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Tyrosine phosphorylation regulates nuclear translocation of PKCδ

Oncogene volume 27, pages 3045–3053 (2008)Cite this article

Abstract

PKCδ is essential for apoptosis, but regulation of the proapoptotic function of this ubiquitous kinase is not well understood. Nuclear translocation of PKCδ is necessary and sufficient to induce apoptosis and is mediated via a C-terminal bipartite nuclear localization sequence. However, PKCδ is found predominantly in the cytoplasm of nonapoptotic cells, and the apoptotic signal that activates its nuclear translocation is not known. We show that in salivary epithelial cells, phosphorylation at specific tyrosine residues in the N-terminal regulatory domain directs PKCδ to the nucleus where it induces apoptosis. Analysis of each tyrosine residue in PKCδ by site-directed mutagenesis identified two residues, Y64 and Y155, as essential for nuclear translocation. Suppression of apoptosis correlated with suppressed nuclear localization of the Y → F mutant proteins. Moreover, a phosphomimetic PKCδ Y64D/Y155D mutant accumulated in the nucleus in the absence of an apoptotic signal. Forced nuclear accumulation of PKCδ-Y64F and Y155F mutant proteins, by attachment of an SV40 nuclear localization sequence, fully reconstituted their ability to induce apoptosis, indicating that tyrosine phosphorylation per se is not required for apoptosis, but for targeting PKCδ to the nucleus. We propose that phosphorylation/dephosphorylation of PKCδ in the regulatory domain functions as a switch to promote cell survival or cell death.

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Acknowledgements

The technical assistance of Melissa Miller and Jonathon Schneider is gratefully acknowledged. We thank Drs Steve Anderson and Peter Parker for helpful discussions over the course of this work. These studies were supported by Grant nos. R01 DE015648-01 (to MER) and POI HD038129 (to MER and JS).

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Authors and Affiliations

  1. School of Dentistry, Program in Cell and Developmental Biology, University of Colorado at Denver and Health Sciences Center, Aurora, CO, USA

    M J Humphries, T S Adwan & M E Reyland

  2. Department of Craniofacial Biology, University of Colorado at Denver and Health Sciences Center, Aurora, CO, USA

    A M Ohm & M E Reyland

  3. Department of Microbiology, School of Medicine, University of Colorado at Denver and Health Sciences Center, Aurora, CO, USA

    J Schaack

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  1. M J Humphries
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  2. A M Ohm
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  3. J Schaack
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  4. T S Adwan
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  5. M E Reyland
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Corresponding author

Correspondence to M E Reyland.

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

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Humphries, M., Ohm, A., Schaack, J. et al. Tyrosine phosphorylation regulates nuclear translocation of PKCδ. Oncogene 27, 3045–3053 (2008). https://doi.org/10.1038/sj.onc.1210967

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