biostudies-literature00460Hiraiwa MMEXT | Japan Society for the Promotion of ScienceMEXT | Japan Society for the Promotion of Science (JSPS)22https://www.ebi.ac.uk/biostudies/studies/S-EPMC8752672biostudies-literatureUnknown5(1)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 Thr²⁴⁹ (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.Communications biologySMURF2 phosphorylation at Thr249 modifies glioma stemness and tumorigenicity by regulating TGF-β receptor stability.PMC875267220H03407Park GHirao AHinoi ETokumura KSabit HNakada MFukasawa KKobayashi MSuzuki AKaneda KHiraiwa MIezaki TMurata MTodo THorie TIwahashi S46falseSMURF2 phosphorylation at Thr249 modifies glioma stemness and tumorigenicity by regulating TGF-β receptor stability.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 Thr²⁴⁹ (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.2022-01-01T00:00:00Z2022 Jan2024-02-14T21:41:11.533Z2022-02-11T15:28:54.759ZS-EPMC87526723501763010.1038/s42003-021-02950-0