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SMURF2 phosphorylation at Thr249 modifies glioma stemness and tumorigenicity by regulating TGF-β receptor stability

Manami Hiraiwa1, Kazuya Fukasawa1, Takashi Iezaki2

  • 1Department of Bioactive Molecules, Pharmacology, Gifu Pharmaceutical University, Gifu, 501-1196, Japan.

Communications Biology
|January 12, 2022
PubMed

Insights

SMAD specific E3 ubiquitin protein ligase 2 (SMURF2) phosphorylation at Thr249 is crucial for maintaining glioma stem cell (GSC) stemness and tumorigenicity. Inactivating this phosphorylation promotes GSC phenotypes by increasing TGF-β receptor stability.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Glioma stem cells (GSCs) drive glioblastoma, the deadliest brain tumor.
  • The role of SMAD specific E3 ubiquitin protein ligase 2 (SMURF2) in GSCs is unclear.
  • SMURF2 phosphorylation at Thr249 (SMURF2^Thr249) activates its E3 ubiquitin ligase activity.

Purpose of the Study:

  • To investigate the role of SMURF2^Thr249 phosphorylation in GSC stemness and tumorigenicity.
  • To elucidate the underlying mechanisms involving SMURF2 in GSC phenotypes.

Main Methods:

  • Studied patient-derived GSCs.
  • Utilized SMURF2 silencing and SMURF2^T249A mutant.
  • Assessed GSC self-renewal and tumorigenicity.
  • Analyzed SMURF2^Thr249 phosphorylation levels in glioblastoma specimens.
  • Investigated the effect on TGF-β receptor (TGFBR) stability and function.

Main Results:

  • SMURF2^Thr249 phosphorylation is essential for GSC stemness and tumorigenicity.
  • SMURF2 silencing increased GSC self-renewal and tumorigenicity.
  • Low SMURF2^Thr249 phosphorylation observed in human glioblastoma.
  • The SMURF2^T249A mutant mimicked SMURF2 silencing effects.
  • Inactivated SMURF2^Thr249 phosphorylation increased TGFBR protein stability.
  • TGFBR1 knockdown counteracted GSC phenotypes induced by the SMURF2^T249A mutant.

Conclusions:

  • SMURF2^Thr249 phosphorylation is a critical regulator of GSC phenotypes.
  • Targeting SMURF2^Thr249 phosphorylation offers a potential therapeutic strategy for glioblastoma.

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