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Sensitivity of the kinase activity of human vaccinia-related kinase proteins to toxic metals

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Abstract

The human vaccinia-related kinase (VRK) proteins VRK1 and VRK2 regulate different processes, such as the cell cycle, DNA damage response, and signaling by mitogen-activated protein kinases in response to growth factors or cellular stress. Alterations in expression levels of these Ser–Thr kinases are associated with cancer and neurodegenerative diseases. These functions suggest that they might also be targets of toxic metals, and thus contribute to the pathogenic effects associated with metal intoxication. VRK1 is inhibited by cadmium, copper, and mercury, and VRK2 is more sensitive to cadmium and much less sensitive to copper and mercury. Both kinases are insensitive to lead and cobalt. VRK1 is in general more sensitive than VRK2 in the low micromolar range. This inhibitory effect induced by these metals was detected in an autophosphorylation assay, as well as in phosphorylation assays using p53 and histone H3 as substrates. The accumulation of these three metals in cells can contribute, by inhibition of VRKs, to their toxic pathogenic effects, particularly their neurological manifestations. In this context copper has not generally been associated with any intoxication syndrome, except Wilson’s syndrome, but it might be implicated in some alterations with which it has not yet been associated.

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Abbreviations

MAPK:

Mitogen-activated protein kinase

VRK:

Vaccinia-related kinase

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Acknowledgments

I.B.-S. and M.V.-C. have fellowships from Universidad de Santiago and JAE/CSIC/Fondo Social Europeo respectively. This work was funded by grants from Ministerio de Educación, Ciencia e Innovación (SAF2010-14935), Junta de Castilla y León (CSI-006A11-2), and Kutxa-Fundación INBIOMED to P.A.L, and from Xunta de Galicia to R. B.

Conflict of interest

The authors declare that there are no conflicts of interest.

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Authors and Affiliations

  1. Departamento de Bioquímica y Biología Molecular, Facultad de Veterinaria, Universidad de Santiago de Compostela, Lugo, Spain

    Iria Barcia-Sanjurjo & Ramiro Barcia

  2. Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC-Universidad de Salamanca, Salamanca, Spain

    Marta Vázquez-Cedeira & Pedro A. Lazo

  3. Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Salamanca, Spain

    Marta Vázquez-Cedeira & Pedro A. Lazo

  4. Centro de Investigación del Cáncer, CSIC-Universidad de Salamanca, Campus Miguel de Unamuno, 37007, Salamanca, Spain

    Pedro A. Lazo

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  1. Iria Barcia-Sanjurjo
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  2. Marta Vázquez-Cedeira
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  3. Ramiro Barcia
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  4. Pedro A. Lazo
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Correspondence to Pedro A. Lazo.

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Barcia-Sanjurjo, I., Vázquez-Cedeira, M., Barcia, R. et al. Sensitivity of the kinase activity of human vaccinia-related kinase proteins to toxic metals. J Biol Inorg Chem 18, 473–482 (2013). https://doi.org/10.1007/s00775-013-0992-6

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  • DOI: https://doi.org/10.1007/s00775-013-0992-6

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