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Protein kinase WNK3 increases cell survival in a caspase-3-dependent pathway

Oncogene volume 25, pages 4172–4182 (2006)Cite this article

Abstract

The subfamily of WNK (with no K=lysine) protein kinases has four human members and germline mutations in the WNK1 and WNK4 genes were recently found to cause pseudohypoaldosteronism type II, a familial hypertension disease. Here, we describe cloning and functional analysis of a further WNK member, human WNK3. Endogenous WNK3 protein is an active protein kinase when immunoprecipitated from cells and its overexpression increases the survival of HeLa cells by delaying the onset of apoptosis. Suppression of endogenous WNK3 protein by RNA interference accelerates the apoptotic response and promotes the activation of caspase-3. The mechanism of WNK3 action involves interaction with procaspase-3 and heat-shock protein 70. These results demonstrate a role for WNK3 in promoting cell survival and suggest a mechanism at the level of procaspase-3 activation.

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Acknowledgements

We thank Sónia Pedro for running the automated ABI sequencer, Jeremy Simpson and Brigitte Joggerst-Thomalla (EMBL) for help in the antibody production, Andrew Riddle (EMBL) for support in handling and interpretation of FACS analysis and the Advanced Light Microscopy Facility staff at EMBL, Heidelberg for support with microinjection and in vivo time-lapse microscopy. We are grateful to R Morimoto (Northwestern University Evanston, IL, USA), VM Dixit (University of Michigan) and the Kazusa Human cDNA Project (Chiba, Japan) for providing plasmids used in this study. Visitron and Zeiss companies are acknowledged for instruments provided to ALMF at EMBL. This work was supported by the Fundação para a Ciência e Tecnologia (Grant POCTI/33221/99, Programa de Financiamento Plurianual do CIGMH and fellowship BD 19936/99) and an EurALMF short-term visitor fellowship to FV.

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Authors and Affiliations

  1. Centro de Genética Humana, Instituto Nacional de Saúde ‘Dr Ricardo Jorge’, Lisboa, Portugal

    F Veríssimo, E Silva & P Jordan

  2. Rayne Institute, Kings College, London, UK

    J D Morris

  3. Cell Biology and Cell Biophysics Programme, European Molecular Biology Laboratory, Heidelberg, Germany

    R Pepperkok

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  1. F Veríssimo
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  2. E Silva
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  3. J D Morris
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  4. R Pepperkok
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  5. P Jordan
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Correspondence to P Jordan.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Veríssimo, F., Silva, E., Morris, J. et al. Protein kinase WNK3 increases cell survival in a caspase-3-dependent pathway. Oncogene 25, 4172–4182 (2006). https://doi.org/10.1038/sj.onc.1209449

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