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Drak/STK17A Drives Neoplastic Glial Proliferation Through Modulation of MRLC Signaling Alexander S

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Drak/STK17A Drives Neoplastic Glial Proliferation Through Modulation of MRLC Signaling Alexander S Published OnlineFirst December 10, 2018; DOI: 10.1158/0008-5472.CAN-18-0482 Cancer Molecular Cell Biology Research Drak/STK17A Drives Neoplastic Glial Proliferation through Modulation of MRLC Signaling Alexander S. Chen1, Joanna Wardwell-Ozgo1, Nilang N. Shah1, Deidre Wright1, Christina L. Appin4,5, Krishanthan Vigneswaran6, Daniel J. Brat3,4,5, Harley I. Kornblum7,8, and Renee D. Read1,2,3 Abstract Glioblastoma (GBM) and lower grade gliomas (LGG) are chain (MRLC), which was necessary for transformation. More- the most common primary malignant brain tumors and are over, Anillin, which is a binding partner of phosphorylated resistant to current therapies. Genomic analyses reveal that Sqh, was upregulated in a Drak-dependent manner in mitotic signature genetic lesions in GBM and LGG include copy cells and colocalized with phosphorylated Sqh in neoplastic gain and amplification of chromosome 7, amplification, cells undergoing mitosis and cytokinesis, consistent with their mutation, and overexpression of receptor tyrosine kinases known roles in nonmuscle myosin-dependent cytokinesis. (RTK) such as EGFR, and activating mutations in components These functional relationships were conserved in human of the PI3K pathway. In Drosophila melanogaster, constitutive GBM. Our results indicate that Drak/STK17A, its substrate co-activation of RTK and PI3K signaling in glial progenitor Sqh/MRLC, and the effector Anillin/ANLN regulate mitosis cells recapitulates key features of human gliomas. Here we use and cytokinesis in gliomas. This pathway may provide a new this Drosophila glioma model to identify death-associated therapeutic target for gliomas. protein kinase (Drak), a cytoplasmic serine/threonine kinase orthologous to the human kinase STK17A, as a downstream Significance: These findings reveal new insights into differ- effector of EGFR and PI3K signaling pathways. Drak was ential regulation of cell proliferation in malignant brain necessary for glial neoplasia, but not for normal glial prolif- tumors, which will have a broader impact on research regard- eration and development, and Drak cooperated with EGFR to ing mechanisms of oncogene cooperation and dependencies promote glial cell transformation. Drak phosphorylated Sqh, in cancer. the Drosophila ortholog of nonmuscle myosin regulatory light See related commentary by Lathia, p. 1036 Introduction more variable responses to therapeutics (2). To understand their genesis, these tumors have been subject to extensive Glioblastomas (GBM), the most common primary malig- genomic analyses, which show that signature genetic lesions nant brain tumors, infiltrate the brain, grow rapidly, and are in LGG and GBM include copy gain and amplification of resistant to current therapies (1). Low-grade gliomas (LGG), chromosome 7, amplification, mutation, and/or overexpres- which are related infiltrative malignant neural neoplasms, have sion of receptor tyrosine kinases (RTK), such as EGFR, slower tumor growth rates, longer patient survival, and display and activating mutations in components of the PI3K pathway (1, 3, 4). Nearly 60% of GBMs show focal EGFR copy gain or amplification, which are often accompanied by gain-of-func- 1Department of Pharmacology, Emory University School of Medicine, Atlanta, 2 tion EGFR mutations (4). The most prevalent EGFR mutant Georgia. Department of Hematology and Medical Oncology, Emory University VIII School of Medicine, Atlanta, Georgia. 3Winship Cancer Institute, Emory Univer- variant in GBM is EGFR (5), in which exon 2 to 7 deletion sity School of Medicine, Atlanta, Georgia. 4Department of Pathology, Emory confers constitutive kinase activity, which potently drives University School of Medicine, Atlanta, Georgia. 5Department of Pathology, tumorigenesis (1, 6). The most frequent PI3K pathway muta- Northwestern University Feinberg School of Medicine, Chicago, Illinois. 6Depart- tion in gliomas is loss of PTEN lipid phosphatase (4), which ment of Neurosurgery, Emory University School of Medicine, Atlanta, Georgia. results in unopposed PI3K signaling. 7 Department of Molecular and Medical Pharmacology, University of California Recent mouse models demonstrate that co-activation of Los Angeles, Los Angeles, California. 8Department of Psychiatry and Behavioral Sciences, and Semel Institute for Neuroscience and Human Behavior, University EGFR and PI3K pathways in glial cells or neuro-glial stems of California – Los Angeles, Los Angeles, California. cells induces GBM-like tumors, although these tumors do not show the full range of GBM phenotypes (7–9). Furthermore, to Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). date, pharmacologic inhibitors of EGFR and PI3K pathway components are ineffective in improving LGG and GBM out- A.S. Chen and J. Wardwell-Ozgo are co-first authors. comes (10). Genomic studies indicate that LGGs and GBMs Corresponding Author: Renee D. Read, Emory University, 1510 Clifton Road, have other genomic alterations (3–5); however, it is unknown Atlanta, GA 30322. Phone: 404-727-5985; E-mail: [email protected] how these changes contribute to gliomagenesis. Taken collec- doi: 10.1158/0008-5472.CAN-18-0482 tively, these data suggest that there are still undiscovered Ó2018 American Association for Cancer Research. biological factors that drive tumorigenesis. Given the www.aacrjournals.org 1085 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst December 10, 2018; DOI: 10.1158/0008-5472.CAN-18-0482 Chen et al. aggressive nature of these tumors, there is a pressing need to Materials and Methods better understand their biology and to identify additional Drosophila Strains and culture conditions factors that could serve as new drug therapy targets. Drosophila stocks were obtained from the Bloomington stock To investigate the biology of malignant gliomas, we developed center and VDRC and the specific genotypes and stocks used are models in Drosophila melanogaster (11). Drosophila offers unique listed in the Supplementary Tables S1 and S2. Draknull(Drakdel) advantages for modeling gliomas: flies have orthologs for 70% of was a gift of David Hipfner (18). UAS-sqhD20D21 was a gift of human genes, including most known gliomagenic genes (12); l Guang-Chao Chen (25). UAS- dEGFR was a gift of Trudi Schup- Drosophila neural and glial cell types are homologous to their bach. All stocks were cultured on standard corn meal molasses human counterparts (13); and versatile genetic tools are available food at 25 C. Prior to publication, the UAS-DrakdsRNA stocks were for in vivo cell-type specific gene manipulation including RNAi validated by PCR amplification of the dsRNA element followed by (14). Although Drosophila models cannot address all aspects of sequence validation against the published sequence available at glioma biology, our model demonstrates that constitutive acti- the VDRC. To create UAS-Drak and UAS-DrakKD (kinase dead) vation of EGFR and PI3K signaling in glial progenitor cells gives constructs, the RE12147 Drak cDNA was cloned into pUAS-T, site rise to malignant glial tumors that recapitulate key biological directed mutagenesis was used to convert Lys-66 to Ala, and the features of human gliomas (11). resulting DNA was injected into embryos and stocks for each To discover new pathways that contribute to EGFR–PI3K– construct were established and sequence verified. All genotypes mediated glioma, we performed a kinome-wide RNAi-based were established by standard genetic crossing. To normalize for genetic screen in our EGFR–PI3K Drosophila GBM model (15). l UAS transgene dosage in repo>dEGFR ;dp110CAAX animals, a Kinases were screened because they are highly conserved in terms UAS-lacZ transgene was included in control genotypes. of protein function between Drosophila and mammalian systems. One of the top candidates from this screen was death-associated protein kinase related (Drak; ref. 15). Drak and its human ortholog, Immunohistochemistry fi STK17A, are cytoplasmic serine/threonine kinases in the Drak Larval brains were dissected with forceps, xed in 4% parafor- subfamily of cytoplasmic death-associated protein (DAP) kinases, maldehyde, processed, stained, and imaged as previously which regulate cytoskeletal dynamics, cytokinesis, and cell adhe- described (11). The following antibodies were used: 8D12 sion and mobility (16–18). In Drosophila development, Drak mouse anti-Repo (1:10, Developmental Studies Hybridoma promotes epithelial morphogenesis, acting downstream of Bank), anti-phospho-S21-Sqh (1:500, gift of Robert Ward; ref. 26), Rho-GTPase signaling to control the actin cytoskeleton through anti-Anillin (1:500, gift of Maria Giansanti; ref. 27). Secondary phosphorylation of Spaghetti Squash (Sqh; refs. 18, 19). MRLC, antibodies were conjugated to Cy3 (1:150), Alexa Fluor 488, or the human Sqh ortholog, is a regulator of nonmuscle myosin type Alexa Fluor 647 (1:100; Jackson Laboratories). Brains were II (NMII) motor proteins, and phosphorylated MRLC binds to mounted on glass slides ventral side down in vectashield and NMII and stimulates NMII-dependent contractile activity to pro- whole mount imaged on a Zeiss LSM 700 confocal system. For mote cytoskeletal re-organization, morphogenesis, and cytokine- experiments where protein levels were compared between geno- sis (20, 21). MRLC phosphorylation is dynamic and tightly types, all samples were prepared, subjected to IHC, imaged, and regulated, which allows for precise
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