title: A kinome-wide RNAi screen in Drosophila Glia reveals that the RIO kinases mediate cell proliferation and survival through TORC2-Akt signaling in glioblastoma.
abstract: 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.
authors: Molecular Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, California, USA. renee.read@emory.edu
authors: Renee D
authors: RD
authors: Read
authors: Tim R
authors: TR
authors: Fenton
authors: German G
authors: GG
authors: Gomez
authors: Jill
authors: J
authors: Wykosky
authors: Scott R
authors: SR
authors: Vandenberg
authors: Ivan
authors: I
authors: Babic
authors: Akio
authors: A
authors: Iwanami
authors: Huijun
authors: H
authors: Yang
authors: Webster K
authors: WK
authors: Cavenee
authors: Paul S
authors: PS
authors: Mischel
authors: Frank B
authors: FB
authors: Furnari
authors: John B
authors: JB
authors: Thomas
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D049750:Genome, Insect; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; C469385:RIOK1 protein, human; C542171:RIOK2 protein, human