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.
CDK, CK2, GSK3, NPCs, Olig2, casein kinase 2, cyclin-dependent kinase, glioma, glycogen synthase kinase 3, neural progenitor cells, phosphorylation, protein kinase
Medical Subject Headings
Animals; Carcinogenesis (metabolism, pathology); Casein Kinase II (metabolism); Cell Line, Tumor; Cyclin-Dependent Kinases (metabolism); Disease Models, Animal; Glioma (metabolism, pathology); Glycogen Synthase Kinase 3 (metabolism); Humans; Mice; Oligodendrocyte Transcription Factor 2 (metabolism); Phosphorylation (drug effects); Phosphoserine (metabolism); Small Molecule Libraries (pharmacology); Tumor Suppressor Protein p53 (metabolism)
Digital Object Identifier (DOI)
Zhou, Jing; Tien, An-Chi; Alberta, John A.; Ficarro, Scott B.; Griveau, Amelie; Sun, Yu; Deshpande, Janhavee S.; Card, Joseph D.; Morgan-Smith, Meghan; Michowski, Wojciech; Hashizume, Rintaro; James, C David; Ligon, Keith L.; Snider, William D.; Sicinski, Peter; Marto, Jarrod A.; Rowitch, David H.; and Stiles, Charles D., "A Sequentially Priming Phosphorylation Cascade Activates the Gliomagenic Transcription Factor Olig2" (2017). Translational Neuroscience. 1996.