A Sequentially Priming Phosphorylation Cascade Activates the Gliomagenic Transcription Factor Olig2

Cell Rep. 2017 Mar 28;18(13):3167-3177. doi: 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.

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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogenesis / metabolism*
  • Carcinogenesis / pathology*
  • Casein Kinase II / metabolism
  • Cell Line, Tumor
  • Cyclin-Dependent Kinases / metabolism
  • Disease Models, Animal
  • Glioma / metabolism*
  • Glioma / 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


  • Oligodendrocyte Transcription Factor 2
  • Small Molecule Libraries
  • Tumor Suppressor Protein p53
  • Phosphoserine
  • Casein Kinase II
  • Cyclin-Dependent Kinases
  • Glycogen Synthase Kinase 3
  • glycogen synthase kinase 3 alpha