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      A Kinome-Wide RNAi Screen in Drosophila Glia Reveals That the RIO Kinases Mediate Cell Proliferation and Survival through TORC2-Akt Signaling in Glioblastoma


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          Glioblastoma, the most common primary malignant brain tumor, is incurable with current therapies. Genetic and molecular analyses demonstrate that glioblastomas frequently display mutations that activate receptor tyrosine kinase (RTK) and Pi-3 kinase (PI3K) signaling pathways. In Drosophila melanogaster, activation of RTK and PI3K pathways in glial progenitor cells creates malignant neoplastic glial tumors that display many features of human glioblastoma. In both human and Drosophila, activation of the RTK and PI3K pathways stimulates Akt signaling along with other as-yet-unknown changes that drive oncogenesis. We used this Drosophila glioblastoma model to perform a kinome-wide genetic screen for new genes required for RTK- and PI3K-dependent neoplastic transformation. Human orthologs of novel kinases uncovered by these screens were functionally assessed in mammalian glioblastoma models and human tumors. Our results revealed that the atypical kinases RIOK1 and RIOK2 are overexpressed in glioblastoma cells in an Akt-dependent manner. Moreover, we found that overexpressed RIOK2 formed a complex with RIOK1, mTor, and mTor-complex-2 components, and that overexpressed RIOK2 upregulated Akt signaling and promoted tumorigenesis in murine astrocytes. Conversely, reduced expression of RIOK1 or RIOK2 disrupted Akt signaling and caused cell cycle exit, apoptosis, and chemosensitivity in glioblastoma cells by inducing p53 activity through the RpL11-dependent ribosomal stress checkpoint. These results imply that, in glioblastoma cells, constitutive Akt signaling drives RIO kinase overexpression, which creates a feedforward loop that promotes and maintains oncogenic Akt activity through stimulation of mTor signaling. Further study of the RIO kinases as well as other kinases identified in our Drosophila screen may reveal new insights into defects underlying glioblastoma and related cancers and may reveal new therapeutic opportunities for these cancers.

          Author Summary

          Glioblastomas, the most common primary brain tumor, harbor mutations in receptor tyrosine kinases (RTKs), such as EGFR, and components of the Pi-3 kinase (PI3K) signaling pathway. However, the genes that act downstream of RTK and PI3K signaling to drive glioblastoma remain unclear. To investigate the genetic and molecular basis of this disease, we created a glioblastoma model in the fruit fly Drosophila melanogaster. To identify new genes involved in glioblastoma development, we performed a screen for the genes required for tumor cell proliferation using our Drosophila glioblastoma model and then functionally assessed the activity of human versions of novel genes identified in this screen. Our results revealed that the RIO kinases become overexpressed in human glioblastomas but not in normal human glial or neuronal cells. We found that overexpression of the RIO kinases promotes and maintains signals that drive tumor cell proliferation and survival in RTK- and PI3K-dependent human glioblastoma, and reduction of RIO kinase expression decreased proliferation and prompted cell death and chemosensitivity in glioblastoma cells. Therefore, disruption of the RIO kinases may provide new therapeutic opportunities to target glioblastoma and other RTK- or PI3K-dependent cancers.

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          Author and article information

          Role: Editor
          PLoS Genet
          PLoS Genet
          PLoS Genetics
          Public Library of Science (San Francisco, USA )
          February 2013
          February 2013
          14 February 2013
          : 9
          : 2
          [1 ]Molecular Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, California, United States of America
          [2 ]Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, California, United States of America
          [3 ]Department of Pathology, School of Medicine, University of California San Diego, La Jolla, California, United States of America
          [4 ]Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan
          [5 ]Department of Medicine, School of Medicine, University of California at San Diego, La Jolla, California, United States of America
          University of California San Francisco, United States of America
          Author notes

          The authors have declared that no competing interests exist.

          Conceived and designed the experiments: RDR TRF JBT WKC FBF. Performed the experiments: RDR TRF GGG JW AI HY. Analyzed the data: RDR TRF JBT FBF WKC GGG JW SRV. Contributed reagents/materials/analysis tools: GGG IB PSM. Wrote the paper: RDR TRF. Edited the manuscript: RDR JBT WKC FBF.


          Current address: Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia, United States of America


          This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

          Page count
          Pages: 19
          This work was supported by an American Brain Tumor Association postdoctoral fellowship awarded to RDR, a K99 Award from the National Institute of Neurological Disorders and Stroke to RDR, and a Salk-Sanofi Discovery Grant from Sanofi-Aventis awarded to RDR and JBT. WKC is a fellow of the National Foundation for Cancer Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
          Research Article
          Cancer Genetics
          Genetic Screens
          Genetics of Disease
          Model Organisms
          Molecular Cell Biology
          Signal Transduction
          Signaling Cascades
          Phospholipid Signaling Cascade
          Signaling in Selected Disciplines
          Oncogenic Signaling



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