Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Inactivation of glycogen synthase kinase-3 beta by phosphorylation: new kinase connections in insulin and growth-factor signalling.

ABSTRACT: The beta-isoform of glycogen synthase kinase-3 (GSK3 beta) isolated from rabbit skeletal muscle was inactivated 90-95% following incubation with MgATP and either MAP kinase-activated protein kinase-1 (MAPKAP kinase-1, also termed RSK-2) or p70 S6 kinase (p70S6K), and re-activated with protein phosphatase 2A. MAPKAP kinase-1 and p70S6K phosphorylated the same tryptic peptide on GSK3 beta, and the site of phosphorylation was identified as the serine located nine residues from the N-terminus of the protein. The inhibitory effect of Ser-9 phosphorylation on GSK3 beta activity was observed with three substrates, (inhibitor-2, c-jun and a synthetic peptide), and also with glycogen synthase provided that 0.15 M KCl was added to the assays. The results suggest that Ser-9 phosphorylation underlies the reported inhibition of GSK3 beta by insulin and that GSK3 may represent a point of convergence of two major growth-factor-stimulated protein kinase cascades.

SUBMITTER: Sutherland C

PROVIDER: S-EPMC1137648 | biostudies-other | 1993 Nov

REPOSITORIES: biostudies-other

ACCESS DATA

Json Xml

Similar Datasets

Stimulation of EphB2 attenuates tau phosphorylation through PI3K/Akt-mediated inactivation of glycogen synthase kinase-3?.

Project description:Abnormal tau hyperphosphorylation is an early pathological marker of Alzheimer's disease (AD), however, the upstream factors that regulate tau phosphorylation are not illustrated and there is no efficient strategy to arrest tau hyperphosphorylation. Here, we find that activation of endogenous EphB2 receptor by ligand stimulation (ephrinB1/Fc) or by ectopic expression of EphB2 plus the ligand stimulation induces a remarkable tau dephosphorylation at multiple AD-associated sites in SK-N-SH cells and human embryonic kidney cells that stably express human tau (HEK293-tau). In cultured hippocampal neurons and the hippocampus of human tau transgenic mice, dephosphorylation of tau proteins was also detected by stimulation of EphB2 receptor. EphB2 activation inhibits glycogen synthase kinase-3? (GSK-3?), a crucial tau kinase, and activates phosphatidylinositol-3-kinase (PI3K)/Akt both in vitro and in vivo, whereas simultaneous inhibition of PI3K or upregulation of GSK-3? abolishes the EphB2 stimulation-induced tau dephosphorylation. Finally, we confirm that ephrinB1/Fc treatment induces tyrosine phosphorylation (activation) of EphB2, while deletion of the tyrosine kinase domain (VM) of EphB2 eliminates the receptor stimulation-induced GSK-3? inhibition and tau dephosphorylation. We conclude that activation of EphB2 receptor kinase arrests tau hyperphosphorylation through PI3K-/Akt-mediated GSK-3? inhibition. Our data provide a novel membranous target to antagonize AD-like tau pathology.

| S-EPMC4484244 | biostudies-literature

Mitogen inactivation of glycogen synthase kinase-3 beta in intact cells via serine 9 phosphorylation.

Project description:Glycogen synthase kinase-3 (GSK-3), a protein-serine kinase implicated in cell-fate determination and differentiation, phosphorylates several regulatory proteins that are activated by dephosphorylation in response to hormones or growth factors. GSK-3 beta is phosphorylated in vitro at serine 9 by p70 S6 kinase and p90rsk-1, resulting in its inhibition [Sutherland, Leighton, and Cohen (1993) Biochem. J. 296, 15-19]. Using HeLa cells expressing GSK-3 beta or a mutant containing alanine at residue 9, we demonstrate that serine 9 is modified in intact cells and is targeted specifically by p90rsk-1, and that phosphorylation leads to loss of activity. Since p90rsk-1 is directly activated by mitogen-activated protein kinases, agonists of this pathway, such as insulin, repress GSK-3 function.

| S-EPMC1137602 | biostudies-other

Glycogen synthase kinase-3 beta (GSK3β)-mediated phosphorylation of ETS1 promotes progression of ovarian carcinoma.

Project description:ETS1 - an evolutionarily conserved transcription factor involved in the regulation of a number of cellular processes - is overexpressed in several malignancies, including ovarian cancer. Most studies on ETS1 expression have been focused on the transcriptional and RNA levels, with post-translational control mechanisms remaining relatively unexplored in the pathogenesis of malignancies. Here, we show that ETS1 forms a complex with glycogen synthase kinase-3β (GSK3β). Specifically, GSK3β-mediated phosphorylation of ETS1 at threonine 265 and serine 269 promoted protein stability, induced the transcriptional activation of matrix metalloproteinase (MMP)-9, and increased cell migration. In vivo experiments revealed that a GSK3β inhibitor was able to suppress both endogenous ETS1 expression and induction of MMP-9 expression. Upon generation of a specific antibody against phosphorylated ETS1, we demonstrated that phospho-ETS1 immunohistochemical expression in ovarian cancer specimens was correlated with that of MMP-9. Notably, the cumulative overall survival of patients with low phospho-ETS1 histoscores was significantly longer than that of those showing higher scores. We conclude that the GSK3β/ETS1/MMP-9 axis may regulate the biological aggressiveness of ovarian cancer and can serve as a prognostic factor in patients with this malignancy.

| S-EPMC8202891 | biostudies-literature

Inactivation of glycogen synthase kinase-3? is required for osteoclast differentiation.

Project description:Glycogen synthase kinase-3? (GSK-3?) is a serine/threonine kinase originally identified as a regulator of glycogen deposition. Although the role of GSK-3? in osteoblasts is well characterized as a negative regulator of ?-catenin, its effect on osteoclast formation remains largely unidentified. Here, we show that the GSK-3? inactivation upon receptor activator of NF-?B ligand (RANKL) stimulation is crucial for osteoclast differentiation. Regulation of GSK-3? activity in bone marrow macrophages by retroviral expression of the constitutively active GSK-3? (GSK3?-S9A) mutant inhibits RANKL-induced osteoclastogenesis, whereas expression of the catalytically inactive GSK-3? (GSK3?-K85R) or small interfering RNA (siRNA)-mediated GSK-3? silencing enhances osteoclast formation. Pharmacological inhibition of GSK-3? further confirmed the negative role of GSK-3? in osteoclast formation. We also show that overexpression of the GSK3?-S9A mutant in bone marrow macrophages inhibits RANKL-mediated NFATc1 induction and Ca(2+) oscillations. Remarkably, transgenic mice expressing the GSK3?-S9A mutant show an osteopetrotic phenotype due to impaired osteoclast differentiation. Further, osteoclast precursor cells from the transgenic mice show defects in expression and nuclear localization of NFATc1. These findings demonstrate a novel role for GSK-3? in the regulation of bone remodeling through modulation of NFATc1 in RANKL signaling.

| S-EPMC3234729 | biostudies-literature

Blocked inhibitory serine-phosphorylation of glycogen synthase kinase-3alpha/beta impairs in vivo neural precursor cell proliferation.

Project description:Adult neurogenesis augments neuronal plasticity, and deficient neurogenesis might contribute to mood disorders and schizophrenia and impede treatment responses. Because these diseases might be associated with inadequately controlled glycogen synthase kinase-3 (GSK3), we tested whether blocked inhibitory serine-phosphorylation of GSK3 impairs neurogenesis.Neural precursor cell (NPC) proliferation was measured by dentate gyrus bromodeoxyuridine (BrdU) labeling in GSK3alpha/beta(21A/21A/9A/9A) knockin mice with serine-to-alanine mutations to block inhibitory serine-phosphorylation of GSK3 while it remains within the physiological range, because GSK3 is not overexpressed.There was a drastic 40% impairment in neurogenesis in vivo in GSK3 knockin mice compared with wild-type mice. Impaired neurogenesis could be due to effects of GSK3 in NPCs or in surrounding cells that modulate NPCs. In vitro proliferation was equivalent for NPCs from GSK3 knockin and wild-type mice, suggesting an in vivo deficiency in GSK3 knockin mice of external support for NPC proliferation. Measurements of two neurotrophins that promote neurogenesis demonstrated less hippocampal vascular endothelial growth factor but not brain-derived growth factor in GSK3 knockin mice than wild-type mice, reinforcing the possibility that insufficient environmental support in GSK3 knockin mice might contribute to impaired neurogenesis. In vivo chronic co-administration of lithium and fluoxetine, which each increase inhibitory serine-phosphorylation of wild-type GSK3, increased NPC proliferation in wild-type but not GSK3 knockin mice.Blocked inhibitory control of GSK3 impaired neurogenesis and the capacity of therapeutic drugs to stimulate neurogenesis, likely through deficient environmental factors that support neurogenesis, which might contribute to psychiatric diseases and responses to therapeutic drugs.

| S-EPMC2746934 | biostudies-literature

Tau phosphorylation by glycogen synthase kinase 3β modulates enzyme acetylcholinesterase expression.

Project description:In Alzheimer's disease (AD), the enzyme acetylcholinesterase (AChE) co-localizes with hyperphosphorylated tau (P-tau) within neurofibrillary tangles. Having demonstrated that AChE expression is increased in the transgenic mouse model of tau Tg-VLW, here we examined whether modulating phosphorylated tau levels by over-expressing wild-type human tau and glycogen synthase kinase-3β (GSK3β) influences AChE expression. In SH-SY5Y neuroblastoma cells expressing higher levels of P-tau, AChE activity and protein increased by (20% ± 2%) and (440% ± 150%), respectively. Western blots and qPCR assays showed that this increment mostly corresponded to the cholinergic ACHE-T variant, for which the protein and transcript levels increased ~60% and ~23%, respectively. Moreover, in SH-SY5Y cells differentiated into neurons by exposure to retinoic acid (10 µM), over-expression of GSK3β and tau provokes an imbalance in cholinergic activity with a decrease in the neurotransmitter acetylcholine in the cell (45 ± 10%). Finally, we obtained cerebrospinal fluid (CSF) from AD patients enrolled on a clinical trial of tideglusib, an irreversible GSK3β inhibitor. In CSF of patients that received a placebo, there was an increase in AChE activity (35 ± 16%) respect to basal levels, probably because of their treatment with AChE inhibitors. However, this increase was not observed in tideglusib-treated patients. Moreover, CSF levels of P-tau at the beginning measured by commercially ELISA kits correlated with AChE activity. In conclusion, this study shows that P-tau can modulate AChE expression and it suggests that AChE may possibly increase in the initial phases of AD.

| S-EPMC8359467 | biostudies-literature

Isoform-selective decrease of glycogen synthase kinase-3-beta (GSK-3β) reduces synaptic tau phosphorylation, transcellular spreading, and aggregation.

Project description:It has been suggested that aberrant activation of glycogen synthase kinase-3-beta (GSK-3β) can trigger abnormal tau hyperphosphorylation and aggregation, which ultimately leads to neuronal/synaptic damage and impaired cognition in Alzheimer disease (AD). We examined if isoform-selective partial reduction of GSK-3β can decrease pathological tau changes, including hyperphosphorylation, aggregation, and spreading, in mice with localized human wild-type tau (hTau) expression in the brain. We used adeno-associated viruses (AAVs) to express hTau locally in the entorhinal cortex of wild-type and GSK-3β hemi-knockout (GSK-3β-HK) mice. GSK-3β-HK mice had significantly less accumulation of hyperphosphorylated tau in synapses and showed a significant decrease of tau protein spread between neurons. In primary neuronal cultures from GSK-3β-HK mice, the aggregation of exogenous FTD-mutant tau was also significantly reduced. These results show that a partial decrease of GSK-3β significantly represses tau-initiated neurodegenerative changes in the brain, and therefore is a promising therapeutic target for AD and other tauopathies.

| S-EPMC7848608 | biostudies-literature

Sequential phosphorylation of CCAAT enhancer-binding protein beta by MAPK and glycogen synthase kinase 3beta is required for adipogenesis.

Project description:CCAAT enhancer-binding protein (C/EBP)beta, C/EBPalpha, and peroxisome proliferator activated receptor (PPAR)gamma act in a cascade where C/EBPbeta activates expression of C/EBPalpha and PPARgamma, which then function as pleiotropic activators of genes that produce the adipocyte phenotype. When growth-arrested 3T3-L1 preadipocytes are induced to differentiate, C/EBPbeta is rapidly expressed but still lacks DNA-binding activity. After a long (14-hour) lag, glycogen synthase kinase 3beta enters the nucleus, which correlates with hyperphosphorylation of C/EBPbeta and acquisition of DNA-binding activity. Concurrently, 3T3-L1 preadipocytes synchronously enter S phase and undergo mitotic clonal expansion, a prerequisite for terminal differentiation. Ex vivo and in vitro experiments with C/EBPbeta show that phosphorylation of Thr-188 by mitogen-activating protein kinase "primes" C/EBPbeta for subsequent phosphorylation on Ser-184 and Thr-179 by glycogen synthase kinase 3beta, acquisition of DNA-binding function, and transactivation of the C/EBPalpha and PPARgamma genes. The delayed transactivation of the C/EBPalpha and PPARgamma genes by C/EBPbeta appears necessary to allow mitotic clonal expansion, which would otherwise be prevented, because C/EBPalpha and PPARgamma are antimitotic.

| S-EPMC1175002 | biostudies-literature

Effect of glycogen synthase kinase-3 inactivation on mouse mammary gland development and oncogenesis.

Project description:Many components of the Wnt/β-catenin signaling pathway have critical functions in mammary gland development and tumor formation, yet the contribution of glycogen synthase kinase-3 (GSK-3α and GSK-3β) to mammopoiesis and oncogenesis is unclear. Here, we report that WAP-Cre-mediated deletion of GSK-3 in the mammary epithelium results in activation of Wnt/β-catenin signaling and induces mammary intraepithelial neoplasia that progresses to squamous transdifferentiation and development of adenosquamous carcinomas at 6 months. To uncover possible β-catenin-independent activities of GSK-3, we generated mammary-specific knockouts of GSK-3 and β-catenin. Squamous transdifferentiation of the mammary epithelium was largely attenuated, however, mammary epithelial cells lost the ability to form mammospheres suggesting perturbation of stem cell properties unrelated to loss of β-catenin alone. At 10 months, adenocarcinomas that developed in glands lacking GSK-3 and β-catenin displayed elevated levels of γ-catenin/plakoglobin as well as activation of the Hedgehog and Notch pathways. Collectively, these results establish the two isoforms of GSK-3 as essential integrators of multiple developmental signals that act to maintain normal mammary gland function and suppress tumorigenesis.

| S-EPMC4490903 | biostudies-literature

Leptin inhibits glycogen synthase kinase-3beta to prevent tau phosphorylation in neuronal cells.

Project description:We have previously demonstrated that Leptin reduces extracellular amyloid beta (Abeta) protein both in vitro and in vivo, and intracellular tau phosphorylation in vitro. Further, we have shown that these effects are dependent on activation of AMP-activated protein kinase (AMPK) in vitro. Herein, we investigated downstream effectors of AMPK signaling directly linked to tau phosphorylation. One such target, of relevance to Alzheimer's disease (AD), may be GSK-3beta, which has been shown to be inactivated by Leptin. We therefore dissected the role of GSK-3beta in mediating Leptin's ability to reduce tau phosphorylation in neuronal cells. Our data suggest that Leptin regulates tau phosphorylation through a pathway involving both AMPK and GSK-3beta. This was based on the following: Leptin and the cell-permeable AMPK activator, 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR), reduced tau phosphorylation at AD-relevant sites similarly to the GSK-3beta inhibitor, lithium chloride (LiCl). Further, this reduction of tau phosphorylation was mimicked by the downregulation of GSK-3beta, achieved using siRNA technology and antagonized by the ectopic overexpression of GSK-3beta. These studies provide further insight into Leptin's mechanism of action in suppressing AD-related pathways.

| S-EPMC2681253 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data