Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

The integrin linked kinase (ILK) induces an invasive phenotype via AP-1 transcription factor-dependent upregulation of matrix metalloproteinase 9 (MMP-9)

Oncogene volume 19, pages 5444–5452 (2000)Cite this article

Abstract

Overexpression of Integrin Linked Kinase (ILK) in intestinal and mammary epithelial cells results in a highly invasive phenotype, associated with increased levels of expression of the matrix metalloproteinase MMP-9. This increase was at the transcriptional level as determined by MMP-9 promoter-CAT reporter assays. Mutations in the two AP-1 binding sites within the MMP-9 promoter completely inhibited the reporter activity. We have previously shown that ILK inhibits glycogen synthase kinase-3 (GSK-3) activity. Transient transfection of wild-type GSK-3β in ILK-overexpressing cells decreased MMP-9 promoter activity and AP-1 activity, indicating that ILK can stimulate MMP-9 expression via GSK-3β and AP-1 transcription factor. A small molecule inhibitor of the ILK kinase reduced the in vitro invasiveness of ILK-overexpressing cells as well as the invasiveness of several human brain tumor cell lines. Furthermore, both MMP-9 promoter and AP-1 activities were inhibited by the ILK inhibitor. Invasiveness of ILK-overexpressing cells was also reduced by inhibition of MMP-9. These data demonstrate that ILK can induce an invasive phenotype via AP-1-dependent upregulation of MMP-9.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  • Dedhar S, Williams B and Hannigan G. . 1999 Trends Cell. Biol. 9: 319–323.

  • Delcommenne M, Tan C, Gray V, Ruel L, Woodgett J and Dedhar S. . 1998 Proc. Natl. Acad. Sci. USA 95: 11211–11216.

  • Gum R, Lengyel E, Juarez J, Chen JH, Sato H, Seiki M and Boyd D. . 1996 J. Biol. Chem. 271: 10672–10680.

  • Gum R, Wang H, Lengyel E, Juarez J and Boyd D. . 1997 Oncogene 14: 1481–1493.

  • Hannigan GE, Leung-Hagesteijn C, Fitz-Gibbon L, Coppolino MG, Radeva G, Filmus J, Bell JC and Dedhar S. . 1996 Nature 379: 91–96.

  • Janji B, Melchior C, Gouon V, Vallar L and Kieffer N. . 1999 Int. J. Cancer 83: 255–262.

  • Johnsen M, Lund LR, Romer J, Almholt K and Dano K. . 1998 Curr. Opin. Cell. Biol. 10: 667–671.

  • Kolkhorst V, Sturzebecher J and Wiederanders B. . 1998 J. Cancer Res. Clin. Oncol. 124: 598–606.

  • Liotta LA, Tryggvason K, Garbisa S, Hart I, Foltz CM and Shafie S. . 1980 Nature 284: 67–68.

  • Llorens A, Rodrigo I, Lopez-Barcons L, Gonzalez-Garrigues M, Lozano E, Vinyals A, Quintanilla M, Cano A and Fabra A. . 1998 Lab. Invest. 78: 1131–1142.

  • Luo J, Lubaroff DM and Hendrix MJC. . 1999 Cancer Res. 59: 3552–3556.

  • Mira E, Manes S, Lacalle RA, Marquez G and Martinez-A C. . 1999 Endocrinology 140: 1657–1664.

  • Morimoto AM, Tomlinson MG, Nakatani K, Bolen JB, Roth RA and Herbst R. . 2000 Oncogene 19: 200–209.

  • Mosmann T. . 1983 J. Immunol. Methods 65: 55–63.

  • Murphy G, Ward R, Hembry RM, Reynolds JJ, Kuhn K and Tryggvason K. . 1989 Biochem. J. 258: 463–472.

  • Novak A, Hsu SC, Leung-Hagesteijn C, Radeva G, Papkoff J, Montesano R, Roskelley C, Grosschedl R and Dedhar S. . 1998 Proc. Natl. Acad. Sci. USA 95: 4374–4379.

  • Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer M and Donner DB. . 1999 Nature 401: 82–85.

  • Persad S, Attwell S, Gray V, Delcommenne M, Troussard A, Sanghera J and Dedhar S. . 2000 Proc. Natl. Acad. Sci. USA 97: 3207–3212.

  • Radeva G, Petrocelli T, Behrend E, Leung-Hagesteijn C, Filmus J, Slingerland J and Dedhar S. . 1997 J. Biol. Chem. 272: 13937–13944.

  • Romashkova JA and Makarov SS. . 1999 Nature 401: 86–90.

  • Rao JS, Steck PA, Tofilon P, Boyd D, Ali-Osman F, Stetler-Stevenson WG, Liotta LA and Sawaya R. . 1994 J. Neurooncol. 18: 129–138.

  • Sato F, Shimada Y, Watanabe G, Uchida S, Makino T and Imamura M. . 1999 Br. J. Cancer 80: 1366–1372.

  • Sato H and Seiki M. . 1993 Oncogene 8: 395–405.

  • Simon C, Goepfert H and Boyd D. . 1998 Cancer Res. 58: 1135–1139.

  • Tamaki M, McDonald W, Amberger VR, Moore E and Del Maestro RF. . 1997 J. Neurosurg. 87: 602–609.

  • Tonn JC, Kerkau S, Hanke A, Bouterfa H, Mueller JG, Wagner S, Vince GH and Roosen K. . 1999 Int. J. Cancer 80: 764–772.

  • Troussard AA, Tan C, Yoganathan TN and Dedhar S. . 1999 Mol. Cell. Biol. 19: 7420–7427.

  • Wang Q, Somwar R, Bilan PJ, Liu Z, Jin J, Woodgett JR and Klip A. . 1999 Mol. Cell. Biol. 19: 4008–4018.

  • Westermarck J and Kahari VM. . 1999 FASEB J. 13: 781–792.

  • Woessner JF. . 1991 FASEB J. 5: 2145–2154.

  • Wu C, Keightley SY, Leung-Hagesteijn C, Radeva G, Coppolino M, Goicoechea S, McDonald JA and Dedhar S. . 1998 J. Biol. Chem. 273: 528–536.

Download references

Acknowledgements

We thank Gerry Krystal (British Columbia Cancer Agency, Canada) for constructing the MSCV-ILK-V5 vector, Douglas Boyd (University of Texas, USA) for the MMP-9 promoter plasmids, Christopher Overall (University of British Columbia, Canada) for the MMP inhibitor, and Warren McDonald and Rolando Del Maestro (Brain Research Laboratories, University of Western Ontario, Canada) for carrying out the brain tumor invasion assays. This work was supported by grants from the National Cancer Institute of Canada (NCIC) to S Dedhar and the Canadian Breast Cancer Research Initiative (CBCRI) to CD Roskelley.

Author information

Authors and Affiliations

  1. BC Cancer Agency and Vancouver Hospital, Jack Bell Research Centre, 2660 Oak Street, Vancouver BC , V6H3Z6, Canada

    Armelle A Troussard & Shoukat Dedhar

  2. Kinetek Pharmaceuticals Inc., Vancouver BC, V6P6P2, Canada

    Penny Costello & T Nathan Yoganathan

  3. Kanazawa University, School of Medicine, Ishikawa 920, Japan

    Shigehiro Kumagai

  4. Department of Anatomy, University of British Columbia, Vancouver BC, V6T1Z3, Canada

    Calvin D Roskelley

  5. Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver BC, V6T1Z3, Canada

    Shoukat Dedhar

Authors
  1. Armelle A Troussard
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Penny Costello
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T Nathan Yoganathan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shigehiro Kumagai
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Calvin D Roskelley
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shoukat Dedhar
    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

Troussard, A., Costello, P., Yoganathan, T. et al. The integrin linked kinase (ILK) induces an invasive phenotype via AP-1 transcription factor-dependent upregulation of matrix metalloproteinase 9 (MMP-9). Oncogene 19, 5444–5452 (2000). https://doi.org/10.1038/sj.onc.1203928

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1203928

Keywords

This article is cited by

Search

Advanced search

Quick links

  NODES
INTERN 1
twitter 1