Disease relevance of Gsk3b

• Glycogen synthase kinase-3 (GSK-3) has emerged as a key kinase that is able to interact with several proteins involved in the etiology of Alzheimer's disease and other tauopathies [1].
• GSK-3beta and cyclin-dependent kinase 5 (Cdk5) are two pivotal kinases involved in Alzhermer's disease and other tauopathies. The relationship between these two kinases was unclear. A scaffold protein Axin was phosphorylated by Cdk5 in axons, and this phosphorylation led to GSK-3beta inactivation, hinting that Axin may link these two kinases in the etiology of tauopathies [2].
• Cdk5 was known to indirectly inhibited GSK-3beta.
• Using adenoviruses in lipopolysaccharide-stimulated mice, overexpression of GSK-3beta significantly decreased TNF-alpha expression in lung and heart tissues (38 and 15%, respectively), further confirming the anti-inflammatory role of GSK-3beta [3].
• Here we show that disruption of the murine GSK-3beta gene results in embryonic lethality caused by severe liver degeneration during mid-gestation, a phenotype consistent with excessive tumour necrosis factor (TNF) toxicity, as observed in mice lacking genes involved in the activation of the transcription factor activation NF-kappaB [4].
• Inhibition of GSK3 or ablation of the GSK3beta gene ameliorated TLR2-induced peritonitis and arthritis [5].
• Persistent phosphorylation of GSK-3beta could be critical for regulation of glycogen metabolism and cell growth in hepatoma cells [6].
• GSK-3beta appears to control the progression of wound healing and fibrosis by modulating ET-1 levels [7].

Psychiatry related information on Gsk3b

• Lithium, a known mood-stabilizer frequently used in treatment of bipolar disorders, is an effective glycogen synthase kinase-3beta (GSK-3beta) inhibitor [8].
• These data support the involvement of GSK-3 as an important mediator of DA and lithium action in vivo and suggest that modulation of the Akt/GSK-3 pathway might be relevant to DA-related disorders, such as attention deficit hyperactivity disorder and schizophrenia [9].
• Lithium, a widely used drug for affective disorders, inhibits GSK-3 at therapeutically relevant concentrations [10].
• We had previously generated a double transgenic model, overexpressing GSK-3beta in a conditional manner, using the Tet-off system and tau protein carrying a triple FTDP-17 (frontotemporal dementia and parkinsonism linked to chromosome 17) mutation [10].
• When locomotor activity was assessed, we found an association between the effect of lithium and the period of circadian oscillation as well as the level of GSK-3 protein expression [11].

High impact information on Gsk3b

• GSK-3 inhibitor treatment improved neutrophil and megakaryocyte recovery, recipient survival and resulted in enhanced sustained long-term repopulation [12].
• Instead we find that Wnt pathway activation by 6-bromoindirubin-3'-oxime (BIO), a specific pharmacological inhibitor of glycogen synthase kinase-3 (GSK-3), maintains the undifferentiated phenotype in both types of ESCs and sustains expression of the pluripotent state-specific transcription factors Oct-3/4, Rex-1 and Nanog [13].
• Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor [13].
• These results suggest that the use of GSK-3-specific inhibitors such as BIO may have practical applications in regenerative medicine [13].
• Since GSK-3 also phosphorylates tau protein, the principal component of neurofibrillary tangles, inhibition of GSK-3alpha offers a new approach to reduce the formation of both amyloid plaques and neurofibrillary tangles, two pathological hallmarks of Alzheimer's disease [14].

Chemical compound and disease context of Gsk3b

• Glycogen synthase kinase 3 (GSK3) is a serine/threonine kinase that has been implicated in pathological conditions such as diabetes and Alzheimer's disease [15].
• Streptozotocin-induced hyperglycemia and increased brain Akt and GSK3 phosphorylation were reversed by lowering blood glucose with insulin administration [16].
• Long term hyperglycemia also increased brain Akt and GSK3 phosphorylation, both 4 weeks after streptozotocin and in db/db insulin-resistant mice [16].
• Icatibant and adenovirus carrying a catalytically inactive GSK-3beta mutant (Ad.GSK-3beta-KM) abolished kallikrein's effects [17].
• METHODS: This study tested if the antidepressant imipramine or the mood stabilizers lithium and sodium valproate regulated pathophysiological serine-dephosphorylation of GSK3 caused by hypoxia in mouse brain in vivo [18].

Biological context of Gsk3b

• Role that phosphorylation of GSK3 plays in insulin and Wnt signalling defined by knockin analysis [19].
• Glycogen synthase kinase-3 (GSK-3) mediates epidermal growth factor, insulin and Wnt signals to various downstream events such as glycogen metabolism, gene expression, proliferation and differentiation [20].
• Introduction of a point mutation into full-length Axin that prevented GSK-3beta binding also generated a transcriptional activator [21].
• Disrupting Axin-GSK-3beta interaction in developing cortical neurons abolished axon formation [2].
• The binding site of rAxin for GSK-3beta was distinct from the beta-catenin-binding site, and these three proteins formed a ternary complex [20].
• We have isolated here a GSK-3beta-interacting protein from a rat brain cDNA library using a yeast two-hybrid method [20].

Anatomical context of Gsk3b

• NGF-induced axon growth is mediated by localized inactivation of GSK-3beta and functions of the microtubule plus end binding protein APC [22].
• BDNF-, NT-3-induced inactivation of GSK-3beta in the growing axonal growth cone was mediated by the direct Axin-GSK-3beta interaction, which recruited GSK-3beta to the axonal tip and facilitated its inactivation by Akt [2].
• Loss of glycogen synthase kinase 3beta (GSK-3beta) in mice results in embryonic lethality via hepatocyte apoptosis [23].
• However, NF-kappaB DNA binding activity is reduced in GSK-3beta null cells and in cells treated with a pharmacological inhibitor of GSK-3 [23].
• In this study, we used fibroblasts derived from GSK-3beta gene-deleted mice to understand the role of this kinase in TNF signaling [24].
• Interestingly, neither endothelial cell survival nor NFkappaB-mediated expression of anti-apoptotic genes was affected by GSK-3beta overexpression [3].

Associations of Gsk3b with chemical compounds

• Dishevelled (DVL) is associated with axonal microtubules and regulates microtubule stability through the inhibition of the serine/threonine kinase, glycogen synthase kinase 3beta (GSK-3beta) [25].
• In contrast, we demonstrate that the activation of muscle glycogen synthase by contraction, the stimulation of muscle glucose uptake by insulin, or the activation of hepatic glycogen synthase by glucose do not require GSK3 phosphorylation on Ser21/Ser9 [19].
• We propose that the ability of PKB/Akt to act via GSK-3 to promote the recycling of matrix receptors represents a key mechanism whereby integrin function and cell migration can be regulated by growth factors [26].
• Adiponectin-mediated suppression of cyclin D1 expression and attenuation of cell proliferation was abrogated by the GSK-3beta inhibitor lithium chloride [27].
• NF-kappaB activation induced by lipopolysaccharide, interleukin-1beta, or cigarette smoke condensate was completely suppressed in GSK-3beta(-/-) cells [24].
• We found that caspase-2 activation and the subsequent apoptotic events were abolished by the GSK-3beta inhibitors lithium chloride and SB216763, and by GSK-3beta knockdown using short interfering RNA [28].

Physical interactions of Gsk3b

• Expression of a 59 amino acid GSK-3beta-binding region from Axin strongly activated transcription in the absence of an upstream signal [21].
• Myc family transcription factors are destabilized by phosphorylation of a conserved amino-terminal GSK-3beta motif [29].
• In this study we describe a novel PGE(2) signaling pathway that proceeds through EP-2 --> cAMP --> EPAC --> phosphatidylinositol 3-kinase --> protein kinase B --> GSK-3 and results in increased DNA binding of the CCAAT displacement protein (CDP), a potent mammalian transcriptional repressor [30].
• IBU-PO (0.01-1 microM) inhibits glycogen-synthase-kinase-3beta (GSK-3beta) and stabilizes cytoplasmic beta-catenin reverting the silencing of the Wnt pathway caused by Abeta-toxicity and GSK-3beta overexpression [31].

Enzymatic interactions of Gsk3b

• However, GSK-3 is also inhibited when it is phosphorylated by Akt, a downstream target of phosphatidylinositol 3-kinase (PI3K) [32].
• Furthermore, immunoprecipitated SC35 is phosphorylated by recombinant GSK-3beta [1].
• Inhibition of GSK-3 beta leads to a decrease in a phosphorylated form of microtubule-associated protein-1B (MAP-1B), a protein involved in microtubule assembly, and a concomitant decrease in the level of stable microtubules [33].
• D1-T286A, a cyclin D1 mutant that cannot be phosphorylated by GSK-3beta, remains nuclear throughout the cell cycle, a consequence of its reduced binding to CRM1 [34].
• In addition, exercise returned the increased levels of phosphorylated GSK-3beta to those of NTG and decreased levels of phosphorylated CREB in HCM mice to normal levels [35].
• GSK-3beta was inhibited indirectly by Cdk5 through a scaffold protein Axin [2].

Regulatory relationships of Gsk3b

• In GSK3alpha/GSK3beta homozygous knockin cells, Wnt3a induces normal inactivation of GSK3, as judged by the stabilisation of beta-catenin and stimulation of Wnt-dependent transcription [19].
• Here, we have explored mechanisms by which GSK-3beta may control NF-kappaB function [23].
• Here we report that ILK controls tau phosphorylation via regulation of glycogen synthase kinase-3beta (GSK-3beta) activity in N1E-115 cells [36].
• These results suggest that endogenously overproduced Abeta induces increased tau phosphorylation through activation of GSK-3, and that inactivation of PKC is at least one of the mechanisms involved in GSK-3 activation [37].
• Consistent with this, we showed that the effect of GSK3 inhibition on chondrocyte proliferation is repressed in tissues lacking a receptor for FGF18, FGF receptor 3 [38].
• These data provide the first direct evidence that calpain promotes GSK-3 truncation in a way that has implications in signal transduction, and probably in pathological disorders such as Alzheimer disease [39].

Other interactions of Gsk3b

• Additional experiments with LiCl as an inhibitor of GSK-3beta kinase activity indicate that the step affected by betaarr1 is upstream of GSK-3beta and most likely at the level of Dvl [40].
• Therefore, GSK-3beta has profound effects on transcription in a gene-specific manner through a mechanism involving control of promoter-specific recruitment of NF-kappaB [23].
• Expression of certain NF-kappaB-regulated genes, such as IkappaBalpha and macrophage inflammatory protein 2, is minimally affected by the absence of GSK-3beta [23].
• Most surprisingly, TNF-induced Akt activation also required the presence of GSK-3beta [24].
• ILK inactivation resulted in an increase in the active form but a decrease in the inactive form of GSK-3beta, which is a candidate kinase involved in PHF-tau formation [36].
• The direct interaction between GSK-3beta and Axin was required for GSK-3beta inactivation [2].

Analytical, diagnostic and therapeutic context of Gsk3b

• Immunofluorescence studies showed that after GSK-3 inhibition, SC35, a member of the SR family, is redistributed and enriched in nuclear speckles and colocalizes with the kinase [1].
• The aim of this study was to investigate the effects of GSK-3beta inhibition on the degree of experimental spinal cord trauma induced by the application of vascular clips (force of 24 g) to the dura via a four-level T5-T8 laminectomy [41].
• In the present study, using in situ hybridization and in vitro culture of growing oocytes from 8-day-old postnatal mice, we have demonstrated that another Akt substrate, glycogen synthase kinase-3 (GSK-3), is expressed in growing oocytes [42].
• Thus, BCR ligation initiates a PI 3-kinase/Akt/GSK-3 signaling pathway [43].
• Therefore, it was of great interest to test the possible protective effects of lithium in an AD animal model based on GSK-3 overexpression [10].

References