A Sequentially Priming Phosphorylation Cascade Activates the Gliomagenic Transcription Factor Olig2

Jing Zhou, An Chi Tien, John A. Alberta, Scott B. Ficarro, Amelie Griveau, Yu Sun, Janhavee S. Deshpande, Joseph D. Card, Meghan Morgan-Smith, Wojciech Michowski, Rintaro Hashizume, C. David James, Keith L. Ligon, William D. Snider, Peter Sicinski, Jarrod A. Marto, David H. Rowitch*, Charles D. Stiles

*Corresponding author for this work

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3167-3177
Number of pages11
JournalCell reports
Volume18
Issue number13
DOIs
Publication statusPublished - Mar 28 2017

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Keywords

  • CDK
  • CK2
  • GSK3
  • NPCs
  • Olig2
  • casein kinase 2
  • cyclin-dependent kinase
  • glioma
  • glycogen synthase kinase 3
  • neural progenitor cells
  • phosphorylation
  • protein kinase

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Zhou, J., Tien, A. C., Alberta, J. A., Ficarro, S. B., Griveau, A., Sun, Y., ... Stiles, C. D. (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