A Sequentially Priming Phosphorylation Cascade Activates the Gliomagenic Transcription Factor Olig2

Authors

• Jing Zhou, Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
• An-Chi Tien, Departments of Pediatrics and Neurosurgery, University of California, San Francisco, 35 Medical Center Way, San Francisco, CA 94143, USA.
• John A. Alberta, Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
• Scott B. Ficarro, Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
• Amelie Griveau, Departments of Pediatrics and Neurosurgery, University of California, San Francisco, 35 Medical Center Way, San Francisco, CA 94143, USA.
• Yu Sun, Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
• Janhavee S. Deshpande, Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
• Joseph D. Card, Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
• Meghan Morgan-Smith, UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA.
• Wojciech Michowski, Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
• Rintaro Hashizume, Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, 300 E. Superior, Chicago, IL 60611, USA.
• C David James, Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, 300 E. Superior, Chicago, IL 60611, USA.
• Keith L. Ligon, Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
• William D. Snider, UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA.
• Peter Sicinski, Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
• Jarrod A. Marto, Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
• David H. Rowitch, Departments of Pediatrics and Neurosurgery, University of California, San Francisco, 35 Medical Center Way, San Francisco, CA 94143, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, 35 Medical Center Way, San Francisco, CA 94143, USA; Department of Pediatrics, University of Cambridge, Wellcome Trust-MRC Cambridge Stem Cell Institute, Cambridge CB2 0AH, UK. Electronic address: rowitchd@peds.ucsf.edu.
• Charles D. Stiles, Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address: charles_stiles@dfci.harvard.edu.

Document Type

Article

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.

Keywords

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)

Publication Date

3-28-2017

Publication Title

Cell reports

E-ISSN

2211-1247

Volume

18

Issue

13

First Page

3167

Last Page

3177

PubMed ID

28355568

Digital Object Identifier (DOI)

10.1016/j.celrep.2017.03.003

Recommended Citation

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.
https://scholar.barrowneuro.org/neurobiology/1996