Abstract

Glioblastoma (GBM) is the most common primary malignant brain tumor and is resistant to current therapies. Here, using a combination of proteomic and genetic approaches in both Drosophila and human GBM models, we identify novel signaling effectors that act downstream of EGFR and PI3K signaling pathways, which drive GBM. Our results indicate that RIOK2, an atypical serine/threonine kinase, forms a complex with the RNA-binding protein, IMP3 (Imp in Drosophila), and that the dRIOK2/RIOK-Imp/IMP3 pathway is necessary for tumorigenesis. Furthermore, our results indicate that RIOK2 catalytic activity is important for neoplasia and recruits TORC2 to phosphorylate IMP3. Finally, the dRIOK2-Imp pathway regulates protein levels of dMyc, a known Imp target mRNA, and these key findings were recapitulated in human GBM models. Collectively, our data indicates that RIOK2 catalytic activity promotes the activation of TORC2 and recruitment of IMP3, which in turn, modulates MYC mRNA and protein levels to promote tumorigenesis.