Drak, Drak, Goose: A New Signaling Axis in Glioblastoma

Abstract

While many molecular alterations in glioblastoma (GBM), the most common primary malignant brain tumor, have been defined, the intricate signaling networks associated with these alterations that represent actionable therapeutic targets are less well established. Chen and colleagues leverage a Drosophila GBM model to identify a conserved signaling axis downstream of the EGFR and PI3K that involves the death-associated protein kinase (Drak), a cytoplasmic serine/threonine kinase orthologous to the human kinase STK17A. Functional studies revealed that targeting this signaling axis attenuated mitosis and cytokinesis, providing a new pathway for therapeutic development in GBM. See related article by Chen et al., p. 1085

Synaptic components are required for glioblastoma progression in Drosophila

“…It is based on the fusion of synaptobrevin protein (Syb) to the 1-10 fragment of GFP (Syb-GFP 1-10 ), and the expression of a membrane bound form of the 11 fragment of GFP (CD4-GFP 11 ). UAS-nSyb-spGFP 1-10 :lexAop-CD4-sp GFP 11 (BL62314) and lexAop-nSyb-spGFP [1][2][3][4][5][6][7][8][9][10] : UAS-CD4-sp GFP 11 (BL62315) were expressed in neurons (elav-lexA) and glial (repo-Gal4) cells respectively. These complementary GFP fragments will reconstitute a functional fluorescent reporter at the points of contact and therefore, it will allow the identification of the presynaptic and postsynaptic cells (e.g.…”

“…The GB condition is experimentally elicited by the expression of constitutively active forms of EGFR (Epidermal Growth Factor Receptor) and PI3K (Phosphoinositide 3-kinase) in glial cells, which are the two most common mutations in patients [ 9 ]. This experimental model has been previously used to study the contribution of RIO kinases [ 8 ], vesicle transport [ 6 ], the human kinase STK17A orthologue (Drak) [ 10 , 11 ], circadian rhythms [ 12 ] and several metabolic pathways in GB [ 13 ]. Consequently, the Drosophila model of GB is well characterized and suitable to study cellular properties of GB in vivo .…”

Targeting Death-Associated Protein Kinases for Treatment of Human Diseases: Recent Advances and Future Directions

“…DRAK1 is recognized to have a role in cytoskeletal regulation, which participates in cytokinesis, cell adhesion, mobility, and other cellular processes that promote glioma development. 23 Besides, due to the lymphatic specificity of DRAK2, its potential as a therapeutic target for immune diseases has been well studied. 24 Some studies have demonstrated that the DAPK family is an essential member of the Ser/Thr protein kinase family, which mediates the occurrence of many diseases.…”

“…However, DRAK1 and DRAK2 have received little attention in most situations. DRAK1 is recognized to have a role in cytoskeletal regulation, which participates in cytokinesis, cell adhesion, mobility, and other cellular processes that promote glioma development . Besides, due to the lymphatic specificity of DRAK2, its potential as a therapeutic target for immune diseases has been well studied …”

Intratumoral and extratumoral synapses are required for glioblastoma progression in Drosophila

“…The copyright holder for this preprint this version posted October 16, 2021. ; https://doi.org/10.1101/2021.10.14.464400 doi: bioRxiv preprint experimentally elicited by the expression of constitutively active forms of EGFR (Epidermal Growth Factor Receptor) and PI3K (Phosphoinositide 3-kinase) in glial cells, which are the two most common mutations in patients (Read et al, 2009). This experimental model has been previously used to study the contribution of RIO kinases (Read et al, 2013), vesicle transport (Portela et al, 2019a), the human kinase STK17A orthologue (Drak) (Chen et al, 2019;Lathia, 2019), and several metabolic pathways in GB (Chi et al, 2019). Consequently, Drosophila model of GB is well characterized and suitable to study cellular properties of GB in vivo.…”