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

Hiraiwa et al. show that phosphorylation of SMAD specific E3 ubiquitin protein ligase 2 (SMURF2) at Thr249 mediates ubiquitylation and degradation of the TGF-beta receptor TGBR1 leading to loss of glioblastoma stem cell tumorigenic capacity. Their data elucidates a mechanism of regulation of the TGF-beta signaling pathway that controls the stem cell status in glioblastoma. 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-beta 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.