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Glioma stem cells (GSCs) contribute to the pathogenesis of glioblastoma, the most malignant form of glioma. The implication and underlying mechanisms of SMAD specific E3 ubiquitin protein ligase 2 (SMURF2) on the GSC phenotypes remain unknown. We previously demonstrated that SMURF2 phosphorylation at Thr 249  (SMURF2 Thr249 ) activates its E3 ubiquitin ligase activity. Here, we demonstrate that SMURF2 Thr249  phosphorylation plays an essential role in maintaining GSC stemness and tumorigenicity.  SMURF2  silencing augmented the self-renewal potential and tumorigenicity of patient-derived GSCs. The SMURF2 Thr249  phosphorylation level was low in human glioblastoma pathology specimens. Introduction of the  SMURF2  T249A  mutant resulted in increased stemness and tumorigenicity of GSCs, recapitulating the  SMURF2  silencing. Moreover, the inactivation of SMURF2 Thr249  phosphorylation increases TGF-β receptor (TGFBR) protein stability. Indeed,  TGFBR1  knockdown markedly counteracted the GSC phenotypes by  SMURF2  T249A  mutant. These findings highlight the importance of SMURF2 Thr249  phosphorylation in maintaining GSC phenotypes, thereby demonstrating a potential target for GSC-directed therapy.

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