Gene Symbol: Gsk3a
Description: glycogen synthase kinase 3 alpha
Alias: glycogen synthase kinase-3 alpha, GSK-3 alpha, factor A, serine/threonine-protein kinase GSK3A
Species: rat
Products:     Gsk3a

Top Publications

  1. Cross D, Alessi D, Cohen P, Andjelkovich M, Hemmings B. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature. 1995;378:785-9 pubmed
    ..Like the inhibition of GSK3 (refs 10, 14), the activation of PKB is prevented by inhibitors of phosphatidylinositol (PI) 3-kinase. ..
  2. Smillie K, Pawson J, Perkins E, Jackson M, Cousin M. Control of synaptic vesicle endocytosis by an extracellular signalling molecule. Nat Commun. 2013;4:2394 pubmed publisher
    ..Thus, synaptic strength can be modulated by extracellular signalling molecules via a direct inhibition of a synaptic vesicle endocytosis mode. ..
  3. Maurer U, Charvet C, Wagman A, Dejardin E, Green D. Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1. Mol Cell. 2006;21:749-60 pubmed
    ..The results demonstrate that the control of MCL-1 stability by GSK-3 is an important mechanism for the regulation of apoptosis by growth factors, PI3K, and AKT. ..
  4. Rezai Zadeh K, Douglas Shytle R, Bai Y, Tian J, Hou H, Mori T, et al. Flavonoid-mediated presenilin-1 phosphorylation reduces Alzheimer's disease beta-amyloid production. J Cell Mol Med. 2009;13:574-88 pubmed publisher
    ..We suggest that GSK-3 inhibition is a viable therapeutic approach for AD by impacting PS1 phosphorylation-dependent regulation of amyloidogenesis. ..
  5. Oh J, Kim Y, Che L, Kim J, Chang G, Cheong E, et al. Regulation of cAMP and GSK3 signaling pathways contributes to the neuronal conversion of glioma. PLoS ONE. 2017;12:e0178881 pubmed publisher
  6. Zhai P, Gao S, Holle E, Yu X, Yatani A, Wagner T, et al. Glycogen synthase kinase-3alpha reduces cardiac growth and pressure overload-induced cardiac hypertrophy by inhibition of extracellular signal-regulated kinases. J Biol Chem. 2007;282:33181-91 pubmed
    ..The anti-hypertrophic and pro-apoptotic effect of GSK-3alpha is mediated through inhibition of ERK. ..
  7. Ciaraldi T, Nikoulina S, Bandukwala R, Carter L, Henry R. Role of glycogen synthase kinase-3 alpha in insulin action in cultured human skeletal muscle cells. Endocrinology. 2007;148:4393-9 pubmed
    ..We conclude that GSK3alpha is an important regulator of muscle insulin action. ..
  8. Vertino A, Taylor Jones J, Longo K, Bearden E, Lane T, McGehee R, et al. Wnt10b deficiency promotes coexpression of myogenic and adipogenic programs in myoblasts. Mol Biol Cell. 2005;16:2039-48 pubmed
    ..Thus, alteration in Wnt signaling in myoblasts with age may contribute to impaired muscle regenerative capacity and to increased muscle adiposity, both characteristic of aged muscle. ..
  9. Lajoie C, Calderone A, Trudeau F, Lavoie N, Massicotte G, Gagnon S, et al. Exercise training attenuated the PKB and GSK-3 dephosphorylation in the myocardium of ZDF rats. J Appl Physiol (1985). 2004;96:1606-12 pubmed
    ..These anomalies in the Zucker diabetic fatty rat were partially normalized with swimming. These data support the premise that exercise training may protect the heart against the deleterious consequences of diabetes. ..

More Information


  1. Spokoini R, Kfir Erenfeld S, Yefenof E, Sionov R. Glycogen synthase kinase-3 plays a central role in mediating glucocorticoid-induced apoptosis. Mol Endocrinol. 2010;24:1136-50 pubmed publisher
    ..Our data suggest that targeting protein kinases involved in GSK3 inactivation should improve the outcome of GC therapy. ..
  2. Hughes K, Nikolakaki E, Plyte S, Totty N, Woodgett J. Modulation of the glycogen synthase kinase-3 family by tyrosine phosphorylation. EMBO J. 1993;12:803-8 pubmed
    ..However, unlike MAP kinases, GSK-3 is highly phosphorylated on tyrosine and thus active in resting cells. ..
  3. Sequea D, Sharma N, Arias E, Cartee G. Greater filamin C, GSK3?, and GSK3? serine phosphorylation in insulin-stimulated isolated skeletal muscles of calorie restricted 24 month-old rats. Mech Ageing Dev. 2013;134:60-3 pubmed publisher
    ..These results indicate that CR does not uniformly affect insulin-mediated phosphorylation of Akt substrates in fast- or slow-twitch muscles from 24 month-old rats. ..
  4. Hu J, Zhang H, Wagey R, Krieger C, Pelech S. Protein kinase and protein phosphatase expression in amyotrophic lateral sclerosis spinal cord. J Neurochem. 2003;85:432-42 pubmed
    ..G protein-coupled receptor kinase 2 (GRK2; C = 140% increase/P = 140% increase), phospho-Y279/216 glycogen synthase kinase 3 alpha/beta (GSK3alpha/beta; C = 90% increase/P = 220% increase), protein kinase B alpha (PKBalpha; C = 360% ..
  5. Li M, Li X, Zhang X, Ren J, Jiang H, Wang Y, et al. Effects of prenatal chronic mild stress exposure on hippocampal cell proliferation, expression of GSK-3?, ? and NR2B in adult offspring during fear extinction in rats. Int J Dev Neurosci. 2014;35:16-24 pubmed publisher
    ..Taken together, our findings suggest that maternal stress during pregnancy can impair the fear extinction of adult offspring, probably by affecting the neural plasticity of brain. ..
  6. Rao P, Pugazhenthi S, Khandelwal R. Insulin decreases the glycogen synthase kinase-3 alpha mRNA levels by altering its stability in streptozotocin-induced diabetic rat liver. Biochem Biophys Res Commun. 1995;217:250-6 pubmed
    ..This study suggests that the chronic effect of insulin decreases the levels of glycogen synthase kinase-3 alpha mRNA by altering its stability. ..
  7. Azoulay Alfaguter I, Yaffe Y, Licht Murava A, Urbanska M, Jaworski J, Pietrokovski S, et al. Distinct molecular regulation of glycogen synthase kinase-3alpha isozyme controlled by its N-terminal region: functional role in calcium/calpain signaling. J Biol Chem. 2011;286:13470-80 pubmed publisher
    ..We further uncovered a novel link between calcium and nuclear GSK-3?-mediated inhibition of the canonical Wnt/?-catenin pathway. ..
  8. Abaffy T, Cooper G. GSK3 involvement in amylin signaling in isolated rat soleus muscle. Peptides. 2004;25:2119-25 pubmed
    ..2:1. We found that amylin increased GSK3alpha activity, which in turn led to increased phosphorylation of glycogen synthase and decreased glycogen synthesis de novo. ..
  9. Lu F, Su P, Liu F, Daskalakis Z. Activation of GABA(B) receptors inhibits protein kinase B/glycogen synthase kinase 3 signaling. Mol Brain. 2012;5:41 pubmed publisher
    ..Our data may help to identify potentially novel targets through which GABA(B) receptor agents may exert therapeutic effects in the treatment of schizophrenia. ..
  10. Waraich R, Weigert C, Kalbacher H, Hennige A, Lutz S, Haring H, et al. Phosphorylation of Ser357 of rat insulin receptor substrate-1 mediates adverse effects of protein kinase C-delta on insulin action in skeletal muscle cells. J Biol Chem. 2008;283:11226-33 pubmed publisher
    ..Together, these data suggest that phosphorylation of Ser(357) mediates at least in part the adverse effects of PKC-delta activation on insulin action. ..
  11. Barton Pai A, Feleder C, Johnson A. Tumor necrosis factor-? induces increased lung vascular permeability: a role for GSK3?/?. Eur J Pharmacol. 2011;657:159-66 pubmed publisher
    ..The data indicates that pharmacologic inhibition of GSK3? inhibits TNF induced increased endothelial permeability associated with lung inflammation. ..
  12. Lizárraga Mollinedo E, Fernández Millán E, de Miguel Santos L, Martínez Honduvilla C, Alvarez C, Escriva F. Early undernutrition increases glycogen content and reduces the activated forms of GSK3, AMPK, p38 MAPK, and JNK in the cerebral cortex of suckling rats. J Neurochem. 2010;112:123-33 pubmed publisher
    ..Thus, our results indicate that undernutrition gives rise to molecular alterations that may have repercussions on cerebral cortex development and functions. ..
  13. Markou T, Cullingford T, Giraldo A, Weiss S, Alsafi A, Fuller S, et al. Glycogen synthase kinases 3alpha and 3beta in cardiac myocytes: regulation and consequences of their inhibition. Cell Signal. 2008;20:206-18 pubmed
  14. Liang M, Chuang D. Differential roles of glycogen synthase kinase-3 isoforms in the regulation of transcriptional activation. J Biol Chem. 2006;281:30479-84 pubmed
    ..The development of GSK-3 isoform-specific inhibitors is thus crucial for therapeutic intervention of GSK-3-related neuropathological conditions. ..
  15. Oh M, Kim H, Yang I, Park J, Cong W, Baek M, et al. GSK-3 phosphorylates delta-catenin and negatively regulates its stability via ubiquitination/proteosome-mediated proteolysis. J Biol Chem. 2009;284:28579-89 pubmed publisher
    ..These results suggest that GSK-3 interacts with and phosphorylates delta-catenin and thereby negatively affects its stability by enabling its ubiquitination/proteosome-mediated proteolysis. ..
  16. Seo Y, Jung H, Shin H, Kim Y, Yim H, Chung H, et al. Enhanced glycogenesis is involved in cellular senescence via GSK3/GS modulation. Aging Cell. 2008;7:894-907 pubmed publisher
  17. Yamamoto H, Yoo S, Nishita M, Kikuchi A, Minami Y. Wnt5a modulates glycogen synthase kinase 3 to induce phosphorylation of receptor tyrosine kinase Ror2. Genes Cells. 2007;12:1215-23 pubmed
    ..Moreover, it was found that Wnt5a-induced cell migration can be inhibited by SB216763 or by siRNA-mediated suppression of GSK-3alpha (and GSK-3beta) expression, further emphasizing the role(s) of GSK-3 in Wnt5a-induced signaling. ..
  18. Zheng W, Kar S, Quirion R. Insulin-like growth factor-1-induced phosphorylation of the forkhead family transcription factor FKHRL1 is mediated by Akt kinase in PC12 cells. J Biol Chem. 2000;275:39152-8 pubmed
  19. Phiel C, Wilson C, Lee V, Klein P. GSK-3alpha regulates production of Alzheimer's disease amyloid-beta peptides. Nature. 2003;423:435-9 pubmed
  20. Bennett C, Ross S, Longo K, Bajnok L, Hemati N, Johnson K, et al. Regulation of Wnt signaling during adipogenesis. J Biol Chem. 2002;277:30998-1004 pubmed
    ..Finally, we demonstrate that disruption of extracellular Wnt signaling by expression of secreted Frizzled related proteins causes spontaneous adipocyte conversion. ..
  21. Hurtado D, Molina Porcel L, Carroll J, Macdonald C, Aboagye A, Trojanowski J, et al. Selectively silencing GSK-3 isoforms reduces plaques and tangles in mouse models of Alzheimer's disease. J Neurosci. 2012;32:7392-402 pubmed publisher
    ..These findings highlight the potential importance of GSK-3? as a possible therapeutic target for ameliorating behavioral impairments linked to AD SPs and NFTs. ..
  22. Song J, Salek Ardakani S, Rogers P, Cheng M, Van Parijs L, Croft M. The costimulation-regulated duration of PKB activation controls T cell longevity. Nat Immunol. 2004;5:150-8 pubmed
    ..Thus, sustained and periodic PKB signaling has an integral role in regulating T cell longevity. ..
  23. Koo J, Wu X, Mao Z, Khuri F, Sun S. Rictor Undergoes Glycogen Synthase Kinase 3 (GSK3)-dependent, FBXW7-mediated Ubiquitination and Proteasomal Degradation. J Biol Chem. 2015;290:14120-9 pubmed publisher
    ..Hence we suggest that PI3K/Akt signaling may positively regulate mTORC2 signaling, likely through suppressing GSK3-dependent rictor degradation. ..
  24. Tan M, Ma S, Huang Q, Hu K, Song B, Li M. GSK-3?/?-mediated phosphorylation of CRMP-2 regulates activity-dependent dendritic growth. J Neurochem. 2013;125:685-97 pubmed publisher
    ..This data indicate that CRMP-2 functions downstream of GSK-3. Together, these findings identify a novel GSK-3/CRMP-2 pathway that connects neuronal activity to dendritic growth. ..
  25. Popkie A, Zeidner L, Albrecht A, D Ippolito A, Eckardt S, Newsom D, et al. Phosphatidylinositol 3-kinase (PI3K) signaling via glycogen synthase kinase-3 (Gsk-3) regulates DNA methylation of imprinted loci. J Biol Chem. 2010;285:41337-47 pubmed publisher
    ..Finally, we find that N-Myc is a potent Gsk-3-dependent regulator of Dnmt3a2 expression. In summary, we have identified a signal transduction pathway that is capable of altering the DNA methylation of imprinted loci. ..
  26. Forde J, Dale T. Glycogen synthase kinase 3: a key regulator of cellular fate. Cell Mol Life Sci. 2007;64:1930-44 pubmed
    ..The details of these mechanisms will be discussed in the context of specific signalling pathways. ..
  27. Zhou J, Lal H, Chen X, Shang X, Song J, Li Y, et al. GSK-3alpha directly regulates beta-adrenergic signaling and the response of the heart to hemodynamic stress in mice. J Clin Invest. 2010;120:2280-91 pubmed publisher
    ..b>Gsk3a(-/-) mice over 2 months of age developed progressive cardiomyocyte and cardiac hypertrophy and contractile ..
  28. Morris J, Zhang H, Gupte A, Bomhoff G, Stanford J, Geiger P. Measures of striatal insulin resistance in a 6-hydroxydopamine model of Parkinson's disease. Brain Res. 2008;1240:185-95 pubmed publisher
    ..Together, these results support the hypothesis that nigrostriatal DA depletion impairs insulin signaling in the basal ganglia. ..
  29. Hoshi M, Sato M, Kondo S, Takashima A, Noguchi K, Takahashi M, et al. Different localization of tau protein kinase I/glycogen synthase kinase-3 beta from glycogen synthase kinase-3 alpha in cerebellum mitochondria. J Biochem. 1995;118:683-5 pubmed
    ..Although the two GSK-3 isoforms seem to have similar properties, the difference of subcellular localization observed here suggests that TPKI/GSK-3 beta fulfills some specific function in mitochondria. ..
  30. Cai X, Li M, Vrana J, Schaller M. Glycogen synthase kinase 3- and extracellular signal-regulated kinase-dependent phosphorylation of paxillin regulates cytoskeletal rearrangement. Mol Cell Biol. 2006;26:2857-68 pubmed
    ..Hence, phosphorylation of paxillin on serines 126 and 130, which is mediated by an ERK/GSK-3 dual-kinase mechanism, plays an important role in cytoskeletal rearrangement. ..
  31. Song B, Lai B, Zheng Z, Zhang Y, Luo J, Wang C, et al. Inhibitory phosphorylation of GSK-3 by CaMKII couples depolarization to neuronal survival. J Biol Chem. 2010;285:41122-34 pubmed publisher
    ..Furthermore, the pro-survival effect of CaMKII was mediated by GSK-3 phosphorylation and inactivation. These findings identify a novel Ca(2+)/calmodulin/CaMKII/GSK-3 pathway that couples depolarization to neuronal survival. ..
  32. Fang X, Yu S, Lu Y, Bast R, Woodgett J, Mills G. Phosphorylation and inactivation of glycogen synthase kinase 3 by protein kinase A. Proc Natl Acad Sci U S A. 2000;97:11960-5 pubmed
  33. Peineau S, Nicolas C, Bortolotto Z, Bhat R, Ryves W, Harwood A, et al. A systematic investigation of the protein kinases involved in NMDA receptor-dependent LTD: evidence for a role of GSK-3 but not other serine/threonine kinases. Mol Brain. 2009;2:22 pubmed publisher
    ..The present study is the first to investigate the role of 58 ser/thr protein kinases in LTD in the same study. Of these 58 protein kinases, we have found evidence for the involvement of only one, GSK-3, in LTD. ..
  34. Woodgett J. Molecular cloning and expression of glycogen synthase kinase-3/factor A. EMBO J. 1990;9:2431-8 pubmed
    ..Partial purification of GSK-3 activity from bovine brain results in the isolation of active alpha and beta proteins. The physiological importance of these two proteins in cellular signal transduction is discussed. ..
  35. Cuadrado A. Structural and functional characterization of Nrf2 degradation by glycogen synthase kinase 3/β-TrCP. Free Radic Biol Med. 2015;88:147-157 pubmed publisher
    ..The GSK-3/β-TrCP axis provides a novel therapeutic strategy to modulate Nrf2 activity. ..
  36. Xiao H, Deng M, Yang B, Tang J, Hu Z. Role of glycogen synthase kinase 3 in ischemia-induced blood-brain barrier disruption in aged female rats. J Neurochem. 2017;142:194-203 pubmed publisher
    ..Thus, our study suggested that activation of ER? may protect against brain ischemia-induced BBB disruption by inhibiting GSK3?-mediated signaling. ..
  37. Kobayashi S, Nakamura T, Wakabayashi S. Calcineurin B homologous protein 3 negatively regulates cardiomyocyte hypertrophy via inhibition of glycogen synthase kinase 3 phosphorylation. J Mol Cell Cardiol. 2015;84:133-42 pubmed publisher
    ..These findings suggest that CHP3 functions as a novel negative regulator of cardiomyocyte hypertrophy via inhibition of GSK3α/β phosphorylation and subsequent enzymatic activation of GSK3α/β. ..