A Sequentially Priming Phosphorylation Cascade Activates the Gliomagenic Transcription Factor Olig2

Abstract

SUMMARY During development of the vertebrate central nervous system, the 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 (GSK3α/β, CK2 and 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.

Harnessing OLIG2 function in tumorigenicity and plasticity to target malignant gliomas

“…Phosphorylation of a highly conserved triple serine motif in the N-terminus of OLIG2 at S10, S13, and S14 has also been shown to be important for regulation of glioma cell proliferation and invasion. 30,58,59 Hyper-phosphorylated OLIG2, mimicked by a triple phosphomimetic (TPM) variant, results in greater cell proliferation, while a triple phosphonull (TPN) variant results in impaired cell proliferation. 58 This is partially due to attenuation of p53-mediated responses by both wildtype and phosphomimetic forms of OLIG2.…”

“…A recent series of elegant experiments, 3 serine/threonine protein kinases, glycogen synthase kinase 3a/b (GSK3a/b), casein kinase 2 (CK2) and cyclin-dependent kinase 1/2 (CDK1/ 2), have been identified as necessary and sufficient to phosphorylate the S10, S13, and S14 residues in OLIG2, respectively. 59 In the proposed sequentially priming model, phosphorylation of S13 and S10 by GSK3 and CK2, respectively, is contingent upon phosphorylation of S14 by CDK1/2, which initiates a phosphorylation cascade that also includes 3 additional serine residues, S3, S6, and S9, hence forming a hexa-phosphoserine "acid blob," which can oppose the actions of p53. Inhibition of GSK3a/b, CK2, and CDK1/2 in murine NPCs by treatment with small molecule inhibitors results in elevation of a p53-target p21, consistent with a repressive function of OLIG2 on p21 expression.…”

A Glial Signature and Wnt7 Signaling Regulate Glioma-Vascular Interactions and Tumor Microenvironment

“…Moreover, these roles depend on the genetic context, as a critical function of Olig2 is antagonism of p53 activity (Sun et al, 2011). While Olig2 status may not be useful in determining clinical prognosis, it has been proposed as a direct therapeutic target (Mehta et al, 2011) through inhibitors that prevent phosphorylation needed for its pro-tumorigenic activities (Zhou et al, 2017). …”

Fe₃O₄<em>@</em>Au composite magnetic nanoparticles modified with cetuximab for targeted magneto-photothermal therapy of glioma cells

“…Therefore, for decades, considerable efforts have been devoted to developing more effective antitumor agents and better strategies for targeting human glioma. 9,10 Recently, nanostructures with combined diagnostic and therapeutic functions represent a potential application for tumor therapy. [11][12][13][14] Many inorganic nanoparticles with various compositions, physical features, and functionalities have been widely synthesized and used as drug vehicles, for instance, polymer Prussian blue, zeolitic imidazolate framework, alginate, and calcium phosphate.…”