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Whole proteome analysis of human tankyrase knockout cells reveals targets of tankyrase-mediated degradation

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  • Amit Bhardwaj

    (Department of Pathology, New York University School of Medicine)

  • Yanling Yang

    (New York University School of Medicine)

  • Beatrix Ueberheide

    (New York University School of Medicine)

  • Susan Smith

    (Department of Pathology, New York University School of Medicine)

Abstract

Tankyrase 1 and 2 are poly(ADP-ribose) polymerases that function in pathways critical to cancer cell growth. Tankyrase-mediated PARylation marks protein targets for proteasomal degradation. Here, we generate human knockout cell lines to examine cell function and interrogate the proteome. We show that either tankyrase 1 or 2 is sufficient to maintain telomere length, but both are required to resolve telomere cohesion and maintain mitotic spindle integrity. Quantitative analysis of the proteome of tankyrase double knockout cells using isobaric tandem mass tags reveals targets of degradation, including antagonists of the Wnt/β-catenin signaling pathway (NKD1, NKD2, and HectD1) and three (Notch 1, 2, and 3) of the four Notch receptors. We show that tankyrases are required for Notch2 to exit the plasma membrane and enter the nucleus to activate transcription. Considering that Notch signaling is commonly activated in cancer, tankyrase inhibitors may have therapeutic potential in targeting this pathway.

Suggested Citation

  • Amit Bhardwaj & Yanling Yang & Beatrix Ueberheide & Susan Smith, 2017. "Whole proteome analysis of human tankyrase knockout cells reveals targets of tankyrase-mediated degradation," Nature Communications, Nature, vol. 8(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-02363-w
    DOI: 10.1038/s41467-017-02363-w
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    Cited by:

    1. Jerome Perrard & Susan Smith, 2023. "Multiple E3 ligases control tankyrase stability and function," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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