SpringerLink
Log in

The plasminogen activator inhibitor-1 gene is induced by cell adhesion through the MEK/ERK pathway

  • Original Paper
  • Published:
Journal of Biomedical Science

Abstract

The type-I plasminogen activator inhibitor (PAI-1), the primary inhibitor of both tissue-type and urokinase-type plasminogen activators (t-PA, u-PA), is the primary regulator of plasminogen activation and possibly of extracellular proteolysis. In anchorage-dependent cells, the PAI-1 gene is regulated by cell adhesion. PAI-1 gene expression is induced more evidently in cells that adhered to the culture plate than in those that did not adhere. In this study, we further demonstrate that the PAI-1 gene expression associated with cell adhesion is elicited through the activation of MEK and p42/p44 mitogen-activated protein (MAP) kinase (MAPK; ERK) signal pathways. We found that the MEK inhibitors, PD98059 and U0126, inhibited the induction of PAI-1 gene and protein expression during cell adhesion, PD98059 also inhibited the adhesion of cells to the culture plate, and cell adhesion elicited the kinase activities of MEK and ERK. In addition, we illustrate that two transcription response elements, the serum response element (SRE) and the hypoxia response element (HRE), which exist in the PAI-1 promoter, might be correlated with PAI-1 gene expression during cell adhesion. We discovered that the binding ability of nucleoproteins to both SRE and HRE was enhanced by cell adhesion and was dependent on MEK. Based on these results, we suggest that both MEK and ERK are involved in the induction of PAI-1 gene expression during cell adhesion. Furthermore, the subsequent downstream molecules, Elk-1 and HIF-1, may also participate.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Germany)

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Aplin AE, Short SM, Juliano RL. Anchorage-dependent regulation of the mitogen-activated protein kinase cascade by growth factors is supported by a variety of integrin alpha chains. J Biol Chem 274:31223–31228;1999.

    Article  PubMed  Google Scholar 

  2. Aplin AE, Stewart SA, Assoian RK, Juliano RL. Integrin-mediated adhesion regulates ERK nuclear translocation and phosphorylation of Elk-1. J Cell Biol 153:273–281;2001.

    PubMed  Google Scholar 

  3. Banfi C, Eriksson P, Giandomenico G, Mussoni L, Sironi L, Hamsten A, Tremoli E. Transcriptional regulation of plasminogen activator inhibitor type 1 gene by insulin: Insights into the signaling pathway. Diabetes 50:1522–1530;2001.

    PubMed  Google Scholar 

  4. Blasi F. Proteolysis, cell adhesion, chemotaxis, and invasiveness are regulated by the u-PA-u-PAR-PAI-1 system. Thromb Haemost 82:298–304;1999.

    PubMed  Google Scholar 

  5. Chen RH, Sarnecki C, Blenis J. Nuclear localization and regulation of ERK- and RSK-encoded protein kinases. Mol Cell Biol 12:915–927;1992.

    PubMed  Google Scholar 

  6. Conese M, Nykjaer A, Petersen CM, Cremona O, Pardi R, Andreasen PA, Gliemann J, Christensen EI, Blasi F. Alpha-2 macroglobulin receptor/Ldl receptor-related protein (Lrp)-dependent internalization of the urokinase receptor. J Cell Biol 131:1609–1622;1995.

    PubMed  Google Scholar 

  7. Cubellis MV, Wun TC, Blasi F. Receptor-mediated internalization and degradation of urokinase is caused by its specific inhibitor PAI-1. EMBO J 9:1079–1085;1990.

    PubMed  Google Scholar 

  8. Deng G, Curriden SA, Wang S, Rosenberg S, Loskutoff DJ. Is plasminogen activator inhibitor-1 the molecular switch that governs urokinase receptor-mediated cell adhesion and release? J Cell Biol 134:1563–1571;1996.

    PubMed  Google Scholar 

  9. Giancotti FG, Ruoslahti E. Integrin signaling. Science 285:1028–1032;1999.

    Article  PubMed  Google Scholar 

  10. Gille HA, Sharrocks D, Shaw PE. Phosphorylation of transcription factor p62TCF by MAP kinase stimulates ternary complex formation at c-fos promoter. Nature 358:414–417;1992.

    PubMed  Google Scholar 

  11. Gorlach A, Diebold I, Schini-Kerth VB, Berchner-Pfannschmidt U, Roth U, Brandes RP, Kietzmann T, Busse R. Thrombin activates the hypoxia-inducible factor-1 signaling pathway in vascular smooth muscle cells: Role of the p22 (phox)-containing NADPH oxidase. Circ Res 89:47–54;2001.

    PubMed  Google Scholar 

  12. Hill CS, Wynne J, Treisman R. The Rho family GTPases RhoA, Rac1, and CDC42Hs regulate transcriptional activation by SRF. Cell 81:1159–1170;1995.

    Article  PubMed  Google Scholar 

  13. Jonathan S, Christian OG. Technical Report CBIL-TR-1997-1001-v0.0 TESS: Transcription Element Search Software on the WWW. URL: http://www.cbil.upenn.edu/tess; 1997.

  14. Kanse SM, Kost C, Wilhelm OG, Andreasen PA, Preissner KT. The urokinase receptor is a major vitronectin-binding protein on endothelial cells. Exp Cell Res 224:344–353;1996.

    PubMed  Google Scholar 

  15. Kjoller L, Kanse SM, Kirkegaard T, Rodenburg KW, Ronne E, Goodman SL, Preissner KT, Ossowski L, Andreasen PA. Plasminogen activator inhibitor-1 represses integrin- and vitronectin-mediated cell migration independently of its function as an inhibitor of plasminogen activation. Exp Cell Res 232:420–429;1997.

    Article  PubMed  Google Scholar 

  16. Kobayashi N, Nakano S, Mita S, Kobayashi T, Honda T, Tsubokou Y, Matsuoka H. Involvement of Rho-kinase pathway for angiotensin II-induced plasminogen activator inhibitor-1 gene expression and cardiovascular remodeling in hypertensive rats. J Pharmacol Exp Ther 301:459–466;2002.

    Article  PubMed  Google Scholar 

  17. Kortenjann M, Thomae O, Shaw PE. Inhibition of v-raf-dependent c-fos expression and transformation by a kinase-defective mutant of the mitogen-activated protein kinase Erk2. Mol Cell Biol 14:4815–4824;1994.

    PubMed  Google Scholar 

  18. Kutz SM, Hordines J, McKeown-Longo PJ, Higgins PJ. TGF-beta1-induced PAI-1 gene expression requires MEK activity and cell-to-substrate adhesion. J Cell Sci 114:3905–3914;2001.

    PubMed  Google Scholar 

  19. Kwaan HC, Wang J, Svoboda K, Declerck PJ. Plasminogen activator inhibitor 1 may promote tumour growth through inhibition of apoptosis. Br J Cancer 82:1702–1708;2000.

    PubMed  Google Scholar 

  20. Lee CC, Shyu KG, Lin S, Wang BW, Liu YC, Chang H. Cell adhesion regulates the plasminogen activator inhibitor-1 gene expression in anchorage-dependent cells. Biochem Biophys Res Commun 291:185–190;2002.

    Article  PubMed  Google Scholar 

  21. Lenormand P, Sardet C, Pages G, L'Allemain G, Brunet A, Pouyssegur J. Growth factors induce nuclear translocation of MAP kinases (p42mapk and p44mapk) but not of their activator MAP kinase kinase (p45 mapkk) in fibroblasts. J Cell Biol 122:1079–1088;1993.

    Article  PubMed  Google Scholar 

  22. Lin S, Huang HC, Chen LL, Lee CC, Huang TS. GL331 induces down-regulation of cyclin D1 expression via enhanced proteolysis and repressed transcription. Mol Pharmacol 60:768–774;2001.

    PubMed  Google Scholar 

  23. Lin TH, Chen Q, Howe A, Julinano RL. Cell anchorage permits efficient signal transduction between Ras and its downstream kinases. J Biol Chem 272:8849–8852;1997.

    PubMed  Google Scholar 

  24. Lin S, Wang W, Wilson GM, Yang X, Brewer G, Holbrook NJ, Gorospe M. Down-regulation of cyclin D1 expression by prostaglandin A2 is mediated by enhanced cyclin D1 mRNA turnover. Mol Cell Biol 20:7903–7913;2000.

    Article  PubMed  Google Scholar 

  25. Lopez S, Peiretti F, Morange P, Laouar A, Fossat C, Bonardo B, Huberman E, Juhan-Vague I, Nalbone G. Activation of plasminogen activator inhibitor-1 synthesis by phorbol esters in human promyelocyte HL-60 — Roles of PKCβ and MAPK p42. Thromb Haemost 81:415–422;1999.

    PubMed  Google Scholar 

  26. Loskutoff KJ, Sawdey M, Mimuro J, Coller B. Progress in Hemostasis and Thrombosis, ed 9. Philadelphia, Saunders, 87–115;1989.

    Google Scholar 

  27. Maniatis T, Fritsch EF, Sambrook J. Molecular Cloning: A Laboratory Manual. Cold Spring Harbor, Cold Spring Harbor Laboratory Press, 1982.

    Google Scholar 

  28. Marais R, Wynne J, Treisman R. The SRF accessory protein Elk-1 contains a growth factor-regulated transcriptional activation domain. Cell 73:381–393;1993.

    Article  PubMed  Google Scholar 

  29. Miyamoto S, Teramoto H, Gutkind JS, Yamada KM. Integrins can collaborate with growth factors for phosphorylation of receptor tyrosine kinases and MAP kinase activation: Roles of integrin aggregation and occupancy of receptors. J Cell Biol 135:1633–1642;1996.

    Article  PubMed  Google Scholar 

  30. Nykjaer A, Conese M, Christensen EI, Olson D, Cremona O, Gliemann J, Blasi F. Recycling of the urokinase receptor upon internalization of the uPA:serpin complexes. EMBO J 16:2610–2620;1997.

    Article  PubMed  Google Scholar 

  31. Palmier D, Lee JW, Juliano RL, Church FC. Plasminogen activator inhibitor-1 and -3 increase cell adhesion and motility of MDA-MB-435 breast cancer cells. J Biol Chem 277:40950–40957;2002.

    Article  PubMed  Google Scholar 

  32. Renshaw MW, Ren XD, Schwartz MA: Growth factor activation of MAP kinase requires cell adhesion. EMBO J 16:5592–5599;1997.

    Article  PubMed  Google Scholar 

  33. Richard DE, Berra E, Gothie E, Roux D, Pouyssegur J. p42/p44 mitogen-activated protein kinases phosphorylate hypoxia-inducible factor 1(HIF-1) and enhance the transcriptional activity of HIF-1. J Biol Chem 274:32631–32637;1999.

    Article  PubMed  Google Scholar 

  34. Ryan MP, Kutz SM, Higgins PJ. Complex regulation of plasminogen activator inhibitor type-1 (PAI-1) gene expression by serum and substrate adhesion. Biochem J 314:1041–1046;1996.

    PubMed  Google Scholar 

  35. Schneiderman J, Loskutoff DJ. Plasminogen activator inhibitors. Trends Cardiovasc Med 1:99–102;1991.

    Article  Google Scholar 

  36. Schwartz MA, Schaller MD, Ginsberg MH. Integrins: Emerging paradigms of signal transduction. Annu Rev Cell Dev Biol 11:549–599;1995.

    Article  PubMed  Google Scholar 

  37. Short SM, Boyer JL, Juliano RL. Integrins regulate the linkage between upstream and downstream events in G-protein-coupled receptor signaling to mitogen-activated protein kinase. J Biol Chem 275:12970–12977;2000.

    Article  PubMed  Google Scholar 

  38. Sprengers ED, Kluft C. Plasminogen activator inhibitors. Blood 69:381–387;1987.

    PubMed  Google Scholar 

  39. Stefansson S, Lawrence DA. The serpin PAI-1 inhibits cell migration by blocking integrin alpha V beta 3 binding to vitronectin. Nature 383:441–443;1996.

    Article  PubMed  Google Scholar 

  40. Takeda K, Ichiki T, Tokunou T, Iino N, Fujii S, Kitabatake A, Shimokawa H, Takeshita A. Critical role of Rho-kinase and MEK/ERK pathways for angiotensin II-induced plasminogen activator inhibitor type-1 gene expression. Arterioscler Thromb Vasc Biol 21:868–873;2001.

    PubMed  Google Scholar 

  41. Fink T, Kazlauskas A, Poellinger L, Ebbesen P, Zachar V. Identification of a tightly regulated hypoxia-response element in the promoter of human plasminogen activator inhibitor-1. Blood 99:2077–2083;2002.

    Article  PubMed  Google Scholar 

  42. Webb DJ, Thomas KS, Gonias SL. Plasminogen activator inhibitor 1 functions as a urokinase response modifier at the level of cell signaling and thereby promotes MCF-7 cell growth. J Cell Biol 152:741–751;2001.

    Article  PubMed  Google Scholar 

  43. Whitmarsh AJ, Shore P, Sharrocks AD, Davis RJ. Integration of MAP kinase signal transduction pathways at the serum response element. Science 269:403–407;1995.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Surgical Department, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan, ROC

    Hang Chang

  2. Surgical Department, Taipei Medical University, Taipei, Taiwan, ROC

    Hang Chang

  3. Central Laboratory, Shin Kong Wu Ho-Su Memorial Hospital, 95 Wen Chang Road, 111, Shihlin, Taipei, Taiwan (ROC)

    Kou-Gi Shyu, Shankung Lin, Shiow-Chwen Tsai, Bao-Wei Wang, Ya-Chen Liu, Yu-Ling Sung & Chun-Chung Lee PhD

Authors
  1. Hang Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kou-Gi Shyu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shankung Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shiow-Chwen Tsai
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bao-Wei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ya-Chen Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yu-Ling Sung
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chun-Chung Lee PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chang, H., Shyu, KG., Lin, S. et al. The plasminogen activator inhibitor-1 gene is induced by cell adhesion through the MEK/ERK pathway. J Biomed Sci 10, 738–745 (2003). https://doi.org/10.1007/BF02256326

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02256326

Key Words

Search

Navigation