Title

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

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