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The Cdk inhibitor p57Kip2 controls LIM-kinase 1 activity and regulates actin cytoskeleton dynamics

Oncogene volume 28, pages 4175–4188 (2009)Cite this article

Abstract

The cyclin-dependent kinase inhibitor p57Kip2 gene has been suggested to be a tumor suppressor gene, being inactivated in various cancer types, linked to tumor progression and poor patient outcome. Here, we report that p57Kip2 interacts with the actin cytoskeleton modifying enzyme, LIM-kinase 1 (LIMK-1) but not LIMK-2. This interaction enhances activity of LIMK-1, independently of its activator Rho-associated kinase. This resulted in an increased phosphorylation and consequent inactivation of the actin depolymerization factor, cofilin. In accordance, selective p57Kip2 expression promotes actin stress fiber formation in cancer cells. Fluorescence recovery after photobleaching analysis of fluorescent-labeled actin further demonstrated that p57Kip2 expression results in reduction of actin protein mobile fraction, which affects its turnover rate in cell. Finally, we present evidence that the p57Kip2 control of LIMK-1 ultimately affects cell mobility negatively. Thus, in addition to its established function in control of proliferation and cell death, these results indicate that p57Kip2 is critical in the regulation of actin cytoskeleton dynamic and by this means migration ability of cancer cells.

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Acknowledgements

We thank Dr Y Xiong (University of North Carolina, USA), Dr S Leibovitch (Centre National de la Recherche Scientifique, France), Dr K Mizuno (Tohoku University, Japan), Dr H Toyoshima (Tsukuba University, Japan), Dr P Hotulainen (University of Helsinki, Finland) and Dr S Okret (Karolinska Institute) for providing us with different DNA constructs and HeLa cell line, respectively. This work was supported by the Swedish Research Council, the Swedish Cancer Society, the Ã…ke Wiberg Foundation, the Swedish Medical Society and the Karolinska Institutet Foundations (KI Cancer).

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  1. Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institute, Stockholm, Sweden

    P Vlachos & B Joseph

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Correspondence to B Joseph.

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Vlachos, P., Joseph, B. The Cdk inhibitor p57Kip2 controls LIM-kinase 1 activity and regulates actin cytoskeleton dynamics. Oncogene 28, 4175–4188 (2009). https://doi.org/10.1038/onc.2009.269

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