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doi: 10.1242/10.1242/jcs.00384
Commentary |
Ontario Cancer Institute, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada
* Author for correspondence (e-mail: jwoodget{at}uhnres.utoronto.ca)
Glycogen synthase kinase 3 (GSK-3) is a multifunctional serine/threonine kinase found in all eukaryotes. The enzyme is a key regulator of numerous signalling pathways, including cellular responses to Wnt, receptor tyrosine kinases and G-protein-coupled receptors and is involved in a wide range of cellular processes, ranging from glycogen metabolism to cell cycle regulation and proliferation. GSK-3 is unusual in that it is normally active in cells and is primarily regulated through inhibition of its activity. Another peculiarity compared with other protein kinases is its preference for primed substrates, that is, substrates previously phosphorylated by another kinase. Several recent advances have improved our understanding of GSK-3 regulation in multiple pathways. These include the solution of the crystal structure of GSK-3, which has provided insight into GSK-3's penchant for primed substrates and the regulation of GSK-3 by serine phosphorylation, and findings related to the involvement of GSK-3 in the Wnt/ß-catenin and Hedgehog pathways. Finally, since increased GSK-3 activity may be linked to pathology in diseases such as Alzheimer's disease and non-insulin-dependent diabetes mellitus, several new GSK-3 inhibitors, such as the aloisines, the paullones and the maleimides, have been developed. Although they are just starting to be characterized in cell culture experiments, these new inhibitors hold promise as therapeutic agents.
Key words: Signal transduction, Phosphorylation, Wnt signalling, Insulin signalling, Protein structure-function
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J. W. Tullai, J. Chen, M. E. Schaffer, E. Kamenetsky, S. Kasif, and G. M. Cooper Glycogen Synthase Kinase-3 Represses Cyclic AMP Response Element-binding Protein (CREB)-targeted Immediate Early Genes in Quiescent Cells J. Biol. Chem., March 30, 2007; 282(13): 9482 - 9491. [Abstract] [Full Text] [PDF]
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 F. Neria, C. Caramelo, H. Peinado, F. R. Gonzalez-Pacheco, J. JP. Deudero, A. J. de Solis, R. Fernandez-Sanchez, S. Penate, A. Cano, and M{a} A. Castilla Mechanisms of endothelial cell protection by blockade of the JAK2 pathway Am J Physiol Cell Physiol, March 1, 2007; 292(3): C1123 - C1131. [Abstract] [Full Text] [PDF]
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 V. A.M. van de Schans, S. W.M. van den Borne, A. E. Strzelecka, B. J.A. Janssen, J. L.J. van der Velden, R. C.J. Langen, A. Wynshaw-Boris, J. F.M. Smits, and W. M. Blankesteijn Interruption of Wnt Signaling Attenuates the Onset of Pressure Overload-Induced Cardiac Hypertrophy Hypertension, March 1, 2007; 49(3): 473 - 480. [Abstract] [Full Text] [PDF]
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M. Wrzaczek, W. Rozhon, and C. Jonak A Proteasome-regulated Glycogen Synthase Kinase-3 Modulates Disease Response in Plants J. Biol. Chem., February 23, 2007; 282(8): 5249 - 5255. [Abstract] [Full Text] [PDF]
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E. Rodionova, M. Conzelmann, E. Maraskovsky, M. Hess, M. Kirsch, T. Giese, A. D. Ho, M. Zoller, P. Dreger, and T. Luft GSK-3 mediates differentiation and activation of proinflammatory dendritic cells Blood, February 15, 2007; 109(4): 1584 - 1592. [Abstract] [Full Text] [PDF]
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M.-H. Liang and D.-M. Chuang Regulation and Function of Glycogen Synthase Kinase-3 Isoforms in Neuronal Survival J. Biol. Chem., February 9, 2007; 282(6): 3904 - 3917. [Abstract] [Full Text] [PDF]
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E. I. Danek, J. Tcherkezian, I. Triki, M. Meriane, and N. Lamarche-Vane Glycogen Synthase Kinase-3 Phosphorylates CdGAP at a Consensus ERK 1 Regulatory Site J. Biol. Chem., February 9, 2007; 282(6): 3624 - 3631. [Abstract] [Full Text] [PDF]
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I. Oinuma, H. Katoh, and M. Negishi R-Ras Controls Axon Specification Upstream of Glycogen Synthase Kinase-3beta through Integrin-linked Kinase J. Biol. Chem., January 5, 2007; 282(1): 303 - 318. [Abstract] [Full Text] [PDF]
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D. Morrow, C. Sweeney, Y. A. Birney, S. Guha, N. Collins, P. M. Cummins, R. Murphy, D. Walls, E. M. Redmond, and P. A. Cahill Biomechanical regulation of hedgehog signaling in vascular smooth muscle cells in vitro and in vivo Am J Physiol Cell Physiol, January 1, 2007; 292(1): C488 - C496. [Abstract] [Full Text] [PDF]
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S. Naska, K. J. Park, G. E. Hannigan, S. Dedhar, F. D. Miller, and D. R. Kaplan An Essential Role for the Integrin-Linked Kinase-Glycogen Synthase Kinase-3{beta} Pathway during Dendrite Initiation and Growth J. Neurosci., December 20, 2006; 26(51): 13344 - 13356. [Abstract] [Full Text] [PDF]
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I. Shiojima and K. Walsh Regulation of cardiac growth and coronary angiogenesis by the Akt/PKB signaling pathway Genes & Dev., December 15, 2006; 20(24): 3347 - 3365. [Abstract] [Full Text] [PDF]
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V. Rider, K. Isuzugawa, M. Twarog, S. Jones, B. Cameron, K. Imakawa, and J. Fang Progesterone initiates Wnt-{beta}-catenin signaling but estradiol is required for nuclear activation and synchronous proliferation of rat uterine stromal cells J. Endocrinol., December 1, 2006; 191(3): 537 - 548. [Abstract] [Full Text] [PDF]
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S. Seng, H. K. Avraham, S. Jiang, S. Venkatesh, and S. Avraham KLHL1/MRP2 Mediates Neurite Outgrowth in a Glycogen Synthase Kinase 3{beta}-Dependent Manner Mol. Cell. Biol., November 15, 2006; 26(22): 8371 - 8384. [Abstract] [Full Text] [PDF]
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 T. P. Ciaraldi, D. K. Oh, L. Christiansen, S. E. Nikoulina, A. P. S. Kong, S. Baxi, S. Mudaliar, and R. R. Henry Tissue-specific expression and regulation of GSK-3 in human skeletal muscle and adipose tissue Am J Physiol Endocrinol Metab, November 1, 2006; 291(5): E891 - E898. [Abstract] [Full Text] [PDF]
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R. Ilouz, N. Kowalsman, M. Eisenstein, and H. Eldar-Finkelman Identification of Novel Glycogen Synthase Kinase-3beta Substrate-interacting Residues Suggests a Common Mechanism for Substrate Recognition J. Biol. Chem., October 13, 2006; 281(41): 30621 - 30630. [Abstract] [Full Text] [PDF]
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M.-H. Liang and D.-M. Chuang Differential Roles of Glycogen Synthase Kinase-3 Isoforms in the Regulation of Transcriptional Activation J. Biol. Chem., October 13, 2006; 281(41): 30479 - 30484. [Abstract] [Full Text] [PDF]
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A. Gartner, X. Huang, and A. Hall Neuronal polarity is regulated by glycogen synthase kinase-3 (GSK-3{beta}) independently of Akt/PKB serine phosphorylation J. Cell Sci., October 1, 2006; 119(19): 3927 - 3934. [Abstract] [Full Text] [PDF]
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 A. V. Ougolkov, M. E. Fernandez-Zapico, V. N. Bilim, T. C. Smyrk, S. T. Chari, and D. D. Billadeau Aberrant Nuclear Accumulation of Glycogen Synthase Kinase-3{beta} in Human Pancreatic Cancer: Association with Kinase Activity and Tumor Dedifferentiation Clin. Cancer Res., September 1, 2006; 12(17): 5074 - 5081. [Abstract] [Full Text] [PDF]
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J. Prickaerts, D. Moechars, K. Cryns, I. Lenaerts, H. van Craenendonck, I. Goris, G. Daneels, J. A. Bouwknecht, and T. Steckler Transgenic mice overexpressing glycogen synthase kinase 3beta: a putative model of hyperactivity and mania. J. Neurosci., August 30, 2006; 26(35): 9022 - 9029. [Abstract] [Full Text] [PDF]
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A. Hergovich, J. Lisztwan, C. R. Thoma, C. Wirbelauer, R. E. Barry, and W. Krek Priming-Dependent Phosphorylation and Regulation of the Tumor Suppressor pVHL by Glycogen Synthase Kinase 3 Mol. Cell. Biol., August 1, 2006; 26(15): 5784 - 5796. [Abstract] [Full Text] [PDF]
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 S. J. Crozier, X. Zhang, J. Wang, J. Cheung, S. R. Kimball, and L. S. Jefferson Activation of signaling pathways and regulatory mechanisms of mRNA translation following myocardial ischemia-reperfusion J Appl Physiol, August 1, 2006; 101(2): 576 - 582. [Abstract] [Full Text] [PDF]
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 M.-A. Arevalo and A. Rodriguez-Tebar Activation of Casein Kinase II and Inhibition of Phosphatase and Tensin Homologue Deleted on Chromosome 10 Phosphatase by Nerve Growth Factor/p75NTR Inhibit Glycogen Synthase Kinase-3beta and Stimulate Axonal Growth Mol. Biol. Cell, August 1, 2006; 17(8): 3369 - 3377. [Abstract] [Full Text] [PDF]
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 P. Biswas, S. Canosa, D. Schoenfeld, J. Schoenfeld, P. Li, L. C. Cheas, J. Zhang, A. Cordova, B. Sumpio, and J. A. Madri PECAM-1 Affects GSK-3{beta}-Mediated {beta}-Catenin Phosphorylation and Degradation Am. J. Pathol., July 1, 2006; 169(1): 314 - 324. [Abstract] [Full Text] [PDF]
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A. Vines, S. Cahoon, I. Goldberg, U. Saxena, and S. Pillarisetti Novel Anti-inflammatory Role for Glycogen Synthase Kinase-3beta in the Inhibition of Tumor Necrosis Factor-{alpha}- and Interleukin-1beta-induced Inflammatory Gene Expression J. Biol. Chem., June 23, 2006; 281(25): 16985 - 16990. [Abstract] [Full Text] [PDF]
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A. Valerio, V. Ghisi, M. Dossena, C. Tonello, A. Giordano, A. Frontini, M. Ferrario, M. Pizzi, P. Spano, M. O. Carruba, et al. Leptin Increases Axonal Growth Cone Size in Developing Mouse Cortical Neurons by Convergent Signals Inactivating Glycogen Synthase Kinase-3beta J. Biol. Chem., May 5, 2006; 281(18): 12950 - 12958. [Abstract] [Full Text] [PDF]
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S. Chien Mechanical and Chemical Regulation of Endothelial Cell Polarity Circ. Res., April 14, 2006; 98(7): 863 - 865. [Full Text] [PDF]
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X. Cai, M. Li, J. Vrana, and M. D. Schaller Glycogen synthase kinase 3- and extracellular signal-regulated kinase-dependent phosphorylation of paxillin regulates cytoskeletal rearrangement. Mol. Cell. Biol., April 1, 2006; 26(7): 2857 - 2868. [Abstract] [Full Text] [PDF]
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 W. Yan and H.-H. Tai Glycogen Synthase Kinase-3 Phosphorylation, T-Cell Factor Signaling Activation, and Cell Morphology Change following Stimulation of Thromboxane Receptor {alpha} J. Pharmacol. Exp. Ther., April 1, 2006; 317(1): 267 - 274. [Abstract] [Full Text] [PDF]
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