scholarly journals Glycogen Synthase Kinase-3β Is a Negative Regulator of Cardiomyocyte Hypertrophy

2000 ◽  
Vol 151 (1) ◽  
pp. 117-130 ◽  
Author(s):  
Syed Haq ◽  
Gabriel Choukroun ◽  
Zhao Bin Kang ◽  
Hardeep Ranu ◽  
Takashi Matsui ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Signaling Pathways ◽  
Cellular Response ◽  
Glycogen Synthase ◽  
Negative Regulator ◽  
Glycogen Synthase Kinase ◽  
Cardiomyocyte Hypertrophy ◽  
Glycogen Synthase Kinase 3Β ◽  
Activated T Cells ◽  
Gsk 3Β

Hypertrophy is a basic cellular response to a variety of stressors and growth factors, and has been best characterized in myocytes. Pathologic hypertrophy of cardiac myocytes leads to heart failure, a major cause of death and disability in the developed world. Several cytosolic signaling pathways have been identified that transduce prohypertrophic signals, but to date, little work has focused on signaling pathways that might negatively regulate hypertrophy. Herein, we report that glycogen synthase kinase-3β (GSK-3β), a protein kinase previously implicated in processes as diverse as development and tumorigenesis, is inactivated by hypertrophic stimuli via a phosphoinositide 3-kinase–dependent protein kinase that phosphorylates GSK-3β on ser 9. Using adenovirus-mediated gene transfer of GSK-3β containing a ser 9 to alanine mutation, which prevents inactivation by hypertrophic stimuli, we demonstrate that inactivation of GSK-3β is required for cardiomyocytes to undergo hypertrophy. Furthermore, our data suggest that GSK-3β regulates the hypertrophic response, at least in part, by modulating the nuclear/cytoplasmic partitioning of a member of the nuclear factor of activated T cells family of transcription factors. The identification of GSK-3β as a transducer of antihypertrophic signals suggests that novel therapeutic strategies to treat hypertrophic diseases of the heart could be designed that target components of the GSK-3 pathway.

scholarly journals Cyclic AMP Promotes Neuronal Survival by Phosphorylation of Glycogen Synthase Kinase 3β

2000 ◽  
Vol 20 (24) ◽  
pp. 9356-9363 ◽  
Author(s):  
Mingtao Li ◽  
Xiaomin Wang ◽  
Mary Kay Meintzer ◽  
Tracey Laessig ◽  
Morris J. Birnbaum ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cyclic Amp ◽  
Glycogen Synthase ◽  
Neuronal Survival ◽  
Glycogen Synthase Kinase ◽  
Intracellular Camp ◽  
Glycogen Synthase Kinase 3Β ◽  
Gsk 3Β ◽  
Camp Levels

ABSTRACT Agents that elevate intracellular cyclic AMP (cAMP) levels promote neuronal survival in a manner independent of neurotrophic factors. Inhibitors of phosphatidylinositol 3 kinase and dominant-inactive mutants of the protein kinase Akt do not block the survival effects of cAMP, suggesting that another signaling pathway is involved. In this report, we demonstrate that elevation of intracellular cAMP levels in rat cerebellar granule neurons leads to phosphorylation and inhibition of glycogen synthase kinase 3β (GSK-3β). The increased phosphorylation of GSK-3β by protein kinase A (PKA) occurs at serine 9, the same site phosphorylated by Akt. Purified PKA is able to phosphorylate recombinant GSK-3β in vitro. Inhibitors of GSK-3 block apoptosis in these neurons, and transfection of neurons with a GSK-3β mutant that cannot be phosphorylated interferes with the prosurvival effects of cAMP. These data suggest that activated PKA directly phosphorylates GSK-3β and inhibits its apoptotic activity in neurons.

scholarly journals Axil, a Member of the Axin Family, Interacts with Both Glycogen Synthase Kinase 3β and β-Catenin and Inhibits Axis Formation ofXenopus Embryos

1998 ◽  
Vol 18 (5) ◽  
pp. 2867-2875 ◽  
Author(s):  
Hideki Yamamoto ◽  
Shosei Kishida ◽  
Takaaki Uochi ◽  
Satoshi Ikeda ◽  
Shinya Koyama ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Binding Site ◽  
Glycogen Synthase ◽  
Wnt Signaling Pathway ◽  
Amino Acid Identity ◽  
Negative Regulator ◽  
Glycogen Synthase Kinase ◽  
Axis Formation ◽  
Glycogen Synthase Kinase 3Β ◽  
Gsk 3Β

ABSTRACT Using a yeast two-hybrid method, we identified a novel protein which interacts with glycogen synthase kinase 3β (GSK-3β). This protein had 44% amino acid identity with Axin, a negative regulator of the Wnt signaling pathway.We designated this protein Axil for Axin like. Like Axin, Axil ventralized Xenopus embryos and inhibited Xwnt8-induced Xenopus axis duplication. Axil was phosphorylated by GSK-3β. Axil bound not only to GSK-3β but also to β-catenin, and the GSK-3β-binding site of Axil was distinct from the β-catenin-binding site. Furthermore, Axil enhanced GSK-3β-dependent phosphorylation of β-catenin. These results indicate that Axil negatively regulates the Wnt signaling pathway by mediating GSK-3β-dependent phosphorylation of β-catenin, thereby inhibiting axis formation.

scholarly journals Glycogen Synthase Kinase 3β Is Positively Regulated by Protein Kinase Cζ-Mediated Phosphorylation Induced by Wnt Agonists

2015 ◽  
Vol 36 (5) ◽  
pp. 731-741 ◽  
Author(s):  
Nydia Tejeda-Muñoz ◽  
Héctor González-Aguilar ◽  
Paula Santoyo-Ramos ◽  
M. Cristina Castañeda-Patlán ◽  
Martha Robles-Flores
Keyword(s):  
Protein Kinase ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Resting Cells ◽  
Malignant Cells ◽  
Glycogen Synthase Kinase 3Β ◽  
Colon Cells ◽  
Basal Activity ◽  
Gsk 3Β

The molecular events that drive Wnt-induced regulation of glycogen synthase kinase 3β (GSK-3β) activity are poorly defined. In this study, we found that protein kinase Cζ (PKCζ) and GSK-3β interact mainly in colon cancer cells. Wnt stimulation induced a rapid GSK-3β redistribution from the cytoplasm to the nuclei in malignant cells and a transient PKC-mediated phosphorylation of GSK-3β at a different site from serine 9. In addition, while Wnt treatment induced a decrease in PKC-mediated phosphorylation of GSK-3β in nonmalignant cells, in malignant cells, this phosphorylation was increased. Pharmacological inhibition and small interfering RNA (siRNA)-mediated silencing of PKCζ abolished all of these effects, but unexpectedly, it also abolished the constitutive basal activity of GSK-3β.In vitroactivity assays demonstrated that GSK-3β phosphorylation mediated by PKCζ enhanced GSK-3β activity. We mapped Ser147 of GSK-3β as the site phosphorylated by PKCζ, i.e., its mutation into alanine abolished GSK-3β activity, resulting in β-catenin stabilization and increased transcriptional activity, whereas phosphomimetic replacement of Ser147 by glutamic acid maintained GSK-3β basal activity. Thus, we found that PKCζ phosphorylates GSK-3β at Ser147 to maintain its constitutive activity in resting cells and that Wnt stimulation modifies the phosphorylation of Ser147 to regulate GSK-3β activity in opposite manners in normal and malignant colon cells.

scholarly journals Inhibition of Glycogen Synthase Kinase 3β Increases the Proportion and Suppressive Function of CD19+CD24hiCD27+ Breg Cells

2020 ◽  
Vol 11 ◽  
Author(s):  
Jinyang Li ◽  
Ji Gao ◽  
Haoming Zhou ◽  
Jinren Zhou ◽  
Zhenghua Deng ◽  
...  
Keyword(s):  
B Cells ◽  
Glycogen Synthase ◽  
Inflammatory Diseases ◽  
Adaptive Immune System ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β ◽  
Activated T Cells ◽  
Novel Strategy ◽  
Gsk 3Β

CD19+CD24hiCD27+ memory Breg cells exhibit decreased abundance in patients with chronic graft-versus-host disease (cGVHD) after liver transplantation and produce less IL-10 than those from patients without cGVHD and healthy donors. Due to the lack of Breg cells and the difficulty in expanding them in vitro, in mouse models and early human clinical trials, the adoptive transfer of Breg cells to autoimmune diseases is greatly restricted. Glycogen synthase kinase 3β (GSK-3β) is a multifunctional serine/threonine (ser/thr) protein kinase that can participate in B cell growth, metabolic activity, and proliferation. Phosphoprotein array analysis showed that p-GSK-3β-s9 was highly expressed in mBreg cells. Furthermore, here, we demonstrated that GSK-3β expression in mBreg cells is lower than that observed in B cells by flow cytometry. We found that the treatment of B cells with the specific GSK-3β inhibitor SB216763 can significantly increase the proportion and immunosuppressive function of mBreg cells in vitro. Nuclear factor of activated T cells (NFAT) is one of a pivotal regulator of gene expression in adaptive immune system. Here, we observed that inhibition of GSK-3β by SB216763 results in enhanced expression of NFATc1 in B cells, which is essential in regulating the ability of B cells to secrete IL-10. By constructing a xGVHD mouse model, we observed that SB216763-treated mBreg cells effectively prevent xenogeneic GVHD. Here we propose a novel strategy using SB216763 to inhibit GSK-3β and then enhance the proportion and immunosuppressive function of mBreg cells by increasing the expression of NFATc1. This approach may be used as a therapy to ameliorate GVHD and inflammatory diseases.

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