Phosphorylation of Smurf2, a novel therapeutic target, regulates stemness and tumorigenicity of glioma stem cells

Smurf2 belongs to the E3 ubiquitin ligase family. Although the role of Smurf2 in glioblastoma has been investigated previously, here we show that phosphorylation of Smurf2 at Thr249 plays an essential role in maintenance of stemness of glioma-initiating cells (GICs). Infection Smurf2 T249A mutant in GICs resulted in a significantly increase of tumorigenesis and stemness related genes, in contrast Smurf2 WT has reverse effect on GICs. Mechanistically, we demonstrated that Smurf2 regulates the TGFBR1 degradation through its ubiquitylation. Indeed, knockdown of TGFBR1 with shRNA markedly rescued the tumorigenesis observed in GICs infected with Smurf2 T249A mutant. Furthermore, phosphorylation of Smurf2 at Thr249 significantly decreased in human glioblastoma. These finding highlight the importance of phosphorylation of Smurf2 in maintenance of stemness of GICs.