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The Ste20-like kinase SLK is required for ErbB2-driven breast cancer cell motility

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Abstract

The Ste20-like kinase, SLK, is involved in the control of cell motility through its effects on actin reorganization and focal adhesion turnover. Here we investigated the role of SLK in chemotaxis downstream of the tyrosine kinase receptor, HER2/ErbB2/Neu, which is frequently overexpressed in human breast cancers. Our results show that SLK is required for the efficient cell migration of human and mouse mammary epithelial cell lines in the presence of the Neu activator, heregulin, as a chemoattractant. SLK activity is stimulated by heregulin treatment or by overexpression of activated Neu. Phosphorylation of tyrosine 1201 or tyrosines 1226/7 on Neu is a key event for SLK activation and cell migration, and cancer cell invasion mediated by these tyrosines is inhibited by kinase-inactive SLK. Signaling pathway inhibitors show that Neu-mediated SLK activation is dependent on MEK, PI3K, PLCγ and Shc signaling. Furthermore, heregulin-stimulated SLK activity requires signals from the focal adhesion proteins, FAK and src. Finally, phospho-FAK analysis shows that SLK is required for Neu-dependent focal adhesion turnover. Together, these studies define an interaction between Neu and SLK signaling in the regulation of cancer cell motility.

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Acknowledgements

This work was supported by the Canadian Breast Cancer Foundation, the Canadian Institute for Health Research and a Premier's Research for Excellence Award. KR is supported by the Canadian Breast Cancer Foundation, SW is supported by OGSST and NSERC studentships and CJS is the recipient of a Canadian Heart and Stroke Foundation Fellowship. PMS is a research scientist of the National Cancer Institute of Canada and LAS is the recipient of a CIHR scholar award.

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Authors and Affiliations

  1. Centre for Cancer Therapeutics, Ottawa Health Research Institute, Cancer Therapeutics, Ottawa, Ontario, Canada

    K Roovers, C J Storbeck, P O'Reilly & L A Sabourin

  2. Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada

    S Wagner, V Lo & L A Sabourin

  3. Department of Biochemistry, McGill University, Montreal, Quebec, Canada

    J J Northey, W J Muller & P M Siegel

  4. Department of Medicine, McGill University, Montreal, Quebec, Canada

    J Chmielecki & W J Muller

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  1. K Roovers
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  2. S Wagner
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  3. C J Storbeck
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  4. P O'Reilly
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  5. V Lo
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  7. J Chmielecki
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  8. W J Muller
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  9. P M Siegel
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  10. L A Sabourin
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Correspondence to L A Sabourin.

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Roovers, K., Wagner, S., Storbeck, C. et al. The Ste20-like kinase SLK is required for ErbB2-driven breast cancer cell motility. Oncogene 28, 2839–2848 (2009). https://doi.org/10.1038/onc.2009.146

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  • DOI: https://doi.org/10.1038/onc.2009.146

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