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Modulation of Wnt3a-mediated nuclear β-catenin accumulation and activation by integrin-linked kinase in mammalian cells

Oncogene volume 25, pages 7747–7757 (2006)Cite this article

Abstract

The Wnt gene family encodes secreted signaling molecules that play important roles in tumorgenesis and embryogenesis. The canonical Wnt signaling pathway regulates target gene expression via the stabilization and nuclear translocation of the cytoplasmic pool of β-catenin. The activation of integrin-linked kinase (ILK) is also known to regulate the stabilization and subsequent nuclear translocation of β-catenin in several epithelial cell models. We now report that molecular and pharmacological inhibition of ILK activity in mammalian cells directly modulates Wnt signaling by suppressing the stabilization and nuclear translocation of β-catenin, as well as β-catenin/Lef-mediated transcription. Inhibition of ILK activity, but not phosphatidylinositol-3 kinase (PI3K) or MEK activities suppresses nuclear β-catenin stabilization in cells stably expressing Wnt3a as well as in cells exposed to either Wnt3a conditioned media or purified Wnt3a. Furthermore, ILK inhibition reverses the Wnt3a-induced suppression of β-catenin phosphorylation that accompanies β-catenin stabilization. In addition, we show that ILK can be identified in a complex with Wnt pathway components such as adenomatous polyposis coli and GSK-3. Upon treatment of L cells with Wnt3a-CM, glycogen synthase kinase-3 (GSK-3β) becomes highly phosphorylated on Ser 9, which is completely abolished upon inhibition of ILK activity. However, acute exposure of L cells to purified Wnt3a does not result in the stimulation of GSK-3β Ser 9 phosphorylation, despite β-catenin stabilization. Together our data demonstrate that ILK activity can modulate acute Wnt3a mediated β-catenin phosphorylation, stabilization and nuclear activation in a PI3K-independent manner, as well as the more prolonged PI3K-dependent secondary effects of Wnt signaling on GSK-3 phosphorylation. Finally, we suggest that a novel small molecule inhibitor of ILK, QLT-0267, may be a useful tool in the regulation of pathological Wnt signaling.

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References

  • Bafico A, Liu G, Goldin L, Harris V, Aaronson SA . (2004). Cancer Cell 6: 497–506.

  • Barth AI, Nathke IS, Nelson WJ . (1997). Curr Opin Cell Biol 9: 683–690.

  • Bienz M . (2002). Nat Rev Mol Cell Biol 3: 328–338.

  • Brown JD, Moon RT . (1998). Curr Opin Cell Biol 10: 182–187.

  • Cadigan KM, Nusse R . (1997). Genes Dev 11: 3286–3305.

  • Cowin P . (1994). Proc Natl Acad Sci USA 91: 10759–10761.

  • D’Amico M, Hulit J, Amanatullah DF, Zafonte BT, Albanese C, Bouzahzah B et al. (2000). J Biol Chem 275: 32649–32657.

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

  • Erdodi F, Kiss E, Walsh MP, Stefansson B, Deng JT, Eto M et al. (2003). Biochem Biophys Res Commun 306: 382–387.

  • Fukumoto S, Hsieh CM, Maemura K, Layne MD, Yet SF, Lee KH et al. (2001). J Biol Chem 276: 17479–17483.

  • Giles RH, van Es JH, Clevers H . (2003). Biochim Biophys Acta 1653: 1–24.

  • Hannigan G, Troussard AA, Dedhar S . (2005). Nat Rev Cancer 5: 51–63.

  • Hannigan GE, Leung-Hagesteijn C, Fitz-Gibbon L, Coppolino MG, Radeva G, Filmus J et al. (1996). Nature 379: 91–96.

  • Hart MJ, de los Santos R, Albert IN, Rubinfeld B, Polakis P . (1998). Curr Biol 8: 573–581.

  • Hinck L, Nelson WJ, Papkoff J . (1994). J Cell Biol 124: 729–741.

  • Kang UG, Seo MS, Roh MS, Kim Y, Yoon SC, Kim YS . (2004). FEBS Lett 560: 115–119.

  • Kishida M, Koyama S, Kishida S, Matsubara K, Nakashima S, Higano K et al. (1999). Oncogene 18: 979–985.

  • Korinek V, Barker N, Morin PJ, van Wichen D, de Weger R, Kinzler KW et al. (1997). Science 275: 1784–1787.

  • Li L, Yuan H, Weaver CD, Mao J, Farr III GH, Sussman DJ et al. (1999). EMBO J 18: 4233–4240.

  • Li Y, Podsypanina K, Liu X, Crane A, Tan LK, Parsons R et al. (2001). BMC Mol Biol 2: 2.

  • Mackinnon AC, Qadota H, Norman KR, Moerman DG, Williams BD . (2002). Curr Biol 12: 787–797.

  • McManus EJ, Sakamoto K, Armit LJ, Ronaldson L, Shpiro N, Marquez R et al. (2005). EMBO J 24: 1571–1583.

  • Miller JR, Hocking AM, Brown JD, Moon RT . (1999). Oncogene 18: 7860–7872.

  • Miller JR, Moon RT . (1996). Genes Dev 10: 2527–2539.

  • Mills J, Digicaylioglu M, Legg AT, Young CE, Young SS, Barr AM et al. (2003). J Neurosci 23: 1638–1648.

  • Moon RT, Bowerman B, Boutros M, Perrimon N . (2002). Science 296: 1644–1646.

  • Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B et al. (1997). Science 275: 1787–1790.

  • Nagafuchi A, Takeichi M . (1989). Cell Regul 1: 37–44.

  • Nelson WJ, Nusse R . (2004). Science 303: 1483–1487.

  • Novak A, Dedhar S . (1999). Cell Mol Life Sci 56: 523–537.

  • Novak A, Hsu SC, Leung-Hagesteijn C, Radeva G, Papkoff J, Montesano R et al. (1998). Proc Natl Acad Sci USA 95: 4374–4379.

  • Oloumi A, McPhee T, Dedhar S . (2004). Biochim Biophys Acta 1691: 1–15.

  • Paling NR, Wheadon H, Bone HK, Welham MJ . (2004). J Biol Chem 46: 48063–48070.

  • Papkoff J, Rubinfeld B, Schryver B, Polakis P . (1996). Mol Cell Biol 16: 2128–2134.

  • Persad S, Attwell S, Gray V, Mawji N, Deng JT, Leung D et al. (2001a). J Biol Chem 276: 27462–27469.

  • Persad S, Troussard AA, McPhee TR, Mulholland DJ, Dedhar S . (2001b). J Cell Biol 153: 1161–1174.

  • Pevarello P, Brasca MG, Amici R, Orsini P, Traquandi G, Corti L et al. (2004). J Med Chem 47: 3367–3380.

  • Polakis P . (2002). Curr Biol 12: R499–R501.

  • Rosin-Arbesfeld R, Cliffe A, Brabletz T, Bienz M . (2003). EMBO J 22: 1101–1113.

  • Rubinfeld B, Robbins P, El-Gamil M, Albert I, Porfiri E, Polakis P . (1997). Science 275: 1790–1792.

  • Salic A, Lee E, Mayer L, Kirschner MW . (2000). Mol Cell 5: 523–532.

  • Seidensticker MJ, Behrens J . (2000). Biochim Biophys Acta 1495: 168–182.

  • Shibamoto S, Higano K, Takada R, Ito F, Takeichi M, Takada S . (1998). Genes Cells 3: 659–670.

  • Shimizu H, Julius MA, Giarre M, Zheng Z, Brown AM, Kitajewski J . (1997). Cell Growth Differ 8: 1349–1358.

  • Smalley MJ, Dale TC . (1999). Cancer Metastasis Rev 18: 215–230.

  • Somasiri A, Howarth A, Goswami D, Dedhar S, Roskelley CD . (2001). J Cell Sci 114: 1125–1136.

  • Tan C, Costello P, Sanghera J, Dominguez D, Baulida J, de Herreros AG et al. (2001). Oncogene 20: 133–140.

  • Tan C, Cruet-Hennequart S, Troussard A, Fazli L, Costello P, Sutton K et al. (2004). Cancer Cell 5: 79–90.

  • Torres MA, Nelson WJ . (2000). J Cell Biol 149: 1433–1442.

  • Troussard AA, Costello P, Yoganathan TN, Kumagai S, Roskelley CD, Dedhar S . (2000). Oncogene 19: 5444–5452.

  • Troussard AA, McDonald PC, Wederell ED, Mawji NM, Filipenko NR, Gelmon KA et al. (2006). Cancer Res 66: 393–403.

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

  • Waltzer L, Bienz M . (1999). Cancer Metastasis Rev 18: 231–246.

  • Willert K, Brown JD, Danenberg E, Duncan AW, Weissman IL, Reya T et al. (2003). Nature 423: 448–452.

  • Willert K, Shibamoto S, Nusse R . (1999). Genes Dev 13: 1768–1773.

  • Wu C, Dedhar S . (2001). J Cell Biol 155: 505–510.

  • Wu C, Keightley SY, Leung-Hagesteijn C, Radeva G, Coppolino M, Goicoechea S et al. (1998). J Biol Chem 273: 528–536.

  • Yasunaga T, Kusakabe M, Yamanaka H, Hanafusa H, Masuyama N, Nishida E . (2005). Genes Cells 10: 369–379.

  • Younes MN, Kim S, Yigitbasi OG, Mandal M, Jasser SA, Dakak Yazici Y et al. (2005). Mol Cancer Ther 4: 1146–1156.

  • Zervas CG, Gregory SL, Brown NH . (2001). J Cell Biol 152: 1007–1018.

  • Zhou FQ, Zhou J, Dedhar S, Wu YH, Snider WD . (2004). Neuron 42: 897–912.

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Acknowledgements

This work was carried out by grants to SD from the Canadian Institute of Health Research (CIHR) and the National Institute of Canada (NCIC) through funds raised by the Canadian Cancer Society.

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  1. S Syam

    Present address: Department of Molecular and Cellular Biology, Sunnybrook and Women's College Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario, Canada

Authors and Affiliations

  1. British Columbia Cancer Agency, Vancouver, British Columbia, Canada

    A Oloumi & S Dedhar

  2. Sunnybrook and Women's College Health Sciences Centre, Toronto, Ontario, Canada

    S Syam

  3. Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada

    S Dedhar

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  1. A Oloumi
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Correspondence to S Dedhar.

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Oloumi, A., Syam, S. & Dedhar, S. Modulation of Wnt3a-mediated nuclear β-catenin accumulation and activation by integrin-linked kinase in mammalian cells. Oncogene 25, 7747–7757 (2006). https://doi.org/10.1038/sj.onc.1209752

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