A Sequentially Priming Phosphorylation Cascade Activates the Gliomagenic Transcription Factor Olig2

Publication date: 28 March 2017
Source:Cell Reports, Volume 18, Issue 13
Author(s): 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
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.

Graphical abstract

Teaser

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.


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