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

doi:10.1016/j.celrep.2017.03.003

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.

Authors

Jing Zhou¹, An-Chi Tien², John A Alberta¹, Scott B Ficarro³, Amelie Griveau², Yu Sun¹, Janhavee S Deshpande⁴, Joseph D Card⁴, Meghan Morgan-Smith⁵, Wojciech Michowski⁶, Rintaro Hashizume⁷, C David James⁷, Keith L Ligon⁸, William D Snider⁵, Peter Sicinski⁶, Jarrod A Marto⁹, David H Rowitch¹⁰, Charles D Stiles¹¹

Affiliations

¹ Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
² Departments of Pediatrics and Neurosurgery, University of California, San Francisco, 35 Medical Center Way, San Francisco, CA 94143, USA.
³ 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.
⁴ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁵ UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA.
⁶ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
⁷ Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, 300 E. Superior, Chicago, IL 60611, USA.
⁸ 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.
⁹ 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.
¹⁰ 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: [email protected].
¹¹ Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address: [email protected].

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.

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

Substances

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding