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Integrin-linked kinase activity regulates Rac- and Cdc42-mediated actin cytoskeleton reorganization via α-PIX

Oncogene volume 24, pages 5837–5849 (2005)Cite this article

Abstract

Cell spreading and migration are regulated in a Rho family GTPase-dependent manner by growth factors and integrin-mediated cell–extracellular matrix (ECM) interactions. The molecular mechanisms involved in the ECM- and growth factor-mediated activation of these small GTPases remain unclear. In the present study, we demonstrate that integrin-linked kinase (ILK), which is a focal adhesion protein activated by both ECM and growth factors, is required for the activation of Rac and Cdc42 in epithelial cells. Ectopic expression of active ILK in mammary epithelial cells induces dramatic reorganization of the actin cytoskeleton and promotes rapid cell spreading on fibronectin. These effects are associated with constitutive activation of both Rac and Cdc42, but not Rho. The use of ILK siRNA or small molecule inhibitors to inhibit ILK expression and kinase activity, respectively, results in diminished cell spreading and actin cytoskeleton reorganization, concomitant with a reduction in Rac and Cdc42 activation. Studies into the mechanism of ILK-mediated Rac activation suggest an important role for the ILK–β-parvin interaction and the activity of the Rac/Cdc42-specific guanine nucleotide exchange factor α-PIX downstream of ILK. Taken together, these data demonstrate an essential role of ILK kinase activity in Rac- and Cdc42-mediated actin cytoskeleton reorganization in epithelial cells, further solidifying a role for ILK in the regulation of cancer cell motility and invasiveness.

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Acknowledgements

The constructs for GST-PBD, WT Rac1, N17 Rac1, WT Cdc42 and N17 Cdc42 were provided by Dr Keith Burridge (University of North Carolina, Chapel Hill, NC, USA). The construct for the dominant negative α-PIX was provided Dr Hurohiko Sugimura (Hamamatsu, Japan). The constructs for FLAG-tagged β-parvin and HA-tagged WT α-PIX were provided by Dr Kirsten Kutsche (Hamburg, Germany). We thank the members of the Dedhar laboratory, Paul McDonald and Timothy McPhee, for helpful discussions and critical reading of the manuscript. SA was supported by a studentship from the Natural Sciences and Engineering Research Council of Canada (NSERC). NRF is supported by postdoctoral fellowships from the Canadian Institutes of Health Research (CIHR) and jointly by the Michael Smith Foundation for Medical Research (MSFHR) and the Vancouver General Hospital/University of British Columbia Hospital Foundation. This work was supported by grants from the National Cancer Institute of Canada (NCIC) with funds raised by the Canadian Cancer Society and the Terry Fox Foundation.

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Author notes

  1. Sarah Attwell

    Present address: Departments of Biochemistry & Molecular Biology and Oncology, Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada, T2N 4N1

Authors and Affiliations

  1. British Columbia Cancer Agency, British Columbia, Canada

    Nolan R Filipenko, Sarah Attwell & Shoukat Dedhar

  2. Department of Anatomy and Cell Biology, University of British Columbia, British Columbia, Canada

    Calvin Roskelley

  3. The Prostate Centre at Vancouver General Hospital, British Columbia, Canada

    Shoukat Dedhar

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

    Shoukat Dedhar

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Correspondence to Shoukat Dedhar.

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Filipenko, N., Attwell, S., Roskelley, C. et al. Integrin-linked kinase activity regulates Rac- and Cdc42-mediated actin cytoskeleton reorganization via α-PIX. Oncogene 24, 5837–5849 (2005). https://doi.org/10.1038/sj.onc.1208737

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