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Proteome and phosphoproteome analyses reveal the kinase regulatory network involved in glycogen synthesis kinase 3β

ABSTRACT: To analyze the roles of GSK-3β in podocytes, GSK-3β knockdown lentivirus by Clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein (Cas)9 was applied to establish stable cell lines. Phosphoproteome and proteome evaluation was conducted using TMT labeled LC-MS/MS technologies.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Kidney

SUBMITTER: Mingyang Hu

LAB HEAD: Sijie Zhou

PROVIDER: PXD024543 | Pride | 2021-09-10

REPOSITORIES: Pride

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Proteome and Phosphoproteome Analyses Reveal the Kinase Regulatory Network Involved in Glycogen Synthesis Kinase 3β.

Hu Mingyang M Fang Jiuyuan J Wang Huijuan H Zhou Sijie S

Frontiers in genetics 20210407

Diabetic nephropathy is the most common chronic kidney disease in the world and the main cause of end-stage renal disease (ESRD). The structural integrity of podocytes is fundamental to the normal function of the glomerulus, and the role of glycogen synthase kinase 3β (GSK-3β) in podocytes is complicated. A thorough understanding of GSK-3β is crucial to understand the mechanism of diabetic nephropathy. To analyze the roles of GSK-3β in podocytes, GSK-3β knockdown lentivirus by clustered regularl ...[more]

PMID: 33897769

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Massive Expansion of Functional Human iPSC-derived Cardiomyocytes by Concomitant Glycogen Synthase Kinase-3 Beta Inhibition and Removal of Cell-Cell Contact

Project description:Modulating signaling pathways including Wnt and Hippo can induce cardiomyocyte proliferation in vivo. Applying these signaling modulators to human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in vitro can expand CMs only to modest extent (< 5-fold). Here, we demonstrate massive expansion of hiPSC-CMs in vitro (i.e. 100-250-fold) by glycogen synthase kinase-3β (GSK-3β) inhibition using CHIR99021 and concurrent removal of cell-cell contact. We show GSK-3β inhibition suppresses CM maturation while contact removal prevents CMs from cell cycle exit. Remarkably, contact removal enabled 10-to-25-times greater expansion beyond GSK-3β inhibition alone. Mechanistically, cell cycle re-activation required both LEF/TCF activity and AKT phosphorylation, but it was independent from Yes associated protein (YAP) activity. Engineered heart tissues from expanded hiPSC-CMs showed the comparable contractility to those from unexpanded hiPSC-CMs, demonstrating uncompromised cellular functionality after expansion. In sum, we uncovered a molecular interplay that enables massive expansion hiPSC-CMs for large-scale drug screening and tissue engineering.

2020-08-03 | GSE148586 | GEO

Glycogen synthase kinase (GSK) 3β phosphorylates and protects nuclear myosin 1c from proteasome-mediated degradation to activate rDNA transcription in early G1 cells

Project description:Nuclear myosin 1c (NM1) mediates RNA polymerase I (pol I) transcription activation and cell cycle progression by facilitating PCAF-mediated H3K9 acetylation, but the molecular mechanism by which NM1 is regulated remains unclear. Here, we report that at early G1 the glycogen synthase kinase (GSK) 3β phosphorylates and stabilizes NM1, allowing for NM1 association with the chromatin. Genomic analysis by ChIP-Seq showed that this mechanism occurs on the rDNA as active GSK3β selectively occupies the gene. ChIP assays and transmission electron microscopy in GSK3β-/- mouse embryonic fibroblasts indicated that at G1 rRNA synthesis is suppressed due to decreased H3K9 acetylation leading to a chromatin state incompatible with transcription. We found that GSK3β directly phosphorylates the endogenous NM1 on a single serine residue (Ser-1020) located within the NM1 C-terminus. In G1 this phosphorylation event stabilizes NM1 and prevents NM1 polyubiquitination by the E3 ligase UBR5 and proteasome-mediated degradation. We conclude that GSK3β-mediated phosphorylation of NM1 is required for pol I transcription activation. Examination of GSK3beta with the genome in mouse embryonic fibroblasts

2014-05-02 | E-GEOD-57153 | biostudies-arrayexpress

Phosphatidylinositol 3-Kinase (PI3K) Signaling via Glycogen Synthase Kinase-3 (Gsk-3) Regulates DNA Methylation of Imprinted Loci.

Project description:The two vertebrate Gsk-3 isoforms, Gsk-3a and Gsk-3b, are encoded by distinct genetic loci and exhibit mostly redundant function in murine embryonic stem cells (ESCs). Here we report that deletion of both Gsk-3a and Gsk-3b in mouse ESCs results in misregulated expression of imprinted genes and hypomethylation of corresponding imprinted loci. Treatment of wild-type ESCs with small molecule inhibitors of Gsk-3 phenocopies the DNA hypomethylation of imprinted loci observed in Gsk-3 null ESCs. We provide evidence that DNA hypomethylation in Gsk-3 null ESCs is due to a reduction in the levels of the de novo DNA methyltransferase, Dnmt3a2. Gsk-3 activity serves as a node for several signal transduction pathways, and its regulation of Dnmt3a2 expression raises the possibility that DNA methylation could be transiently affected by different types of environmental stimuli. Our data suggest that modulating Gsk-3 activity could have further reaching effects in the regulation of the epigenome. Keywords: Gene expression array-based The study was designed to examine the changes in gene expression between wild-type and Gsk-3a-/-;Gsk-3b-/- mouse embryonic stem cells.

2010-11-15 | E-GEOD-20015 | biostudies-arrayexpress

Phosphatidylinositol 3-Kinase (PI3K) Signaling via Glycogen Synthase Kinase-3 (Gsk-3) Regulates DNA Methylation of Imprinted Loci.

2010-11-15 | GSE20015 | GEO

GSK-3β inhibition promotes engraftment of ex vivo expanded hematopoietic stem cells

Project description:Glycogen synthase kinase-3β (GSK-3β) has been recently identified as an important regulator of stem cell function. In vitro studies show that GSK-3β inhibition delays proliferation of human haematopoietic progenitor cells while increasing numbers of late dividing multipotent progenitors. Gene expression analysis revealed that GSK-3β inhibition modulates the expression of a subset of genes that are transcriptional targets for cytokines. GSK-3β inhibition antagonised down-regulation of genes encoding cyclin dependent kinase inhibitor p57 and a member of the growth arrest and DNA damage 45 family, GADD45B as well as up-regulation of cyclin D1 by cytokines, providing a possible mechanism for the BIO-induced delay in cell cycle progression. Surprisingly, inhibition of GSK-3β earlier shown to prevent β-catenin degradation and promote the nuclear accumulation of β-catenin was not sufficient to activate its transcriptional targets in haematopoietic stem cells. GSK-3β inhibition up-regulated the expression of a several positive regulators of stem cell function suppressed during cytokine-induced proliferation. The data supports a clinical role for GSK-3β inhibition to improve engraftment efficiency of ex vivo expanded stem cells.

2010-03-26 | GSE21073 | GEO

The Glycogen Synthase Kinase-3 Phosphoproteome: GSK-3 Phosphorylates Multiple Splicing Factors and Regulates Alternative Splicing

Project description:Glycogen Synthase Kinase-3 (GSK-3) is a constitutively active, ubiquitously expressed protein kinase that regulates multiple signaling pathways. Over 100 putative GSK-3 substrates have been reported in diverse cell types based on in vitro kinase assays or genetic and pharmacological manipulation of GSK-3. Many more have been predicted based on a recurrent GSK-3 consensus motif, but this prediction has not been tested by analyzing the GSK-3 phosphoproteome. We used stable isotope labeling of amino acids in culture (SILAC) and mass spectrometry to analyze the repertoire of GSK-3 dependent substrates in mouse embryonic stem cells (ESCs). A comparison of wild-type and Gsk3a;Gsk3b knockout (DKO) ESCs revealed prominent GSK-3-dependent phosphorylation of multiple splicing factors and regulators of RNA biosynthesis, as well as proteins that regulate transcription, translation, and cell division. We demonstrate direct, GSK-3-dependent phosphorylation of the splicing factors RBM8A and PSF as well as the nucleolar protein NPM1. RNA sequencing to compare the transcriptomes of wild-type and Gsk3 DKO ESCs identified more than 210 genes that are alternatively spliced in a GSK-3-dependent manner, supporting a broad role for GSK-3 in regulating alternative splicing. Overall, this study provides the first unbiased analysis of the GSK-3 phosphoproteome and strong evidence for GSK-3 as a regulator of alternative splicing.

2017-08-24 | GSE90921 | GEO

9-ING-41 in Patients With Advanced Cancers

Project description:GSK-3β is a potentially important therapeutic target in human malignancies. The Actuate 1801 Phase 1/2 study is designed to evaluate the safety and efficacy of 9-ING-41, a potent GSK-3β inhibitor, as a single agent and in combination with cytotoxic agents, in patients with refractory cancers.

| 2284734 | ecrin-mdr-crc

Glycogen synthase kinase (GSK) 3β phosphorylates and protects nuclear myosin 1c from proteasome-mediated degradation to activate rDNA transcription in early G1 cells

2014-05-02 | GSE57153 | GEO

9-ING-41, a small molecule inhibitor of GSK-3β, potentiates the effects of chemotherapy in KRAS mutated colorectal cancer

Project description:Despite the prevalence of KRAS mutations in colorectal cancer, there is no K-Ras targeted therapies for these tumors and available treatment options are limited for metastatic disease. GSK-3β has been demonstrated to be a critically important kinase for survival and proliferation of K-Ras-depended pancreatic cancer cells. In this study we tested 9-ING-41, a small molecule inhibitor of GSK-3β, in patient-derived tumor organoid models of colorectal cancer. We demonstrated that addition of 9-ING-41 to the standard of care drugs 5-FU and oxaliplatin could significantly enhance inhibition of the growth of colorectal cancer cells harboring KRAS mutations. The results of the transcriptomic analysis support our findings of cell cycle arrest and DNA repair deficiency in 9-ING-41-treated colorectal cancer cells. Moreover, we found substantial similarity in the changes of transcriptomic profile after inhibition of GSK-3β and suppression of STK33, another critically important kinase for K-Ras-dependent cells. Overall, the results of this study provide a rationale for the inclusion of patients with mutant KRAS colorectal cancer in clinical studies of 9-ING-41 and other GSK-3 inhibitors.

2021-10-31 | GSE184125 | GEO

Glycogen Synthase Kinase-3-beta Regulates Glucocorticoid Signaling by Phosphorylating the Glucocorticoid Receptor

Project description:Glucocorticoids (GCs) bind to the glucocorticoid receptor (GR) to regulate diverse biological functions from cell growth to apoptosis. Drugs that mimic their action are the most commonly prescribed therapeutic agents in the world and are currently used for the treatment of many diseases including asthma, autoimmune disorders, and some cancers. However, the mechanisms by which one hormone, via one receptor, modulates such diverse biological functions remain unclear. We hypothesized that epigenetic alteration to the GR may contribute to its signaling diversity, and here we demonstrate that Glycogen Synthase Kinase-3-beta phosphorylates GR on Serine 404 in a glucocorticoid-dependent manner. U-2 OS cells expressing a mutant GR that is incapable of Ser404 phosphorylation have enhanced global transcriptional responses, stronger NF-kappaB transrepression, and enhanced cell death in response to dexamethasone. Conversely, presence of Ser404 phosphorylation on the GR inhibits glucocorticoid-dependent NF-kappaB transrepression and cell death of these osteoblasts. Collectively, our results describe a novel convergence point of the GSK-3-beta pathway with the GR resulting in altered glucocorticoid regulated signaling. Our results also provide a mechanism by which the phosphorylation status of Ser404 in GR can dictate how cells will ultimately respond to GCs. Keywords: Glucocorticoid Receptor; GSK-3-beta; NF-kappaB Transrepression; Phosphorylation

2008-11-24 | GSE11205 | GEO

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