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Plk1 phosphorylation of Numb leads to impaired DNA damage response

Oncogene volume 37, pages 810–820 (2018)Cite this article

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Abstract

Although Numb is well-recognized as a cell-fate determinant in stem/progenitor cells, accumulating evidence supports that Numb also has a critical role in adult tissues and cancers, in particular, in the context of regulation of tumor suppressor p53. Herein, we identified Numb as a novel substrate of Polo-like kinase 1 (Plk1). Of significance, we showed that Plk1-mediated phosphorylation of Numb leads to its enhanced proteasomal degradation and impaired Numb/p53 pathway, thus providing another mechanism how Plk1 antagonizes p53 during DNA damage response. In addition, the novel phosphorylation event identified by us further supports the notion that post-translational modifications of Numb uncouple Numb from p53 and lead to p53 destabilization. Finally, our data generated from both human cancer cell lines and mouse xenograft model showed that cancer cells carrying the unphosphorylated form of Numb by Plk1 are more sensitive to doxorubicin, a classical chemotherapeutic drug. Therefore, our work may provide future strategies for improving the efficacy of chemotherapy by targeting Numb phosphorylation by Plk1.

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Abbreviations

Plk1:

Polo-like kinase 1

GST:

glutathione S-transferase

WT:

wild type

KI:

knock in

MEF:

mouse embryonic fibroblast

AA:

S265A/S284A

DD:

S265D/S284D

PTB:

phosphotyrosine binding

PRR:

proline-rich region.

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Acknowledgements

This work was supported by NIH grants R01 CA157429 (X Liu), R01 CA192894 (X Liu), R01 CA196835 (X Liu), R01 CA196634 (X Liu), R01 AR059130 (N Ahmad) and R01 CA176748 (N Ahmad). The work was also partially supported by Purdue University Center for Cancer Research (P30 CA023168).

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Authors and Affiliations

  1. Department of Biochemistry, Purdue University, West Lafayette, IN, USA

    C Shao, E Farah, Z Li & X Liu

  2. Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, USA

    S-J Chien

  3. Department of Dermatology, University of Wisconsin, Madison, WI, USA

    N Ahmad

  4. Center for Cancer Research, Purdue University, West Lafayette, IN, USA

    X Liu

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  1. C Shao
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Correspondence to X Liu.

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Shao, C., Chien, SJ., Farah, E. et al. Plk1 phosphorylation of Numb leads to impaired DNA damage response. Oncogene 37, 810–820 (2018). https://doi.org/10.1038/onc.2017.379

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