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Physical and functional interaction of the TPL2 kinase with nucleophosmin

Oncogene volume 34, pages 2516–2526 (2015)Cite this article

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Abstract

Tumor Progression Locus 2 (TPL2) is widely recognized as a cytoplasmic mitogen-activated protein 3 kinase with a prominent role in the regulation of inflammatory and oncogenic signal transduction. Herein we report that TPL2 may also operate in the nucleus as a physical and functional partner of nucleophosmin (NPM/B23), a major nucleolar phosphoprotein with diverse cellular activities linked to malignancy. We demonstrate that TPL2 mediates the phosphorylation of a fraction of NPM at threonine 199, an event required for its proteasomal degradation and maintenance of steady-state NPM levels. Upon exposure to ultraviolet C, Tpl2 is required for the translocation of de-phosphorylated NPM from the nucleolus to the nucleoplasm. NPM is an endogenous inhibitor of HDM2:p53 interaction and knockdown of TPL2 was found to result in reduced binding of NPM to HDM2, with concomitant defects in p53 accumulation following genotoxic or ribosomal stress. These findings expand our understanding of the function of TPL2 as a negative regulator of carcinogenesis by defining a nuclear role for this kinase in the topological sequestration of NPM, linking p53 signaling to the generation of threonine 199-phosphorylated NPM.

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Acknowledgements

We thank Moshe Oren and Varda Rotter (Weizmann Institute, Israel), Josef Papamatheakis (FORTH/IMBB, Greece), Angeliki Malliri (Patterson Institute for Cancer Research, UK), Vassilis Gorgoulis (University of Athens Medical School, Greece) and Charalambos Spilianakis (FORTH/IMBB, Greece) for their kind gift of reagents and Marina Ioannou for excellent technical assistance. This work was supported by the European Commission (EC) research program ‘Inflammation & Cancer Research in Europe’ (INFLA-CARE; EC Contract 223151) to AGE and SV, the EC support program ‘Translational Potential’ (TransPOT; EC Contract 285948) to AGE and a University of Crete Maria Manassaki scholarship to DK.

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  1. D C Kanellis: Graduate program: ‘The molecular Basis of Human Diseases’, University of Crete Medical School, Crete, Greece.

Authors and Affiliations

  1. Division of Basic Sciences, Molecular and Cellular Biology Laboratory, University of Crete Medical School, Heraklion, Greece

    D C Kanellis & A G Eliopoulos

  2. Laboratory of Cancer Biology, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology Hellas (FORTH), Heraklion, Greece

    D C Kanellis & A G Eliopoulos

  3. Department of Molecular Medicine and Biotechnology, School of Medicine, University of Rijeka, Rijeka, Croatia

    S Bursac & S Volarevic

  4. Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA, USA

    P N Tsichlis

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Correspondence to A G Eliopoulos.

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Kanellis, D., Bursac, S., Tsichlis, P. et al. Physical and functional interaction of the TPL2 kinase with nucleophosmin. Oncogene 34, 2516–2526 (2015). https://doi.org/10.1038/onc.2014.183

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