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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

A Kinome-Wide RNAi Screen in Drosophila Glia Reveals That the RIO Kinases Mediate Cell Proliferation and Survival through TORC2-Akt Signaling in Glioblastoma
A Kinome-Wide RNAi Screen in Drosophila Glia Reveals That the RIO Kinases Mediate Cell Proliferation and Survival through TORC2-Akt Signaling in Glioblastoma
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.
1553-7390
Read, RD
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Fenton, TR
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Gomez, GG
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Wykosky, J
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Vandenberg, SR
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Babic, I
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Yang, H
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Iwanami, A
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Cavenee, WK
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Mischel, PS
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Furnari, FB
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Thomas, JB
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Read, RD
b5caca7b-0063-438a-b703-7ecbb6fc2b51
Fenton, TR
087260ba-f6a1-405a-85df-099d05810a84
Gomez, GG
0dd77897-fe6e-4ca4-808f-4be30b708991
Wykosky, J
411e9851-1e7e-4548-b23a-d43f56437455
Vandenberg, SR
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Babic, I
dea1f220-998e-4c01-b5a3-086fb48a4b4c
Yang, H
0f90e934-3d0c-4be7-9b3a-b676373d15e3
Iwanami, A
56823670-3090-4bd7-b51a-8a7d777aac74
Cavenee, WK
e92aa948-8cc9-419f-a596-b36ed9ceeb09
Mischel, PS
03cba385-ecb8-4c4a-883a-db8303888c36
Furnari, FB
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Thomas, JB
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Read, RD, Fenton, TR, Gomez, GG, Wykosky, J, Vandenberg, SR, Babic, I, Yang, H, Iwanami, A, Cavenee, WK, Mischel, PS, Furnari, FB and Thomas, JB (2013) A Kinome-Wide RNAi Screen in Drosophila Glia Reveals That the RIO Kinases Mediate Cell Proliferation and Survival through TORC2-Akt Signaling in Glioblastoma. PLoS Genetics, 9 (2). (doi:10.1249/MSS.0b013e31822cb0d2).

Record type: Article

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.

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Published date: 1 February 2013
Additional Information: copyright 2013 Read et al. 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.

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Local EPrints ID: 453909
URI: http://eprints.soton.ac.uk/id/eprint/453909
ISSN: 1553-7390
PURE UUID: 48a0f58e-1659-4ac6-94a7-1f72de100b18
ORCID for RD Read: ORCID iD orcid.org/0000-0002-4297-6728
ORCID for TR Fenton: ORCID iD orcid.org/0000-0002-4737-8233

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Date deposited: 25 Jan 2022 17:52
Last modified: 26 Jan 2022 03:09

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Contributors

Author: RD Read ORCID iD
Author: TR Fenton ORCID iD
Author: GG Gomez
Author: J Wykosky
Author: SR Vandenberg
Author: I Babic
Author: H Yang
Author: A Iwanami
Author: WK Cavenee
Author: PS Mischel
Author: FB Furnari
Author: JB Thomas

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