A Sequentially Priming Phosphorylation Cascade Activates the Gliomagenic Transcription Factor Olig2

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. [Display omitted] •OLIG2 promotes mitosis of normal and malignant neural progenitor cells•These OLIG2 functions are contingent upon phosphorylation of a triple serine motif•Kinases that phosphorylate this motif were identified as GSK3α/β, CK2, and CDK1/2•Small inhibitors of the OLIG2 kinases can suppress gliomagenic functions of OLIG2 The transcription factor OLIG2 promotes mitosis of normal and malignant neural progenitor cells. Zhou et al. have identified a set of protein kinases that are both necessary and sufficient to phosphorylate a key regulatory triple serine motif in OLIG2. Small inhibitors of these kinases suppress gliomagenic functions of OLIG2.