A Sequentially Priming Phosphorylation Cascade Activates the Gliomagenic Transcription Factor Olig2
Elsevier (Cell Press)
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Zhou, J., Tien, A., Alberta, J., Ficarro, S., Griveau, A., Sun, Y., Deshpande, J., et al. (2017). A Sequentially Priming Phosphorylation Cascade Activates the Gliomagenic Transcription Factor Olig2. Cell Reports, 18 (13), 3167-3177. https://doi.org/10.1016/j.celrep.2017.03.003
During development of the vertebrate CNS, the basic helix-loop-helix (bHLH) transcription factor Olig2 sustains replication competence of progenitor cells that give rise to neurons and oligodendrocytes. A pathological counterpart of this developmental function is seen in human glioma, wherein Olig2 is required for maintenance of stem-like cells that drive tumor growth. The mitogenic/gliomagenic functions of Olig2 are regulated by phosphorylation of a triple serine motif (S10, S13, and S14) in the amino terminus. Here, we identify a set of three serine/threonine protein kinases (glycogen synthase kinase 3α/β [GSK3α/β], casein kinase 2 [CK2], and cyclin-dependent kinases 1/2 [CDK1/2]) that are, collectively, both necessary and sufficient to phosphorylate the triple serine motif. We show that phosphorylation of the motif itself serves as a template to prime phosphorylation of additional serines and creates a highly charged "acid blob" in the amino terminus of Olig2. Finally, we show that small molecule inhibitors of this forward-feeding phosphorylation cascade have potential as glioma therapeutics.
CDK, CK2, GSK3, NPCs, Olig2, casein kinase 2, cyclin-dependent kinase, glioma, glycogen synthase kinase 3, neural progenitor cells, phosphorylation, protein kinase
We thank the American Brain Tumor Association for postdoctoral fellowship support (to A.-C.T.) and the American Association for Cancer Research (AACR) for a Anna D. Baker Fellowship in Basic Cancer Research (to A.G.). This work was supported by grants from NIH ( NS057727 to C.D.S. and NS040511 to D.H.R.) and by funding from the Dana-Farber Strategic Research Initiative (to J.A.M.), Howard Hughes Medical Institute (to D.H.R.), and A Kids' Brain Tumor Cure Foundation (to C.D.S.).
External DOI: https://doi.org/10.1016/j.celrep.2017.03.003
This record's URL: https://www.repository.cam.ac.uk/handle/1810/264790
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