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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: 3.6). 12/2006; 7(11):1377-88. DOI: 10.2174/1389450110607011377
Source: PubMed

ABSTRACT 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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    • "On the other hand, insulin promotes the dephosphorylation and activation of glycogen synthase (GS) by inactivating glycogen synthase kinase-3 (GSK-3) through phosphorylation [26]. GSK-3 is inactivated through phosphorylation by insulin stimulation through the PI3K/AKT-dependent pathway [27]. Thus, the PI3K/ AKT signaling pathway plays an important role in the modulation of insulin sensitivity and glucose metabolism. "
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    Medical Hypotheses 01/2013; 80(4). DOI:10.1016/j.mehy.2013.01.012 · 1.07 Impact Factor
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    • "It has been shown that GSK3 is an essential element of Wnt/beta-catenin pathway, which is involved in the control of gene expression, cell adhesion and cell polarity, and plays major roles in neurodevelopment and in the regulation of neuronal plasticity and cell survival (Grimes and Jope, 2001). GSK3 is constitutively active and regulates the activity of a number of targets including transcriptional factors, enzymes and cytoskeletal proteins (Kockeritz et al., 2006). Converging studies in animal models show an involvement of GSK3 in the regulation of behavior by 5- HT and dopamine (DA), and in the mechanism of action of lithium and serotonergic antidepressants (Gould and Manji, 2005; Beaulieu et al., 2009).The inhibition of GSK3 occurs in the context of the signaling cascades in response to serotonin (5-HT), 5-HT 1 receptor agonists, lithium, and several antidepressants (Beaulieu et al., 2009). "
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    Neuroscience 09/2012; 226:411–420. DOI:10.1016/j.neuroscience.2012.09.020 · 3.33 Impact Factor
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    • "Glycogen synthase kinase 3-b (GSK3-b) is an essential element of the Wnt/beta-catenin pathway, which is involved in the control of gene expression, cell behavior, cell adhesion, and cell polarity, and has major roles in neurodevelopment and regulation of neuronal polarity, neuronal plasticity, and cell survival (Grimes and Jope, 2001b). GSK3-b is constitutively active and regulates the activity of many targets, including transcriptional factors, enzymes and cytoskeletal proteins (Kockeritz et al, 2006). GSK3-b is considered a primary regulator in a range of cellular processes, including differentiation, growth, motility, and apoptosis: increasing GSK3 activity increases apoptosis in neuronal cells, whereas inhibiting GSK has neuroprotective effects (Forde and Dale, 2007). "
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