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A novel role for Plk4 in regulating cell spreading and motility

Oncogene volume 34, pages 3441–3451 (2015)Cite this article

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Abstract

Polo family kinase 4 (Plk4) is required for mitotic progression, and is haploinsufficient for tumor suppression and timely hepatocyte polarization in regenerating liver. At the same time, recent evidence suggests that Plk4 expression may have a role in clinical cancer progression, although the mechanisms are not clear. Here we identify a gene expression pattern predictive of reduced motility in Plk4+/− murine embryonic fibroblasts (MEFs) and validate this prediction with functional assays of cell spreading, migration and invasion. Increased Plk4 expression enhances cell spreading in Plk4+/− MEFs and migration in human embryonic kidney 293T cells, and increases invasion by DLD-1 colon cancer cells. Plk4 depletion impairs invasion of wild-type MEFs and suppresses invasion by MDA-MB231 breast cancer cells. Cytoskeletal reorganization and development of polarity are impaired in Plk4-deficient cells that have been stimulated to migrate. Endogenous Plk4 phosphorylated at the autophosphorylation site S305 localizes to the protrusions of motile cells, coincident with the RhoA GEF Ect2, GTP-bound RhoA and the RhoA effector mDia. Taken together, our findings reveal an unexpected activity of Plk4 that promotes cell migration and may underlie an association between increased Plk4 expression, cancer progression and death from metastasis in solid tumor patients.

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Acknowledgements

This work was supported by grants from CIHR (CJS) and NCIC (JWD), and from the Syd Cooper Program for the Prevention of Cancer Progression (CJS). We acknowledge Karina Pacholczyk, Peter E Wu and Kevin Yau for technical assistance, Judy Pawling for manuscript review, and Jayne Danska and Laurence Pelletier for helpful discussions.

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Authors and Affiliations

  1. Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada

    C O Rosario, K Kazazian, F S W Zih, O Brashavitskaya, Y Haffani, R S Z Xu, A George, J W Dennis & C J Swallow

  2. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada

    C O Rosario, O Brashavitskaya, J W Dennis & C J Swallow

  3. Department of Surgery, University of Toronto, Toronto, ON, Canada

    K Kazazian, F S W Zih & C J Swallow

  4. Institute of Medical Science, University of Toronto, Toronto, ON, Canada

    K Kazazian, F S W Zih, R S Z Xu & C J Swallow

  5. Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada

    J W Dennis

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  1. C O Rosario
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Correspondence to C J Swallow.

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Rosario, C., Kazazian, K., Zih, F. et al. A novel role for Plk4 in regulating cell spreading and motility. Oncogene 34, 3441–3451 (2015). https://doi.org/10.1038/onc.2014.275

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