Glycogen Synthase Kinase-3 - An Overview of An Over-Achieving Protein Kinase
Ontario Cancer Institute, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada.Current drug targets (Impact Factor: 3.02). 12/2006; 7(11):1377-88. DOI: 10.2174/1389450110607011377
Glycogen synthase kinase-3 (GSK-3) has attracted much scrutiny due to its plethora of cellular functions, novel mechanisms of regulation and its potential as a therapeutic target for several common diseases. In mammals, GSK-3 is encoded by two genes, termed GSK-3alpha and GSK-3beta, that yield related but distinct protein-serine kinases. GSK-3 is unusual in that its protein kinase activity tends to be high in resting cells and cellular stimuli, such as hormones and growth factors, result in its catalytic inactivation. Further, many of the substrate proteins of GSK-3 are functionally inhibited by phosphorylation. Thus, signals that inhibit GSK-3 often cause activation of its diverse array of target proteins. Regulation of GSK-3 is important for normal development, regulation of metabolism, neuronal growth and differentiation and modulation of cell death. Dysregulation of GSK-3 activity has been implicated in human pathologies such as neurodegenerative diseases and type-2 diabetes. In this introductory chapter we provide a primer on the modes of GSK-3 regulation and a description of the various signaling pathways and cellular processes in which GSK-3 is an active participant.
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- "A number of human diseases are connected to dysfunctions of GSK-3 (e.g. Alzheimer's disease, type 2 diabetes and cancer)        . The diversity of GSK-3 functions led to speculations about possible physiological roles of PfGSK-3, including metabolism regulation, cell cycle control and differentiation processes  . "
ABSTRACT: Plasmodium falciparum glycogen synthase kinase-3 (PfGSK-3) is one of the eukaryotic protein kinases that were identified as essential for the parasite causing malaria tropica. Although the physiological functions of PfGSK-3 are still unknown, it had been suggested as a putative target for novel antimalarial drugs. The high structural similarity of PfGSK-3 and its human orthologue HsGSK-3 makes the development of selective PfGSK-3 inhibitors a challenging task. Actually, established GSK-3 inhibitors are either unselective or are more potent for inhibition of the mammalian GSK-3. A high throughput screening campaign identified thieno[2,3-b]pyridines as a new class of PfGSK-3 inhibitors. Systematic variation of the substitution pattern at the parent scaffold led to compounds which selectively inhibited the plasmodial enzyme. These compounds also exhibited activity against erythrocyte stages of the parasites. A hypothetical explanation for the selectivity of the new antimalarial compounds was enunciated based on the results of docking a selective inhibitor into a PfGSK-3 homology model and by comparison of the results with an x-ray structure of HsGSK-3 co-crystallized with a similar but unselective compound. Copyright © 2015. Published by Elsevier B.V.
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- "Several publications revealed that GSK3β is involved in neurodegenerative diseases (Frame and Cohen 2001, Kockeritz et al. 2006; Muyllaert et al. 2006, 2008; Hooper et al. 2008; Terwel et al. 2008; Lei et al. 2011; Jacobs et al. 2012). Lovestone et al. (2007) described that dysregulation of GSK3β is one of the causative factors of schizophrenia. "
ABSTRACT: Typical form of neurons is crucially important for their functions. This is maintained by microtubules and associated proteins like tau. Hyperphosphorylation of tau is a major concern in neurodegenerative diseases. Glycogen synthase kinase3β (GSK3β) and cyclin-dependent protein kinase 5 (Cdk5) are the enzymes that govern tau phosphorylation. Currently, efforts are being made to target GSK3β and Cdk5 as possible therapeutic avenues to control tau phosphorylation and treat neurodegenerative diseases related to taupathies. In a number of studies, caloric restriction mimetic 2-deoxyglucose (C6H12O5) was found to be beneficial in improving the brain functions. However, no reports are available on the effect of 2-deoxyglucose 2-DG on tau phosphorylation. In the present study, hippocampal pyramidal neurons from E17 mouse embryos were isolated and cultured on poly-L-lysine-coated coverslips. Neurons from the experimental group were treated with 10 mM 2-deoxyglucose. The treatment of 2-DG resulted in healthier neuronal morphology in terms of significantly lower number of cytoplasmic vacuoles, little or no membrane blebbings, maintained axon hillock and intact neurites. There were decreased immunofluorescence signals for GSK3β, pTau at Ser262, Cdk5 and pTau at Ser235 suggesting decreased tau phosphorylation, which was further confirmed by Western blotting. The results indicate the beneficial effects of 2-DG in controlling the tau phosphorylation and maintaining the healthy neuronal cytoarchitecture.
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- "GSK3β is a highly activated serine/threonine kinase in resting cells with normal metabolism . Besides its influence on the glycogen synthesis GSK3β is involved in Wnt/β-catenin and Phosphatidylinositole 3 kinase (PI3K)/Akt signaling antagonizing cell growth and cell cycle progression in both pathways. "
ABSTRACT: Prognosis of adult patients suffering from acute lymphoblastic leukemia (ALL) is still unsatisfactory. Targeted therapy via inhibition of deregulated signaling pathways appears to be a promising therapeutic option for the treatment of ALL. Herein, we evaluated the influence of a novel arylindolylmaleimide (PDA-66), a potential GSK3beta inhibitor, on several ALL cell lines. ALL cell lines (SEM, RS4;11, Jurkat and MOLT4) were exposed to different concentrations of PDA-66. Subsequently, proliferation, metabolic activity, apoptosis and necrosis, cell cycle distribution and protein expression of Wnt and PI3K/Akt signaling pathways were analyzed at different time points. PDA-66 inhibited the proliferation of ALL cells significantly by reduction of metabolic activity. The 72 h IC50 values ranged between 0.41 to 1.28 muM PDA-66. Additionally, caspase activated induction of apoptosis could be detected in the analyzed cell lines. PDA-66 influenced the cell cycle distribution of ALL cell lines differently. While RS4;11 and MOLT4 cells were found to be arrested in G2 phase, SEM cells showed an increased cell cycle in G0/1 phase. PDA-66 displays significant antileukemic activity in ALL cells and classifies as candidate for further evaluation as a potential drug in targeted therapy of ALL.
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