determining protein levels using ELISA [16].
  • After 7 days (i.e., when elements of the BBB are present), astrocyte-endothelial cocultures (compared with endothelial mono-cultures) showed a 50.7%+/-27.1% (mean +/- SD) reduction in tPA mRNA (P < 0.03) and a 183.3%+/-86.9% increase in PAI-1 mRNA expression (P < 0.02) [8].
  • Both tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA) were identified in the ECM by fibrin zymography, immunoblotting, and inhibition of plasminogen activation by anti-u-PA and anti-t-PA antibodies [17].
  • High-performance affinity chromatography was performed on five ligand-bound columns in an attempt to purify tissue-type plasminogen activator (t-PA), which is a glycoprotein with a high affinity for fibrin and also has two Kringle structures and finger-domain in its molecule [18].
  • Stability of Protein-Encapsulating DRV Liposomes After Freeze-Drying: A Study with BSA and t-PA* [19].


  1. Effect of clopidogrel on tissue-plasminogen activator-induced in vitro thrombolysis of feline whole blood thrombi. Hogan, D.F., Ward, M.P. Am. J. Vet. Res. (2004) [Pubmed]
  2. A rapid and strong increase of plasminogen activator induced by experimental anaphylaxis in rabbits. Shimaya, K., Sumi, H., Maruyama, M., Mihara, H. Enzyme (1992) [Pubmed]
  3. The contribution of the exosite residues of plasminogen activator inhibitor-1 to proteinase inhibition. Ibarra, C.A., Blouse, G.E., Christian, T.D., Shore, J.D. J. Biol. Chem. (2004) [Pubmed]
  4. Distinct mechanisms contribute to stringent substrate specificity of tissue-type plasminogen activator. Coombs, G.S., Dang, A.T., Madison, E.L., Corey, D.R. J. Biol. Chem. (1996) [Pubmed]
  5. Heparin selectively inhibits the transcription of tissue-type plasminogen activator in primate arterial smooth muscle cells during mitogenesis. Au, Y.P., Kenagy, R.D., Clowes, A.W. J. Biol. Chem. (1992) [Pubmed]
  6. Regulation of serine protease inhibitor-E2 and plasminogen activator expression and secretion by follicle stimulating hormone and growth factors in non-luteinizing bovine granulosa cells in vitro. Cao, M., Nicola, E., Portela, V.M., Price, C.A. Matrix Biol. (2006) [Pubmed]
  7. Plasminogen activator and serine protease inhibitor-E2 (protease nexin-1) expression by bovine granulosa cells in vitro. Cao, M., Sahmi, M., Lussier, J.G., Price, C.A. Biol. Reprod. (2004) [Pubmed]
  8. Astrocyte regulation of endothelial tissue plasminogen activator in a blood-brain barrier model. Tran, N.D., Schreiber, S.S., Fisher, M. J. Cereb. Blood Flow Metab. (1998) [Pubmed]
  9. Production of plasminogen activators (PAs) in bovine cumulus-oocyte complexes during maturation in vitro: effects of epidermal growth factor on production of PAs in oocytes and cumulus cells. Park, K.W., Choi, S.H., Song, X.X., Funahashi, H., Niwa, K. Biol. Reprod. (1999) [Pubmed]
  10. Gonadotropin surge-induced up-regulation of the plasminogen activators (tissue plasminogen activator and urokinase plasminogen activator) and the urokinase plasminogen activator receptor within bovine periovulatory follicular and luteal tissue. Dow, M.P., Bakke, L.J., Cassar, C.A., Peters, M.W., Pursley, J.R., Smith, G.W. Biol. Reprod. (2002) [Pubmed]
  11. Structure of the complex of the antistasin-type inhibitor bdellastasin with trypsin and modelling of the bdellastasin-microplasmin system. Rester, U., Bode, W., Moser, M., Parry, M.A., Huber, R., Auerswald, E. J. Mol. Biol. (1999) [Pubmed]
  12. Interaction of heparin with plasminogen activators and plasminogen: effects on the activation of plasminogen. Andrade-Gordon, P., Strickland, S. Biochemistry (1986) [Pubmed]
  13. Differential effects of nonsteroidal antiinflammatory drugs on the IL-1 altered expression of plasminogen activators and plasminogen activator inhibitor-1 by articular chondrocytes. Sadowski, T., Steinmeyer, J. Inflamm. Res. (2002) [Pubmed]
  14. Extracellular and cell-associated localizations of plasminogen activators and plasminogen activator inhibitor-1 in cultured endothelium. Murata, T., Nakashima, Y., Yasunaga, C., Maeda, K., Sueishi, K. Exp. Mol. Pathol. (1991) [Pubmed]
  15. Binding of tissue-type plasminogen activator by the mannose receptor. Otter, M., Barrett-Bergshoeff, M.M., Rijken, D.C. J. Biol. Chem. (1991) [Pubmed]
  16. The effect of IL-1alpha on the expression of matrix metalloproteinases, plasminogen activators, and their inhibitors in osteoblastic ROS 17/2.8 cells. Fujisaki, K., Tanabe, N., Suzuki, N., Mitsui, N., Oka, H., Ito, K., Maeno, M. Life Sci. (2006) [Pubmed]
  17. Extracellular matrix produced by cultured corneal and aortic endothelial cells contains active tissue-type and urokinase-type plasminogen activators. Korner, G., Bjornsson, T.D., Vlodavsky, I. J. Cell. Physiol. (1993) [Pubmed]
  18. High-performance chromatographic method for the purification of tissue-type plasminogen activator. Matsuo, O., Tanbara, Y., Okada, K., Fukao, H., Bando, H., Sakai, T. J. Chromatogr. (1986) [Pubmed]
  19. Stability of Protein-Encapsulating DRV Liposomes After Freeze-Drying: A Study with BSA and t-PA*. Ntimenou, V., Mourtas, S., Christodoulakis, E.V., Tsilimbaris, M., Antimisiaris, S.G. Journal of liposome research (2006) [Pubmed]
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