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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.

Nature Communications
|November 8, 2023
PubMed
Summary
This summary is machine-generated.

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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.

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.

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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.