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NEK10 tyrosine phosphorylates p53 and controls its transcriptional activity

Oncogene volume 39, pages 5252–5266 (2020)Cite this article

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Abstract

In response to genotoxic stress, multiple kinase signaling cascades are activated, many of them directed towards the tumor suppressor p53, which coordinates the DNA damage response (DDR). Defects in DDR pathways lead to an accumulation of mutations that can promote tumorigenesis. Emerging evidence implicates multiple members of the NimA-related kinase (NEK) family (NEK1, NEK10, and NEK11) in the DDR. Here, we describe a function for NEK10 in the regulation of p53 transcriptional activity through tyrosine phosphorylation. NEK10 loss increases cellular proliferation by modulating the p53-dependent transcriptional output. NEK10 directly phosphorylates p53 on Y327, revealing NEK10’s unexpected substrate specificity. A p53 mutant at this site (Y327F) acts as a hypomorph, causing an attenuated p53-mediated transcriptional response. Consistently, NEK10-deficient cells display heightened sensitivity to DNA-damaging agents. Further, a combinatorial score of NEK10 and TP53-target gene expression is an independent predictor of a favorable outcome in breast cancers.

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Fig. 1: NEK10 loss leads to an increase in cellular proliferation and DNA replication.
Fig. 2: NEK10 status modulates the expression of p53-responsive genes.
Fig. 3: NEK10 modulates expression of p53-responsive genes in a kinase-dependent manner.
Fig. 4: NEK10 phosphorylates p53 on Y327 in vitro and in cells.
Fig. 5: Phosphorylation of p53 Y327 by NEK10 effects expression of p53-responsive genes.
Fig. 6: NEK10 modulates the expression of p53-responsive genes in response to genotoxic agents.
Fig. 7: NEK10 loss sensitizes cells to chemotherapeutic agents.
Fig. 8: NEK10 expression correlates with patient survival in patients with functional TP53 and radioresponse.

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Acknowledgements

We thank Ryan Dowling and members of the Stambolic group (Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada) for their helpful discussion and advice. We thank Anne van Vlimmeren for technical assistance. This work was supported by the Princess Margaret Hospital Foundation and by the CIHR strategic training fellowship of the EIRR 21st Program (Awarded to NH). The results published here are in whole or part based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga.

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Authors and Affiliations

  1. Department of Medical Biophysics, Princess Margaret Cancer Research Tower, University of Toronto, Toronto, ON, M5G 1L7, Canada

    Nasir Haider & Vuk Stambolic

  2. Princess Margaret Cancer Centre, University Health Network, Princess Margaret Cancer Research Tower, Toronto, ON, M5G 1L7, Canada

    Nasir Haider, Previn Dutt, Jason Ho & Vuk Stambolic

  3. Center for Precision Cancer Medicine, David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02142, USA

    Bert van de Kooij & Michael Yaffe

  4. ProCURE, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research (IDIBELL), Gran via 199, L’Hospitalet del Llobregat, 08908, Barcelona, Catalonia, Spain

    Luis Palomero & Miquel Angel Pujana

  5. Departments of Biology and Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02142, USA

    Michael Yaffe

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Haider, N., Dutt, P., van de Kooij, B. et al. NEK10 tyrosine phosphorylates p53 and controls its transcriptional activity. Oncogene 39, 5252–5266 (2020). https://doi.org/10.1038/s41388-020-1361-x

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