Abstract
Glioblastoma multiforme (GBM), a tumor derived from glia and glial progenitor cells, is the most aggressive and prevalent form of primary brain cancer and is incurable. Amplification, mutation, and/or overexpression of the EGFR receptor tyrosine kinase and activating mutations in components of the PI3K pathway are common in GBM tumors, although the pathways that act downstream of EGFR and PI3K to drive tumorigenesis remain poorly understood. To better understand the underlying biology of tumorigenesis, we use a Drosophila melanogaster GBM model in which malignant neoplastic tumors arise from glial progenitor cells overexpressing activated oncogenic versions of EGFR and PI3K. This Drosophila model was used in kinome-wide genetic screens that identified Right-Open-Reading-Frame-2 (RIOK2), an atypical serine-threonine kinase, as a possible driver of EGFR-PI3K-dependent GBM. Subsequent studies in patient-derived GBM cell cultures suggest that RIOK2 promotes GBM cell proliferation and survival in response to oncogenic EGFR and PI3K signaling, and that, interestingly, these effects are dependent on RIOK2 catalytic kinase activity. To elucidate downstream targets of RIOK2, we conducted preliminary immunoprecipitation experiments of RIOK2 from patient-derived GBM cell cultures coupled with proteomics and identified several novel RNA-binding proteins (RBPs) as binding partners and potential substrates of RIOK2. Subsequent experiments using our Drosophila GBM model show that RBP knock-down drastically reduced aberrant glial cell proliferation and invasion, similar to RIOK2 knock-down. RBPs are involved in stabilizing and promoting the translation of their target mRNAs. Based on our preliminary results, we hypothesize that RIOK2 drives tumorigenesis by modulating the activity of RBPs, and that this promotes the translation of RBP target mRNAs to drive tumor cell proliferation and survival.