title: A Sequentially Priming Phosphorylation Cascade Activates the Gliomagenic Transcription Factor Olig2.
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.
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Departments of Pediatrics and Neurosurgery, University of California, San Francisco, 35 Medical Center Way, San Francisco, CA 94143, USA.
authors.forename: An-Chi
authors.initials: AC
authors.lastname: Tien
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Alberta
authors.affiliation: 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.
authors.forename: Scott B
authors.initials: SB
authors.lastname: Ficarro
authors.affiliation: Departments of Pediatrics and Neurosurgery, University of California, San Francisco, 35 Medical Center Way, San Francisco, CA 94143, USA.
authors.forename: Amelie
authors.initials: A
authors.lastname: Griveau
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Janhavee S
authors.initials: JS
authors.lastname: Deshpande
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Card
authors.affiliation: UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Meghan
authors.initials: M
authors.lastname: Morgan-Smith
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Michowski
authors.affiliation: Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, 300 E. Superior, Chicago, IL 60611, USA.
authors.forename: Rintaro
authors.initials: R
authors.lastname: Hashizume
authors.affiliation: Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, 300 E. Superior, Chicago, IL 60611, USA.
authors.forename: C David
authors.initials: CD
authors.lastname: James
authors.affiliation: 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.
authors.forename: Keith L
authors.initials: KL
authors.lastname: Ligon
authors.affiliation: UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: William D
authors.initials: WD
authors.lastname: Snider
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Sicinski
authors.affiliation: 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.
authors.forename: Jarrod A
authors.initials: JA
authors.lastname: Marto
authors.affiliation: 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.
authors.forename: David H
authors.initials: DH
authors.lastname: Rowitch
authors.affiliation: 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.
authors.forename: Charles D
authors.initials: CD
authors.lastname: Stiles
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism* / Q000473:pathology*; D047390:Casein Kinase II / Q000378:metabolism; D045744:Cell Line, Tumor; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D051379:Mice; D000076104:Oligodendrocyte Transcription Factor 2 / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D054852:Small Molecule Libraries / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000076104:Oligodendrocyte Transcription Factor 2; D054852:Small Molecule Libraries; D016159:Tumor Suppressor Protein p53; D010768:Phosphoserine; D047390:Casein Kinase II; D018844:Cyclin-Dependent Kinases; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha
keywords: CDK; CK2; GSK3; NPCs; Olig2; casein kinase 2; cyclin-dependent kinase; glioma; glycogen synthase kinase 3; neural progenitor cells; phosphorylation; protein kinase