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GSK3 inhibitors: development and therapeutic potential

Key Points

  • In the late 1970s, glycogen synthase kinase-3 (GSK3) was identified as a protein kinase that inactivates glycogen synthase, but was ignored as a drug target by the pharmaceutical industry until the mid-1990s, when its role in insulin signal transduction was clarified.

  • Several potent inhibitors of GSK3 were identified in the late 1990s, and cell-based assays using these compounds indicated that they might have therapeutic potential for the treatment of diabetes. During the past year or so, very potent and more specific inhibitors of GSK3 have been introduced.

  • GSK3 inhibitors have now been shown to be effective in normalizing blood glucose levels in animal models of type 2 diabetes, with their effects seeming to occur primarily through an increase in hepatic glycogen synthesis and a decrease in hepatic gluconeogenesis.

  • GSK3 inhibitors might also have potential for neurodegenerative disorders, such as Alzheimer's disease. For example, there is recent evidence that GSK3 increases the production of β-amyloid — which has a key role in the pathogenesis of Alzheimer's disease — and that inhibition of GSK3 might reduce β-amyloid levels.

Abstract

Glycogen synthase kinase-3 (GSK3) was initially identified more than two decades ago as an enzyme involved in the control of glycogen metabolism. In recent years it has been shown to have key roles in regulating a diverse range of cellular functions, which have prompted efforts to develop GSK3 inhibitors as therapeutics. Here, we describe the biology of GSK3 relevant to its potential as a target for diabetes and neurodegenerative diseases, and discuss progress in the development of GSK3 inhibitors.

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Figure 1: GSK3 phosphorylates serine and threonine residues, provided that another phosphoserine or phosphothreonine is present four amino acids C-terminal to the site of phosphorylation.
Figure 2: Outline of the signalling pathway by which insulin inhibits GSK3 and stimulates glycogen synthesis.
Figure 3: Outline of the mechanism by which Wnt signalling might lead to the inhibition of GSK3, accumulation of β-catenin and the activation of gene transcription.
Figure 4: Chemical structures of some potent and specific inhibitors of GSK3.
Figure 5: Amyloid plaques in Alzheimer's disease.
Figure 6: Intracellular deposits in Alzheimer's disease and other tauopathies.

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References

  1. Cohen, P. The fifteenth Colworth Medal Lecture. The hormonal control of glycogen metabolism in mammalian muscle by multivalent phosphorylation. Biochem. Soc. Trans. 7, 459–480 (1979).

    CAS  PubMed  Google Scholar 

  2. Embi, N., Rylatt, D. B. & Cohen, P. Glycogen synthase kinase-3 from rabbit skeletal muscle; separation from cyclic-AMP-dependent protein kinase and phosphorylase kinase. Eur. J. Biochem. 107, 519–527 (1980).

    CAS  PubMed  Google Scholar 

  3. Fiol, C. J., Mahrenholz, A. M., Wang, Y., Roeske, R. W. & Roach, P. J. Formation of protein kinase recognition sites by covalent modification of the substrate; molecular mechanism for the synergistic action of casein kinase II and glycogen synthase kinase-3. J. Biol. Chem. 262, 14042–14048 (1987).

    CAS  PubMed  Google Scholar 

  4. Sakanaka, C. Phosphorylation and regulation of β-catenin by casein kinase I. J. Biochem (Tokyo) 132, 687–703 (2002).

    Google Scholar 

  5. Gregory, M. A., Qi, Y. & Hann, S. R. Phosphorylation by glycogen synthase kinase-3 controls c-myc proteolysis and subnuclear localisation. J. Biol. Chem. 278, 51606–51612 (2003).

    CAS  PubMed  Google Scholar 

  6. Frame, S. & Cohen, P. GSK3 takes centre stage more than 20 years after its discovery. Biochem. J. 359, 1–16 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Hughes, K., Mikolakaki, E., Plyte, S. E., Totty, N. F. & Woodgett, J. R. Modulation of the glycogen synthase kinase-3 family by tyrosine phosphorylation. EMBO J. 12, 803–808 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Cole, A., Frame, S. & Cohen, P. Further evidence that the tyrosine phosphorylation of glycogen synthase kinase-3 (GSK3) in mammalian cells is an autophosphorylation event. Biochem. J. 377, 249–255 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Cohen, P. The Croonian Lecture 1998. Identification of a protein kinase cascade of major importance in insulin signal transduction. Phil. Trans. R. Soc. Lond. B 354, 485–495 (1999).

    CAS  Google Scholar 

  10. Cohen, P. & Frame, S. The renaissance of GSK3. Nature Rev. Mol. Cell. Biol. 2, 769–776 (2001).

    CAS  Google Scholar 

  11. Frame, S., Cohen, P. & Biondi, R. M. A common phosphate binding site explains the unique substrate specificity of GSK3 and its inactivation by phosphorylation. Mol. Cell 7, 1321–1327.

  12. Dajani, R. et al. Crystal structure of glycogen synthase kinase-3β: structural basis for phosphate-primed substrate specificity and autoinhibition. Cell 105, 721–732 (2001).

    CAS  PubMed  Google Scholar 

  13. Kim, L. & Kimmel, A. R. GSK3, a master switch regulating cell fate specification and tumorigenesis. Curr. Opin. Genet. Dev. 10, 508–514 (2000).

    CAS  PubMed  Google Scholar 

  14. Seidensticker, M. J. & Behrens, J. Biochemical interactions in the Wnt pathway. Biochim. Biophys. Acta 1495, 168–182 (2000).

    CAS  PubMed  Google Scholar 

  15. Eldar-Finkelman, H., Schreyer, S. A., Shinohara, M. M., LeBoeuf, R. C. & Krebs, E. G. Increased glycogen synthase kinase-3 activity in diabetes- and obesity-prone C57BL/6J mice. Diabetes 48, 1–5 (1999).

    Google Scholar 

  16. Nikoulina, S. E. et al. Potential role of glycogen synthase kinase-3 in skeletal muscle insulin resistance of type 2 diabetes. Diabetes 49, 263–271 (2000).

    CAS  PubMed  Google Scholar 

  17. Eldar-Finkelman, H. & Krebs, E. G. Phosphorylation of insulin receptor substrate 1 by glycogen synthase kinase 3 impairs insulin action. Proc. Natl. Acad. Sci. USA 94, 9660–9664 (1997).

    CAS  PubMed  Google Scholar 

  18. Klein, P. S. & Melton, D. A. A molecular mechanism for the effect of lithium on development. Proc. Natl. Acad. Sci. USA 93, 8455–8459 (1996).

    CAS  PubMed  Google Scholar 

  19. Stambolic, V., Ruel, L. & Woodgett, J. R. Lithium inhibits glycogen synthase kinase-3 activity and mimics wingless signalling in intact cells. Curr. Biol. 6, 1664–1668 (1996).

    CAS  PubMed  Google Scholar 

  20. Davies, S. P., Reddy, H., Caivano, M. & Cohen, P. Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem. J. 351, 95–105 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Cheng, K., Creacy, S. & Larner, J. 'Insulin-like' effects of lithium on isolated rat adipocytes. II. Specific activation of glycogen synthase. Mol. Cell. Biochem. 56, 183–189 (1983).

    CAS  PubMed  Google Scholar 

  22. Coghlan, M. P. et al. Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription. Chem. Biol. 7, 793–803 (2000). The first paper describing a relatively selective small-molecule inhibitor of GSK3 developed by targeting this protein kinase for drug discovery. It demonstrates that these compounds mimic the ability of insulin to activate glycogen synthase and to stimulate the conversion of glucose to glycogen in a liver cell line.

    CAS  PubMed  Google Scholar 

  23. Norman, P. Emerging fundamental themes in modern medicinal chemistry. Drug News Persp. 14, 242–247 (2001).

    CAS  Google Scholar 

  24. Lochhead, P. A., Coghlan, M., Rice, S. Q. J. & Sutherland, C. Inhibition of GSK-3 selectively reduces glucose-6-phosphatase and phosphoenolpyruvate carboxykinase gene expression. Diabetes 50, 937–946 (2001). This paper exploits GSK3 inhibitors to identify a novel role for this protein kinase in the control of gluconeogenesis. This finding indicated that GSK3 inhibitors might lower blood glucose levels by suppressing the production of glucose by the liver as well as by stimulating the conversion of glucose to glycogen.

    CAS  PubMed  Google Scholar 

  25. LeClerc, C. et al. Indirubins inhibit glycogen synthase kinase-3β and CDK5/p25, two protein kinases involved in abnormal tau phosphorylation in Alzheimer's disease. A property common to most cyclin-dependent kinase inhibitors? J. Biol. Chem. 276, 251–260 (2001).

    CAS  PubMed  Google Scholar 

  26. Meijer, L. et al. GSK3-selective inhibitors derived from tyrian purple indirubins. Chem. Biol. 10, 1255–1266 (2003).

    CAS  PubMed  Google Scholar 

  27. Polychronopoulos, P. et al. Structural basis for the synthesis of indirubins as potent and selective inhibitors of glycogen synthase kinase-3 and cyclin-dependent kinases. J. Med. Chem. 47, 935–946 (2004).

    CAS  PubMed  Google Scholar 

  28. Leost, M. et al. Paullones are potent inhibitors of glycogen synthase kinase-3β and cyclin-dependent kinase 5/p25. Eur. J. Biochem. 267, 5983–5994 (2000).

    CAS  PubMed  Google Scholar 

  29. Meijer, L. et al. Inhibition of cyclin-dependent protein kinases, GSK-3β and CK1 by hymenialdisine, a marine sponge constituent. Chem. Biol. 7, 51–63 (1999).

    Google Scholar 

  30. Bain, J., McLauchlan, H., Elliott, M. & Cohen, P. The specificities of protein kinase inhibitors: an update. Biochem. J. 371, 199–204 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Phiel, C. J. & Klein, P. S. Molecular targets of lithium action. Annu. Rev. Pharmacol. Toxicol. 41, 789–913 (2001).

    CAS  PubMed  Google Scholar 

  32. Kunick, C., Lauenroth, K., Leost, M., Meijer, L. & Lemcke, T. 1-Azakenpaullone is a selective inhibitor of glycogen synthase kinase-3β. Bioorg. Med. Chem. Lett. 14, 413–416 (2004).

    CAS  PubMed  Google Scholar 

  33. Conde, S., Pérez, D. I., Martínez, A., Perez, C. & Moreno, F. J. Thienyl and phenyl α-halomethyl ketones: new inhibitors of glycogen synthase kinase (GSK-3β) from a library of compound searching. J. Med. Chem. 46, 4631–4633 (2003).

    CAS  PubMed  Google Scholar 

  34. Cline, G. W. et al. Effects of a novel glycogen synthase kinase-3 inhibitor on insulin-stimulated glucose metabolism in Zucker Diabetic Fatty (fa/fa) rats. Diabetes 51, 2903–2910 (2003). The first paper demonstrating that a potent and specific GSK3 inhibitor can normalize blood glucose levels in an animal model of type 2 diabetes. The study also indicated that GSK3 is unlikely to regulate glucose uptake into muscle and that the blood-glucose-lowering effects of GSK3 inhibitors are largely confined to the liver.

    Google Scholar 

  35. Ring D. B. et al. Selective glycogen synthase kinase-3 inhibitors potentiate insulin activation of glucose transport and utilisation in vitro and in vivo. Diabetes 52, 588–595 (2003). This paper describes the most potent and specific inhibitors of GSK3 whose structures have been reported so far. It also established their blood-glucose-lowering effects in both acute and more chronic experiments and in several animal models of type 2 diabetes.

    CAS  PubMed  Google Scholar 

  36. Bhat, R. et al. Structural insights and biological effects of glycogen synthase kinase 3-specific inhibitor AR-A014418. J. Biol. Chem. 278, 45937–45945 (2003). Description of another potent and specific GSK3 inhibitor, which confirmed that such compounds have the ability to suppress neuronal apoptosis. The three-dimensional structure of GSK3 complexed to this inhibitor was also reported.

    CAS  PubMed  Google Scholar 

  37. Kuo, G. -H. et al. Synthesis and discovery of macrocyclic polyoxygenated bis-7-azaindolylmaleimides as a novel series of potent and highly selective glycogen synthase kinase-3β inhibitors. J. Med. Chem. 46, 4021–4031 (2003).

    CAS  PubMed  Google Scholar 

  38. Bae, S. S., Cho, H., Mu, J. & Birnbaum, M. J. Isoform-specific regulation of insulin-dependent glucose uptake by Akt/protein kinase B. J. Biol. Chem. 278, 49530–49536 (2003).

    CAS  PubMed  Google Scholar 

  39. MacAulay, K. et al. Use of lithium and SB-415286 to explore the role of glycogen synthase kinase-3 in the regulation of glucose transport and glycogen synthase. Eur. J. Biochem. 270, 3829–3838 (2003).

    CAS  PubMed  Google Scholar 

  40. Lee, V. M.-Y., Goedert, M. & Trojanowski, J. Q. Neurodegenerative tauopathies. Annu. Rev. Neurosci. 24, 1121–1159 (2001).

    CAS  PubMed  Google Scholar 

  41. Annaert, W. & De Strooper, B. A cell biological perspective on Alzheimer's disease. Annu. Rev. Cell Dev. Biol. 18, 25–51 (2002).

    CAS  PubMed  Google Scholar 

  42. Sun, X. et al. Lithium inhibits amyloid secretion in COS7 cells transfected with amyloid precursor protein C100. Neurosci. Lett. 321, 61–64 (2002).

    CAS  PubMed  Google Scholar 

  43. Phiel, C. J., Wilson, C. A., Lee, V. M.-Y. & Klein, P. S. GSK-3α regulates production of Alzheimer's disease amyloid-β peptides. Nature 423, 435–439 (2003).

    CAS  PubMed  Google Scholar 

  44. Ryder, J. et al. Divergent roles of GSK3 and CDK5 in APP processing. Biochem. Biophys. Res. Commun. 312, 922–929 (2003). References 42–44 demonstrate that GSK3 increases β-amyloid production and that lithium chloride and kenpaullone can reduce β-amyloid levels.

    CAS  PubMed  Google Scholar 

  45. Goate, A. et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 349, 704–706 (1991).

    CAS  PubMed  Google Scholar 

  46. Sherrington, R. E. et al. (1995) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature 375, 754–760.

    CAS  PubMed  Google Scholar 

  47. Levy-Lahad, E. W. et al. Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science 269, 970–973 (1995).

    CAS  PubMed  Google Scholar 

  48. Rogaev, E. I. et al. Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature 376, 775–778 (1995).

    CAS  PubMed  Google Scholar 

  49. Selkoe, D. J. & Schenk, D. Alzheimer's disease: Molecular understanding predicts amyloid-based therapeutics. Annu. Rev. Pharmacol. Toxicol. 43, 545–584 (2003).

    CAS  PubMed  Google Scholar 

  50. Aplin, A. E., Gibbs, G. M., Jacobsen, J. S., Gallo, J. M. & Anderton, B. H. In vitro phosphorylation of the cytoplasmic domain of the amyloid precursor protein by glycogen synthase kinase-3β. J. Neurochem. 67, 699–707 (1996).

    CAS  PubMed  Google Scholar 

  51. Lee, M. -S. et al. (2003) APP processing is regulated by cytoplasmic phosphorylation. J. Cell Biol. 163, 83–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Poorkaj, P. et al. (1998) Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann. Neurol. 43, 815–825.

    CAS  PubMed  Google Scholar 

  53. Hutton, M. et al. (1998) Association of missense and 5'-splice site mutations in tau with the inherited dementia FTDP-17. Nature 393, 702–705.

    CAS  PubMed  Google Scholar 

  54. Spillantini, M. G. et al. Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc. Natl. Acad. Sci. USA 95, 7737–7741 (1998).

    CAS  PubMed  Google Scholar 

  55. Hanger, D. P., Hughes, K., Woodgett, J. R., Brion, J. P. & Anderton, B. H. Glycogen synthase kinase-3 induces Alzheimer's disease-like phosphorylation of tau: generation of paired helical filament epitopes and neuronal localisation of the kinase. Neurosci. Lett. 147, 58–62 (1992).

    CAS  PubMed  Google Scholar 

  56. Mandelkow, E. M. et al. Glycogen synthase kinase-3 and the Alzheimer-like state of microtubule-associated protein tau. FEBS Lett. 314, 315–321 (1992).

    CAS  PubMed  Google Scholar 

  57. Lovestone, S. et al. (1994) Alzheimer's disease-like phosphorylation of the microtubule-associated protein tau by glycogen synthase kinase-3 in transfected mammalian cells. Curr. Biol. 4, 1077–1086.

    CAS  PubMed  Google Scholar 

  58. Sperber, B. R., Leight, S., Goedert, M. & Lee, V. M. -Y. (1995) Glycogen synthase kinase-3β phosphorylates tau protein at multiple sites in intact cells. Neurosci. Lett. 197, 149–153.

    CAS  PubMed  Google Scholar 

  59. Ishiguro, K. et al. Phosphorylation sites on tau by protein kinase I, a bovine-derived kinase generating an epitope of paired helical filaments. Neurosci. Lett. 148, 202–206 (1992).

    CAS  PubMed  Google Scholar 

  60. Goedert, M. et al. Epitope mapping of monoclonal antibodies to the paired helical filaments of Alzheimer's disease: identification of phosphorylation sites in tau protein. Biochem. J. 301, 871–877 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Hasegawa, M. et al. Characterization of mAb AP422, a novel phosphorylation-dependent monoclonal antibody against tau protein. FEBS Lett. 384, 25–30 (1996).

    CAS  PubMed  Google Scholar 

  62. Hong, M., Chen, D. C., Klein, P. S. & Lee, V. M. -Y. Lithium reduces tau phosphorylation by inhibition of glycogen synthase kinase-3. J. Biol. Chem. 272, 25326–25332 (1997).

    CAS  PubMed  Google Scholar 

  63. Munoz-Montano, J. R., Moreno, F. J., Avila, J. & Diaz-Nido, J. Lithium inhibits Alzheimer's disease-like tau protein phosphorylation in neurons. FEBS Lett. 411, 183–188 (1997). References 62 and 63 show that exposure to lithium chloride reduces tau phosphorylation in nerve cells.

    CAS  PubMed  Google Scholar 

  64. Spittaels, K. et al. Glycogen synthase kinase-3β phosphorylates protein tau and rescues the axonopathy in the central nervous system of human four-repeat tau transgenic mice. J. Biol. Chem. 275, 41340–41349 (2000).

    CAS  PubMed  Google Scholar 

  65. Lucas, J. J. et al. Decreased nuclear β-catenin, tau hyperphosphorylation and neurodegeneration in GSK-3β conditional transgenic mice. EMBO J. 20, 27–39 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Jackson, G. R. et al. Human wild-type tau interacts with wingless pathway components and produces neurofibrillary pathology in Drosophila. Neuron 34, 509–519 (2002).

    CAS  PubMed  Google Scholar 

  67. Pérez, M., Hernández, F., Lim, F., Diaz-Nido & Avila, J. Chronic lithium treatment decreases mutant tau protein aggregation in a transgenic mouse model. J. Alzheimer's Res. 5, 301–308 (2003).

    Google Scholar 

  68. Lim, F., Hernández, F., Lucas, J. J., Gomez-Ramos, P., Moran, M. A. & Avila, J. (2001) FTDP-17 mutations in tau transgenic mice provoke lysosomal abnormalities and tau filaments in forebrain. Mol. Cell. Neurosci. 18, 702–714.

    CAS  PubMed  Google Scholar 

  69. Lewis, J. et al. Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nature Genet. 25, 402–405 (2000).

    CAS  PubMed  Google Scholar 

  70. Allen, B. et al. Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein. J. Neurosci. 22, 9340–9351 (2002).

    CAS  PubMed  Google Scholar 

  71. Hernández, F. et al. Glycogen synthase kinase-3 plays a crucial role in tau exon 10 splicing and intranuclear distribution of SC35. J. Biol. Chem. 279, 3801–3806 (2004). Exposure of cultured nerve cells to lithium chloride or AR-A014418 was found to increase the relative proportion of exon-10-containing tau transcripts. It suggests that chronic inhibition of GSK3 might lead to a relative overproduction of four-repeat tau in human brain.

    PubMed  Google Scholar 

  72. The Huntington's Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 72, 971–983 (1993).

  73. Davies, S. W. et al. Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 90, 537–548 (1997).

    CAS  PubMed  Google Scholar 

  74. Carmichael, J., Sugars, K. L., Bao, Y. P. & Rubinsztein, D. C. Glycogen synthase kinase-3β inhibitors prevent cellular polyglutamine toxicity caused by the Huntington's disease mutation. J. Biol. Chem. 277, 33791–33798 (2002).

    CAS  PubMed  Google Scholar 

  75. Plotkin, B., Kaidanovich, O., Talior, I. & Eldar-Finkelman, H. Insulin mimetic action of synthetic phosphorylated peptide inhibitors of glycogen synthase kinase-3. J. Pharmacol. Exp. Therap. 305, 974–980 (2003).

    CAS  Google Scholar 

  76. Pap, M. & Cooper, G. M. Role of glycogen synthase kinase-3 in the phosphatidylinositol 3-kinase/Akt cell survival pathway. J. Biol. Chem. 273, 19929–19932 (1998).

    CAS  PubMed  Google Scholar 

  77. Cross, D. A. E. et al. Selective small molecule inhibitors of glycogen synthase kinase-3 activity protect primary neurones from death. J. Neurochem. 77, 94–102 (2001).

    CAS  PubMed  Google Scholar 

  78. Cade, J. Lithium salts in the treatment of psychotic excitement. Med. J. Aust. 2, 349–352 (1949).

    CAS  PubMed  Google Scholar 

  79. Zhu, A. J. & Watt, F. M. β-Catenin signalling modulates proliferative potential of human epidermal keratinocytes independently of intercellular adhesion. Development 126, 2285–2298 (1999).

    CAS  PubMed  Google Scholar 

  80. Davis, S. T. et al. Prevention of chemotherapy-induced alopecia in rats by CDK inhibitors. Science 291, 134–137 (2001).

    CAS  PubMed  Google Scholar 

  81. Polakis, P. Wnt signaling and cancer. Genes Dev. 14, 1837–1851 (2000).

    CAS  PubMed  Google Scholar 

  82. Harada, N, et al. Intestinal polyposis in mice with a dominant stable mutation of the β-catenin gene. EMBO. J. 18, 5931–5942 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Morton, S., Davis, R. J., McLaren, A. & Cohen, P. A reinvestigation of the multisite phosphorylation of the transcription factor c-Jun. EMBO J. 22, 3876–3886 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Cohen, Y. et al. Cancer morbidity in psychiatric patients: influence of lithium carbonate treatment. Med. Oncol. 15, 32–36 (1998).

    CAS  PubMed  Google Scholar 

  85. Winder, W. W. & Hardie, D. G. AMP-activated protein kinase, a metabolic master switch: possible roles in type 2 diabetes. Am. J. Physiol. 277, E1–10 (1999).

    CAS  PubMed  Google Scholar 

  86. Zhou, G. et al. Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest. 108, 1167–1174 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Wang, Z., Vogelstein, B. & Kinzler, K. W. Phosphorylation of β-catenin at S33, S37 or T41 can occur in the absence of phosphorylation of T45 in colon cancer cells. Cancer Res. 63, 5234–5235 (2003).

    CAS  PubMed  Google Scholar 

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DATABASES

Entrez Gene

APC

APH1

APP

axin

β-catenin

BACE

dishevelled

FRAT

glycogen synthase

GSK3

huntingtin

IRS1

nicastrin

PEN2

presenilin

Online Mendelian Inheritance in Man

Alzheimer's disease

familial frontotemporal dementia

Huntington's disease

Pick's disease

progressive supranuclear palsy

Glossary

ZUCKER DIABETIC FATTY (ZDF) RAT

A rodent with both a mutant, functionally deficient leptin receptor and a genetic defect that predisposes it to diabetes, as it becomes obese and lipid accumulates in the pancreatic islets.

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Cohen, P., Goedert, M. GSK3 inhibitors: development and therapeutic potential. Nat Rev Drug Discov 3, 479–487 (2004). https://doi.org/10.1038/nrd1415

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