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Multiple E3 ligases control tankyrase stability and function.

Jerome Perrard1, Susan Smith2

  • 1Department of Cell Biology, New York University School of Medicine, New York, NY, 10016, USA.

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New E3 ligases stabilize tankyrase by opposing its degradation, impacting cancer signaling. This discovery reveals novel ubiquitylation mechanisms and potential therapeutic strategies targeting tankyrase inhibitors in cancer therapy.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Tankyrase 1 and 2 are ADP-ribosyltransferases regulating cellular processes.
  • Tankyrase levels are controlled by RNF146-mediated degradation.
  • Understanding tankyrase regulation is crucial for cancer therapy.

Purpose of the Study:

  • To identify novel E3 ligases interacting with tankyrase.
  • To elucidate the mechanisms of tankyrase ubiquitylation and stabilization.
  • To explore the therapeutic implications of tankyrase regulation in cancer.

Main Methods:

  • Co-immunoprecipitation to identify protein interactions.
  • Ubiquitylation assays to study modification types.
  • Western blotting to assess protein levels and stability.

Main Results:

  • RNF114 and RNF166 (RING-UIM E3 ligases) bind and stabilize monoubiquitylated tankyrase.
  • These ligases promote K11-linked diubiquitylation, opposing RNF146-mediated degradation.
  • Tankyrase stabilization impacts its binding partner, Angiomotin, a cancer signaling protein.
  • Multiple PAR-binding E3 ligases were identified that ubiquitylate tankyrase.

Conclusions:

  • Discovery of K11 ubiquitylation opposing tankyrase degradation provides new regulatory insights.
  • Identification of multiple PAR-binding E3 ligases expands the understanding of tankyrase control.
  • These findings suggest novel therapeutic avenues for tankyrase inhibitors in cancer treatment.