Glycogen synthase kinase‐3 and alternative splicing

Advanced Review

Peter S. Klein, Xiaolei Liu

Published Online: Aug 17 2018

DOI: 10.1002/wrna.1501

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Glycogen synthase kinase‐3 (GSK‐3) is a highly conserved negative regulator of receptor tyrosine kinase, cytokine, and Wnt signaling pathways. Stimulation of these pathways inhibits GSK‐3 to modulate diverse downstream effectors that include transcription factors, nutrient sensors, glycogen synthesis, mitochondrial function, circadian rhythm, and cell fate. GSK‐3 also regulates alternative splicing in response to T‐cell receptor activation, and recent phosphoproteomic studies have revealed that multiple splicing factors and regulators of RNA biosynthesis are phosphorylated in a GSK‐3‐dependent manner. Furthermore, inhibition of GSK‐3 alters the splicing of hundreds of mRNAs, indicating a broad role for GSK‐3 in the regulation of RNA processing. GSK‐3‐regulated phosphoproteins include SF3B1, SRSF2, PSF, RBM8A, nucleophosmin 1 (NPM1), and PHF6, many of which are mutated in leukemia and myelodysplasia. As GSK‐3 is inhibited by pathways that are pathologically activated in leukemia and loss of Gsk3 in hematopoietic cells causes a severe myelodysplastic neoplasm in mice, these findings strongly implicate GSK‐3 as a critical regulator of mRNA processing in normal and malignant hematopoiesis. This article is categorized under: RNA Processing > Splicing Mechanisms RNA Processing > Splicing Regulation/Alternative Splicing RNA in Disease and Development > RNA in Disease RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications

Glycogen synthase kinase‐3 (GSK‐3) regulated signaling pathways and splicing factor phosphorylation. Antigen stimulation of the T‐cell receptor (TCR) activates the cytosolic protein kinase AKT, which inhibits GSK‐3 by phosphorylation at a conserved N‐terminal serine. Inhibition of GSK‐3 allows the polypyrimidine tract‐binding protein (PTB)‐associated splicing factor (PSF) to modulate the splicing of CD45 pre‐mRNA, as described in detail in Figure (Heyd & Lynch, ). Growth factor signaling through receptor tyrosine kinases (RTKs) also activates AKT and inhibits GSK‐3, allowing activation of diverse downstream effectors, including glycogen synthase. (Both Akt and GSK‐3 have multiple targets not shown here for the sake of clarity.) This pathway could also modulate GSK‐3‐dependent phosphorylation of splicing factors in the cytosol or within the nucleus (Hartmann et al., ). The Wnt pathway is also suppressed by GSK‐3. In the absence of Wnts, GSK‐3 phosphorylates β‐catenin, promoting its proteosomal degradation. Wnt signaling inhibits GSK‐3 through a distinct, AKT‐independent mechanism, stabilizing β‐catenin, which then activates Wnt target gene expression. Wnts could also regulate splicing factor phosphorylation through inhibition of GSK‐3 as well as through other downstream effectors of Wnt signaling (Goncalves, Matos, & Jordan, ; Hartmann et al., )

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Glycogen synthase kinase‐3 (GSK‐3) phosphorylation of RS motif. GSK‐3‐dependent phosphorylation of serine–arginine (SR)‐rich splicing factors identified by SILAC/MS comparing wild‐type and Gsk3 KO mouse embryonic stem cells (Shinde et al., ). Phosphorylated residues are in red. RS motif is in bold

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Role of glycogen synthase kinase‐3 (GSK‐3) in TCR regulation of CD45 splicing. CD45 encodes a receptor tyrosine phosphatase that serves as a feedback inhibitor of TCR signaling. In the absence of TCR activation, GSK‐3 phosphorylates PSF, which is sequestered by the thyroid hormone receptor associated protein (TRAP)‐150. Under these conditions, the variable exons 4, 5, and 6 are retained (R456), extending the sequence and reducing the activity of CD45 (only exons 3–7 are shown here). Upon antigen engagement of the TCR, GSK‐3 is phosphorylated and inhibited; newly translated PSF binds to exonic splicing silencer (ESS) elements in exons 4, 5, and 6 of the CD45 pre‐mRNA and promotes exon exclusion, leading to expression of a more active PTPase (Heyd & Lynch, , ). Multiple splice variants are expressed; for clarity only the R0 form, lacking all three variable exons, is shown

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