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The role of GSK3 in cell signaling

Here we review the role of GSK3 in insulin, wnt, reelin, and Hedgehog signaling pathways, as well as in neurodegenerative and neurological diseases.

Glycogen Synthase Kinase 3 (GSK3) exists as two distinct isoforms, GSK3α and GSK3β, derived from two independent gene loci. GSK3β also exists as longer splice variants1,2. GSK3α and GSK3β are constitutively active, proline-directed serine/threonine kinases involved in various cellular processes, including glycogen metabolism3, gene transcription4, apoptosis5, and microtubule stability6,7. 

GSK3 activity is negatively regulated by the insulin, wnt, and reelin signaling pathways. Also, GSK3  plays a pivotal role in the hedgehog signaling cascade. Many, but not all, GSK3 substrates require pre-phosphorylation (priming) before phosphorylation by GSK3 can occur.

Insulin signaling

Insulin signaling activates phosphatidylinositol 3-kinase (PI3-kinase). PI3-kinase is a lipid kinase comprising a regulatory subunit (p85) and a catalytic subunit (p110)8,9. The catalytic subunit of PI3-kinase phosphorylates PtdIns(4,5)P2 leading to the formation of PtdIns(3,4,5)P3.

A key downstream effector of PtdIns(3,4,5)P3 is AKT (otherwise known as Protein kinase B: PKB), which is recruited to the plasma membrane. Activation of AKT requires the protein kinase 3-phosphoinositide-dependent protein kinase-1 (PDPK1), which, combined with an as-yet unidentified kinase, leads to the phosphorylation of AKT.

Once active, AKT enters the cytoplasm, where it triggers the phosphorylation of free cytoplasmic GSK3β and GSK3α at serine residues 9 and 21, respectively, rendering the kinases inactive8,9. Regulatory serine phosphorylation results in the generation of an intra-molecular pseudo-substrate, which blocks part of the active site preventing the enzymatic activity of GSK3 towards primed substrates.

The GSK inactivation, in turn, leads to the de-phosphorylation of downstream substrates, such as glycogen synthase and eukaryotic protein synthesis initiation factor-2B (eIF-2B), eliciting an increase in glycogen and protein synthesis10. 

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Role of GSK3 in Insulin signaling

Wnt signaling

Wnt signaling regulates GSK3 activity by physically displacing complexed GSK3 from its regulatory binding partners in the so-called destruction complex, consequently preventing the phosphorylation and degradation of β-catenin.

Without Wnt, the signaling pool of β-catenin is maintained at low levels through degradation11–13. β-catenin is targeted for ubiquitination by the β-transducin repeat-containing protein (βTrCP) and is then degraded by the proteasome. β-catenin is phosphorylated by the serine/threonine kinases, casein kinase 1 (CK1) and GSK3β. Phosphorylation of β-catenin occurs in a multi-protein complex (the destruction complex) comprising axin, adenomatous polyposis coli (APC), and diversin. 

Wnt ligands bind to Frizzled/LRP5-6 receptor complexes at the cell surface, which couple to disheveled, inducing the recruitment of GBP/FRAT1 to the destruction complex, which in turn displaces GSK3β; precluding the phosphorylation and degradation of β-catenin. Stabilized β-catenin is then free to enter the nucleus and associates with T cell factor (TCF)/lymphoid enhancer factor (LEF) transcription factors, leading to the transcription of Wnt target genes. 

GSK3α and GSK3β can function in the Wnt signaling pathway and destruction complex, suggesting that GSK3α is equally as important in Wnt biology as GSK3β10,14. GSK3β and GSK3α can also be regulated by tyrosine (Tyr) phosphorylation at residues 216 or 279, respectively. Normally, GSK3 is phosphorylated at these sites; however, increases in Tyr phosphorylation augment GSK3 activity15,16.

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Role of GSK3 in Wnt signaling

Reelin signaling

Reelin binds to the very-low-density lipoprotein receptor (VLDLR) and the Apolipoprotein E receptor 2 (APOER2) and induces the activation of disabled-1 (DAB1), a cytoplasmic adaptor protein that interacts with NPxY motifs in both receptor tails17,18.

The clustering of DAB1 activates SRC family tyrosine kinases (SFKs), which potentiates tyrosine phosphorylation of DAB1. Phosphorylated DAB1 further activates PI3-kinase and, subsequently, AKT, which in turn inhibits the activity of GSK3β. As a result, the phosphorylation of tau is reduced, thus promoting microtubule stability. 

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Role of GSK3 in Reelin signaling

Hedgehog signaling

The Hedgehog gene was first identified in Drosophila melanogaster19. In Drosophila, Hedgehog signaling is initiated by a Hedgehog ligand binding to Patched (Ptc), a 12-transmembrane protein receptor20,21. Ptc acts as an inhibitor of Smoothened (Smo), a 7-transmembrane protein.
Downstream of Smo is a multi-protein complex known as the Hedgehog signaling complex (HSC). The HSC comprises the transcription factor Cubitus interruptus (Ci), the serine/threonine kinase Fused (Fu), the kinesin-like molecule Costal 2 (Cos2), and the Suppressor of fused (Sufu). Cos2 also binds to protein kinase A (PKA), protein kinase CK1 (formerly casein kinase 1), and GSK3.
In the absence of ligand, Ptc represses Smo preventing the activation of Hedgehog signaling20,21. The HSC is bound to microtubules/membranes and associates with Smo through Cos2. The full-length form of Ci is prevented from nuclear translocation through interactions with Sufu and Cos2.
A portion of full-length Ci is proteolytically cleaved to produce a repressor form of Ci, which enters the nucleus leading to the inhibition of Hedgehog target gene expression. Proteolytic processing of Ci is mediated by PKA, CK1, and GSK3. In the presence of Hedgehog, the inhibitory effects of Ptc on Smo are relieved, and the HSC is freed from microtubules and membranes. 
Smo becomes phosphorylated by PKA and CK1. PKA, CK1 and GSK3 are then released from Cos2, precluding the generation of the repressor form of Ci. Full-length Ci is no longer inhibited by Sufu and is, therefore, free to enter the nucleus to induce the transcription of Hedgehog target genes.
The Hedgehog signaling pathways in vertebrates share many common features with Drosophila Hedgehog signaling, although distinct differences are also apparent20. In mammals, there are three Hedgehog genes, Sonic, Indian and Desert Hedgehog. There are also 2 Ptc genes (Ptc 1 and Ptc 2) and three Ci homologs, Gli1, Gli2 and Gli3. Gli1 and Gli2 are transcriptional activators, whereas Gli3 functions as a transcriptional repressor.

The Hedgehog gene was first identified in Drosophila melanogaster19. In Drosophila, Hedgehog signaling is initiated by a Hedgehog ligand binding to Patched (Ptc), a 12-transmembrane protein receptor20,21. Ptc acts as an inhibitor of Smoothened (Smo), a 7-transmembrane protein.

Downstream of Smo is a multi-protein complex known as the Hedgehog signaling complex (HSC). The HSC comprises the transcription factor Cubitus interruptus (Ci), the serine/threonine kinase Fused (Fu), the kinesin-like molecule Costal 2 (Cos2), and the Suppressor of fused (Sufu). Cos2 also binds to protein kinase A (PKA), protein kinase CK1 (formerly casein kinase 1), and GSK3.
In the absence of ligand, Ptc represses Smo preventing the activation of Hedgehog signaling20,21. The HSC is bound to microtubules/membranes and associates with Smo through Cos2. The full-length form of Ci is prevented from nuclear translocation through interactions with Sufu and Cos2.
A portion of full-length Ci is proteolytically cleaved to produce a repressor form of Ci, which enters the nucleus leading to the inhibition of Hedgehog target gene expression. Proteolytic processing of Ci is mediated by PKA, CK1, and GSK3. In the presence of Hedgehog, the inhibitory effects of Ptc on Smo are relieved, and the HSC is freed from microtubules and membranes. 
Smo becomes phosphorylated by PKA and CK1. PKA, CK1 and GSK3 are then released from Cos2, precluding the generation of the repressor form of Ci. Full-length Ci is no longer inhibited by Sufu and is, therefore, free to enter the nucleus to induce the transcription of Hedgehog target genes.
The Hedgehog signaling pathways in vertebrates share many common features with Drosophila Hedgehog signaling, although distinct differences are also apparent20. In mammals, there are three Hedgehog genes, Sonic, Indian and Desert Hedgehog. There are also 2 Ptc genes (Ptc 1 and Ptc 2) and three Ci homologs, Gli1, Gli2 and Gli3. Gli1 and Gli2 are transcriptional activators, whereas Gli3 functions as a transcriptional repressor.

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Role of GSK3 in Hedgehog signaling

GSK3 in neurodegenerative and neurological disorders

GSK3 plays a pivotal role in the pathology of Alzheimer’s disease (AD), being involved in memory impairment at the synaptic level, tau hyper-phosphorylation and neurofibrillary tangle formation (NFT) as well as the increased production of β-amyloid (Aβ) and hence senile plaque deposition22.

GSK3 displays enhanced activity in the frontal cortex in AD23 and is up-regulated in peripheral lymphocytes in both AD and mild cognitive impairment (MCI)24. GSK3 is also implicated in the pathology of Schizophrenia and psychosis25.

The neurotransmitter dopamine regulates GSK3. Augmented dopamine levels lead to the reduction of inhibitory serine phosphorylation of GSK3, increasing its enzymatic activity, a phenomenon mediated by D2 receptors26,27. D2 receptors stimulate the assembly of a complex containing β-arrestin 2, protein phosphatase 2A (PP2A), AKT, and probably GSK3. PP2A negatively regulates AKT, which in turn augments GSK3 activity.


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Role of GSK3 in Alzheimer

References

  1. Mukai F., Ishiguro K., Sano Y. and Fujita S. C. (2002) Alternative splicing isoform of tau protein kinase I/glycogen synthase kinase 3beta. J. Neurochem. 81, 1073-1083.

  2. Schaffer B., Wiedau-Pazos M. and Geschwind D. H. (2003) Gene structure and alternative splicing of glycogen synthase kinase 3 beta (GSK-3beta) in neural and non-neural tissues. Gene 302, 73-81.

  3. Welsh G. I., Proud C. G. (1993). Glycogen synthase kinase-3 is rapidly inactivated in response to insulin and phosphorylates eukaryotic initiation factor eIF-2B. Biochem. J. 294, 625-629.

  4. Troussard A. A., Tan C., Yoganathan T. N. and Dedhar S. (1999) Cell-extracellular matrix interactions stimulate the AP-1 transcription factor in an integrin-linked kinase- and glycogen synthase kinase 3-dependent manner. Mol. Cell Biol. 19, 7420-7427.

  5. Turenne G. A., Price B. D. (2001). Glycogen synthase kinase3 beta phosphorylates serine 33 of p53 and activates p53's transcriptional activity. BMC Cell Biol. 2, 1471-2121.

  6. Anderton B. H., Betts J., Blackstock W. P., Brion J. P., Chapman S., Connell J., Dayanandan R., Gallo J. M., Gibb G., Hanger D. P., Hutton M., Kardalinou E., Leroy K., Lovestone S., Mack T., Reynolds C. H. and Van S. M. (2001) Sites of phosphorylation in tau and factors affecting their regulation. Biochem. Soc. Symp. 73-80.

  7. Brion J. P., Anderton B. H., Authelet M., Dayanandan R., Leroy K., Lovestone S., Octave J. N., Pradier L., Touchet N. and Tremp G. (2001) Neurofibrillary tangles and tau phosphorylation. Biochem. Soc. Symp. 81-88.

  8. Saltiel A. R., Kahn C. R. (2001). Insulin signaling and the regulation of glucose and lipid metabolism. Nature 414, 799-806.

  9. Lizcano J. M., Alessi D. R. (2002). The insulin signaling pathway. Curr. Biol. 12: 236-238.

  10. Doble B. W., Woodgett J. R. (2003) GSK-3: tricks of the trade for a multi-tasking kinase. J. Cell Sci. 116, 1175-1186.

  11. Dale T. C. (1998). Signal transduction by the Wnt family of ligands. Biochem. J. 329, 209-223.

  12. Huelsken J, Behrens J. 2002. The Wnt signalling pathway. J. Cell Sci. 115:3977-3978.

  13. Nusse R. (2005) Wnt signaling in disease and development. Cell Res. 15, 28-32.

  14. Asuni A. A., Hooper C., Reynolds C. H., Lovestone S., Anderton B. H. and Killick R. (2006) GSK3alpha exhibits beta-catenin and tau directed kinase activities that are modulated by Wnt. Eur. J. Neurosci. 24, 3387-3392.

  15. Bhat R. V., Budd Haeberlein S. L., Avila J. (2004) Glycogen synthase kinase 3: a drug target for CNS therapies. J. Neurochem. 89, 1313-1317.

  16. Bijur G. N. and Jope R. S. (2001) Proapoptotic stimuli induce nuclear accumulation of glycogen synthase kinase-3 beta. J. Biol. Chem. 276, 37436-37442.

  17. Herz J., Chen Y. (2006) Reelin, lipoprotein receptors and synaptic plasticity. Nature Rev. Neurosci. 7, 850-859.

  18. Tissir F., Goffinet A. M. (2003) Reelin and brain development. Nat. Rev. Neurosci. 4, 496-505.

  19. Nusslein-Volhard C., Wieschaus E. (1980) Mutations affecting segment number and polarity in Drosophila. Nature 287, 795-801.

  20. Hooper J. E. Scott M . P. (2005) Communicating with Hedgehogs. Nat. Rev. Mol. Cell Biol. 6, 306-317.

  21. Østerlund T., Kogerman P. (2006) Hedgehog signalling: how to get from Smo to Ci and Gli. Trends in Cell. Biol. 16, 176-180.

  22. Hooper C., Killick R., Lovestone S. (2008) The GSK3 hypothesis of Alzheimer's disease. J. Neurochem. 104, 1433-1439.

  23. Leroy K., Yilmaz Z. and Brion J. P. (2007) Increased level of active GSK-3beta in Alzheimer's disease and accumulation in argyrophilic grains and in neurones at different stages of neurofibrillary degeneration. Neuropathol. Appl. Neurobiol. 33, 43-55.

  24. Hye A., Kerr F., Archer N., Foy C., Poppe M., Brown R., Hamilton G., Powell J., Anderton B. and Lovestone S. (2005) Glycogen synthase kinase-3 is increased in white cells early in Alzheimer's disease. Neurosci. Lett. 373, 1-4.

  25. Lovestone S., Killick R., Di Forti M., Murray R. (2007) Schizophrenia as a GSK3 dysregulation disorder. Trends Neurosci. 30, 142-149.

  26. Beaulieu J. M., Sotnikova T. D., Yao W. D., Kockeritz L., Woodgett J. R., Gainetdinov R. R. and Caron M. G. (2004) Lithium antagonizes dopamine-dependent behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade. Proc. Natl. Acad. Sci U. S. A. 101, 5099-5104.

  27. Beaulieu J. M., Gainetdinov R. R. and Caron M. G. (2007) The Akt-GSK-3 signaling cascade in the actions of dopamine. Trends in Pharmacological Sciences 28, 166-172.