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 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 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.

Coordinated phosphorylation of insulin receptor substrate-1 by glycogen synthase kinase-3 and protein kinase CβII in the diabetic fat tissue

2008 ◽  
Vol 294 (6) ◽  
pp. E1169-E1177 ◽  
Author(s):  
Ziva Liberman ◽  
Batya Plotkin ◽  
Tamar Tennenbaum ◽  
Hagit Eldar-Finkelman
Keyword(s):  
Protein Kinase ◽  
Insulin Receptor ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Insulin Receptor Substrate ◽  
Fat Tissue ◽  
Insulin Receptor Substrate 1 ◽  
Gsk 3Β

Serine/threonine phosphorylation of insulin receptor substrate-1 (IRS-1) is an important negative modulator of insulin signaling. Previously, we showed that glycogen synthase kinase-3 (GSK-3) phosphorylates IRS-1 at Ser332. However, the fact that GSK-3 requires prephosphorylation of its substrates suggested that Ser336 on IRS-1 was the “priming” site phosphorylated by an as yet unknown protein kinase. Here, we sought to identify this “priming kinase” and to examine the phosphorylation of IRS-1 at Ser336 and Ser332 in physiologically relevant animal models. Of several stimulators, only the PKC activator phorbol ester PMA enhanced IRS-1 phosphorylation at Ser336. Treatment with selective PKC inhibitors prevented this PMA effect and suggested that a conventional PKC was the priming kinase. Overexpression of PKCα or PKCβII isoforms in cells enhanced IRS-1 phosphorylation at Ser336 and Ser332, and in vitro kinase assays verified that these two kinases directly phosphorylated IRS-1 at Ser336. The expression level and activation state of PKCβII, but not PKCα, were remarkably elevated in the fat tissues of diabetic ob/ob mice and in high-fat diet-fed mice compared with that from lean animals. Elevated levels of PKCβII were also associated with enhanced phosphorylation of IRS-1 at Ser336/332 and elevated activity of GSK-3β. Finally, adenoviral mediated expression of PKCβII in adipocytes enhancedphosphorylation of IRS-1 at Ser336. Taken together, our results suggest that IRS-1 is sequentially phosphorylated by PKCβII and GSK-3 at Ser336 and Ser332. Furthermore, these data provide evidence for the physiological relevance of these phosphorylation events in the pathogenesis of insulin resistance in fat tissue.

Synthesis of aryl anilinomaleimide based derivatives as glycogen synthase kinase-3β inhibitors with potential role as antidepressant agents

2016 ◽  
Vol 40 (7) ◽  
pp. 6109-6119 ◽  
Author(s):  
Mushtaq A. Tantray ◽  
Imran Khan ◽  
Hinna Hamid ◽  
Mohammad Sarwar Alam ◽  
Abhijeet Dhulap ◽  
...  
Keyword(s):  
Animal Models ◽  
Potential Role ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β ◽  
Antidepressant Agents ◽  
Gsk 3Β

Novel anilinomaleimide based derivatives were found to inhibit GSK-3β activity in vitro and demonstrate anti-depressant effects in animal models.

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.

Synthesis of benzimidazole-based 1,3,4-oxadiazole-1,2,3-triazole conjugates as glycogen synthase kinase-3β inhibitors with antidepressant activity in in vivo models

RSC Advances ◽  
2016 ◽  
Vol 6 (49) ◽  
pp. 43345-43355 ◽  
Author(s):  
Mushtaq A. Tantray ◽  
Imran Khan ◽  
Hinna Hamid ◽  
Mohammad Sarwar Alam ◽  
Abhijeet Dhulap ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Antidepressant Activity ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β ◽  
In Vivo Models ◽  
Gsk 3Β

Synthesized benzimidazole based 1,3,4-oxadiazole-1,2,3-triazole conjugates were found to inhibit GSK-3β activityin vitroand exhibit antidepressant-like activity inin vivostudies.

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