Development and characterisation of SMURF2-targeting modifiers

Dhanoop Manikoth Ayyathan, Gal Levy-Cohen, Moran Shubely, Sandy Boutros-Suleiman, Veronica Lepechkin-Zilbermintz, Michael Shokhen, Amnon Albeck, Arie Gruzman, Michael Blank

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

The C2-WW-HECT-domain E3 ubiquitin ligase SMURF2 emerges as an important regulator of diverse cellular processes. To date, SMURF2-specific modulators were not developed. Here, we generated and investigated a set of SMURF2-targeting synthetic peptides and peptidomimetics designed to stimulate SMURF2’s autoubiquitination and turnover via a disruption of the inhibitory intramolecular interaction between its C2 and HECT domains. The results revealed the effects of these molecules both in vitro and in cellulo at the nanomolar concentration range. Moreover, the data showed that targeting of SMURF2 with either these modifiers or SMURF2-specific shRNAs could accelerate cell growth in a cell-context-dependent manner. Intriguingly, a concomitant cell treatment with a selected SMURF2-targeting compound and the DNA-damaging drug etoposide markedly increased the cytotoxicity produced by this drug in growing cells. Altogether, these findings demonstrate that SMURF2 can be druggable through its self-destructive autoubiquitination, and inactivation of SMURF2 might be used to affect cell sensitivity to certain anticancer drugs.

Original languageEnglish
Pages (from-to)401-409
Number of pages9
JournalJournal of Enzyme Inhibition and Medicinal Chemistry
Volume36
Issue number1
DOIs
StatePublished - 2021

Bibliographical note

Publisher Copyright:
© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

Keywords

  • SMURF2
  • autoubiquitination
  • peptides
  • peptidomimetics

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