Glycogen synthase kinase-3 beta

Glycogen synthase kinase-3 beta, (GSK-3 beta), is an enzyme that in humans is encoded by the GSK3B gene.^[5][6] In mice, the enzyme is encoded by the Gsk3b gene.^[7] Abnormal regulation and expression of GSK-3 beta is associated with an increased susceptibility towards bipolar disorder.^[8]

GSK3B
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1GNG, 1H8F, 1I09, 1J1B, 1J1C, 1O6K, 1O6L, 1O9U, 1PYX, 1Q3D, 1Q3W, 1Q41, 1Q4L, 1Q5K, 1R0E, 1UV5, 2JDO, 2JDR, 2JLD, 2O5K, 2OW3, 2UW9, 2X39, 2XH5, 3CQU, 3CQW, 3DU8, 3E87, 3E88, 3E8D, 3F7Z, 3F88, 3GB2, 3I4B, 3L1S, 3M1S, 3MV5, 3OW4, 3PUP, 3Q3B, 3QKK, 3SAY, 3SD0, 3ZDI, 3ZRK, 3ZRL, 3ZRM, 4ACC, 4ACD, 4ACG, 4ACH, 4AFJ, 4B7T, 4DIT, 4EKK, 4IQ6, 4J1R, 4J71, 4NM0, 4NM3, 4NM5, 4NM7, 4PTC, 4PTE, 4PTG, 5F94, 5F95, 5HLP, 5HLN
Identifiers
Aliases	GSK3B, Gsk3b, 7330414F15Rik, 8430431H08Rik, C86142, GSK-3, GSK-3beta, GSK3, glycogen synthase kinase 3 beta
External IDs	OMIM: 605004; MGI: 1861437; HomoloGene: 55629; GeneCards: GSK3B; OMA:GSK3B - orthologs
EC number	2.7.11.1
Gene location (Human) Chr. Chromosome 3 (human)[1] Band 3q13.33 Start 119,821,321 bp[1] End 120,094,994 bp[1]
Gene location (Mouse) Chr. Chromosome 16 (mouse)[2] Band 16|16 B3 Start 37,909,363 bp[2] End 38,066,446 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in Achilles tendon epithelium of colon sural nerve buccal mucosa cell skin of thigh ventricular zone ganglionic eminence postcentral gyrus left testis right testis Top expressed in spermatid cumulus cell ventromedial nucleus lateral septal nucleus lateral hypothalamus mammillary body retinal pigment epithelium Rostral migratory stream lateral geniculate nucleus Region I of hippocampus proper More reference expression data BioGPS More reference expression data
Gene ontology Molecular function kinase activity ATP binding protein kinase activity protein kinase A catalytic subunit binding protein serine/threonine kinase activity transferase activity NF-kappaB binding tau-protein kinase activity protein binding nucleotide binding p53 binding ubiquitin protein ligase binding protease binding beta-catenin binding protein kinase binding dynactin binding tau protein binding Cellular component cytoplasm membrane mitochondrion nucleus centrosome plasma membrane cytosol beta-catenin destruction complex postsynapse Wnt signalosome nucleoplasm axon dendrite glutamatergic synapse Biological process rhythmic process negative regulation of type B pancreatic cell development negative regulation of protein binding negative regulation of glycogen (starch) synthase activity glycogen metabolic process superior temporal gyrus development negative regulation of canonical Wnt signaling pathway chemical synaptic transmission, postsynaptic negative regulation of protein-containing complex assembly positive regulation of protein export from nucleus positive regulation of GTPase activity protein autophosphorylation cell differentiation negative regulation of protein localization to nucleus phosphorylation positive regulation of cell-matrix adhesion nervous system development dopamine receptor signaling pathway epithelial to mesenchymal transition peptidyl-threonine phosphorylation positive regulation of protein-containing complex assembly positive regulation of neuron death negative regulation of glycogen biosynthetic process multicellular organism development regulation of cellular response to heat negative regulation of signal transduction hippocampus development beta-catenin destruction complex disassembly proteasome-mediated ubiquitin-dependent protein catabolic process Wnt signaling pathway beta-catenin destruction complex assembly protein phosphorylation positive regulation of mitochondrion organization intracellular signal transduction positive regulation of protein catabolic process negative regulation of dopaminergic neuron differentiation ER overload response circadian rhythm peptidyl-serine phosphorylation positive regulation of protein binding positive regulation of proteasomal ubiquitin-dependent protein catabolic process regulation of microtubule-based process cellular response to interleukin-3 negative regulation of apoptotic process canonical Wnt signaling pathway extrinsic apoptotic signaling pathway in absence of ligand positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway carbohydrate metabolic process neuron projection development negative regulation of neuron death positive regulation of gene expression establishment of cell polarity maintenance of cell polarity regulation of axon extension negative regulation of phosphoprotein phosphatase activity regulation of dendrite morphogenesis regulation of axonogenesis excitatory postsynaptic potential regulation of microtubule cytoskeleton organization negative regulation of calcineurin-NFAT signaling cascade extrinsic apoptotic signaling pathway neuron projection retraction negative regulation of protein acetylation cellular response to amyloid-beta positive regulation of protein localization to centrosome regulation of synaptic vesicle exocytosis neuron projection organization positive regulation of autophagy regulation of circadian rhythm regulation of long-term synaptic potentiation regulation of microtubule anchoring at centrosome Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 2932 56637 Ensembl ENSG00000082701 ENSMUSG00000022812 UniProt P49841 Q9WV60 RefSeq (mRNA) NM_001146156 NM_002093 NM_001354596 NM_019827 NM_001347232 RefSeq (protein) NP_001139628 NP_002084 NP_001341525 NP_001334161 NP_062801 Location (UCSC) Chr 3: 119.82 – 120.09 Mb Chr 16: 37.91 – 38.07 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Function

Glycogen synthase kinase-3 (GSK-3) is a proline-directed serine-threonine kinase that was initially identified as a phosphorylating and an inactivating agent of glycogen synthase. Two isoforms, alpha (GSK3A) and beta, show a high degree of amino acid homology.^[5] GSK3B is involved in energy metabolism, neuronal cell development, and body pattern formation.^[9][10] It might be a new therapeutic target for ischemic stroke.

Disease relevance

Homozygous disruption of the Gsk3b locus in mice results in embryonic lethality during mid-gestation.^[7] This lethality phenotype could be rescued by inhibition of tumor necrosis factor.^[7]

Two SNPs at this gene, rs334558 (-50T/C) and rs3755557 (-1727A/T), are associated with efficacy of lithium treatment in bipolar disorder.^[11]

Signaling pathways

Pharmacological inhibition of ERK1/2 restores GSK-3 beta activity and protein synthesis levels in a model of tuberous sclerosis.^[12]

Interactions

GSK3B has been shown to interact with:

• KIAA1211L^[13]
• ATP2A2^[14]

• AKAP11,^[15]
• AXIN1,^[16][17]
• AXIN2,^[18][19]
• AR,^[20]
• CTNNB1,^[21][22]
• DNM1L,^[23]
• MACF1^[24]
• MUC1,^[25][26]
• SMAD3^[27]
• NOTCH1,^[28]
• NOTCH2,^[29]
• P53,^[30]
• PRKAR2A,^[15]
• SGK3,^[31] and
• TSC2.^[16][32]

Overview of signal transduction pathways involved in apoptosis.

See also

• Glycogen synthase kinase 3

References

1. GRCh38: Ensembl release 89: ENSG00000082701 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000022812 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Stambolic V, Woodgett JR (November 1994). "Mitogen inactivation of glycogen synthase kinase-3 beta in intact cells via serine 9 phosphorylation". The Biochemical Journal. 303 (Pt 3): 701–4. doi:10.1042/bj3030701. PMC 1137602. PMID 7980435.
6. Lau KF, Miller CC, Anderton BH, Shaw PC (September 1999). "Molecular cloning and characterization of the human glycogen synthase kinase-3beta promoter". Genomics. 60 (2): 121–8. doi:10.1006/geno.1999.5875. PMID 10486203.
7. Hoeflich KP, Luo J, Rubie EA, Tsao MS, Jin O, Woodgett JR (July 2000). "Requirement for glycogen synthase kinase-3beta in cell survival and NF-kappaB activation". Nature. 406 (6791): 86–90. Bibcode:2000Natur.406...86H. doi:10.1038/35017574. PMID 10894547. S2CID 205007364.
8. Luykx JJ, Boks MP, Terwindt AP, Bakker S, Kahn RS, Ophoff RA (June 2010). "The involvement of GSK3beta in bipolar disorder: integrating evidence from multiple types of genetic studies". European Neuropsychopharmacology. 20 (6): 357–68. doi:10.1016/j.euroneuro.2010.02.008. PMID 20226637. S2CID 43214075.
9. Plyte SE, Hughes K, Nikolakaki E, Pulverer BJ, Woodgett JR (December 1992). "Glycogen synthase kinase-3: functions in oncogenesis and development". Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 1114 (2–3): 147–62. doi:10.1016/0304-419X(92)90012-N. PMID 1333807.
10. "Entrez Gene: GSK3B glycogen synthase kinase 3 beta".
11. Iwahashi K, Nishizawa D, Narita S, Numajiri M, Murayama O, Yoshihara E, et al. (2013). "Haplotype analysis of GSK-3β gene polymorphisms in bipolar disorder lithium responders and nonresponders". Clinical Neuropharmacology. 37 (4): 108–10. doi:10.1097/WNF.0000000000000039. PMC 4206383. PMID 24992082.
12. Pal R, Bondar VV, Adamski CJ, Rodney GG, Sardiello M (June 2017). "Inhibition of ERK1/2 Restores GSK3β Activity and Protein Synthesis Levels in a Model of Tuberous Sclerosis". Scientific Reports. 7 (1): 4174. Bibcode:2017NatSR...7.4174P. doi:10.1038/s41598-017-04528-5. PMC 5482840. PMID 28646232.
13. EMBL-EBI. "EMBL European Bioinformatics Institute". www.ebi.ac.uk. Retrieved 2017-04-26.
14. Gonnot F, Boulogne L, Brun C, Dia M, Gouriou Y, Bidaux G, et al. (June 2023). "SERCA2 phosphorylation at serine 663 is a key regulator of Ca²⁺ homeostasis in heart diseases". Nature Communications. 14 (1): 3346. doi:10.1038/s41467-023-39027-x. PMC 10250397. PMID 37291092.
15. Tanji C, Yamamoto H, Yorioka N, Kohno N, Kikuchi K, Kikuchi A (October 2002). "A-kinase anchoring protein AKAP220 binds to glycogen synthase kinase-3beta (GSK-3beta ) and mediates protein kinase A-dependent inhibition of GSK-3beta". The Journal of Biological Chemistry. 277 (40): 36955–61. doi:10.1074/jbc.M206210200. PMID 12147701.
16. Mak BC, Takemaru K, Kenerson HL, Moon RT, Yeung RS (February 2003). "The tuberin-hamartin complex negatively regulates beta-catenin signaling activity". The Journal of Biological Chemistry. 278 (8): 5947–51. doi:10.1074/jbc.C200473200. PMID 12511557.
17. Nakamura T, Hamada F, Ishidate T, Anai K, Kawahara K, Toyoshima K, et al. (June 1998). "Axin, an inhibitor of the Wnt signalling pathway, interacts with beta-catenin, GSK-3beta and APC and reduces the beta-catenin level". Genes to Cells. 3 (6): 395–403. doi:10.1046/j.1365-2443.1998.00198.x. PMID 9734785. S2CID 10875463.
18. von Kries JP, Winbeck G, Asbrand C, Schwarz-Romond T, Sochnikova N, Dell'Oro A, et al. (September 2000). "Hot spots in beta-catenin for interactions with LEF-1, conductin and APC". Nature Structural Biology. 7 (9): 800–7. doi:10.1038/79039. PMID 10966653. S2CID 40432152.
19. Schwarz-Romond T, Asbrand C, Bakkers J, Kühl M, Schaeffer HJ, Huelsken J, et al. (August 2002). "The ankyrin repeat protein Diversin recruits Casein kinase Iepsilon to the beta-catenin degradation complex and acts in both canonical Wnt and Wnt/JNK signaling". Genes & Development. 16 (16): 2073–84. doi:10.1101/gad.230402. PMC 186448. PMID 12183362.
20. Wang L, Lin HK, Hu YC, Xie S, Yang L, Chang C (July 2004). "Suppression of androgen receptor-mediated transactivation and cell growth by the glycogen synthase kinase 3 beta in prostate cells". The Journal of Biological Chemistry. 279 (31): 32444–52. doi:10.1074/jbc.M313963200. PMID 15178691.
21. Davies G, Jiang WG, Mason MD (April 2001). "The interaction between beta-catenin, GSK3beta and APC after motogen induced cell-cell dissociation, and their involvement in signal transduction pathways in prostate cancer". International Journal of Oncology. 18 (4): 843–7. doi:10.3892/ijo.18.4.843. PMID 11251183.
22. Kishida S, Yamamoto H, Hino S, Ikeda S, Kishida M, Kikuchi A (June 1999). "DIX domains of Dvl and axin are necessary for protein interactions and their ability to regulate beta-catenin stability". Molecular and Cellular Biology. 19 (6): 4414–22. doi:10.1128/mcb.19.6.4414. PMC 104400. PMID 10330181.
23. Hong YR, Chen CH, Cheng DS, Howng SL, Chow CC (August 1998). "Human dynamin-like protein interacts with the glycogen synthase kinase 3beta". Biochemical and Biophysical Research Communications. 249 (3): 697–703. doi:10.1006/bbrc.1998.9253. PMID 9731200.
24. Wu X, Shen QT, Oristian DS, Lu CP, Zheng Q, Wang HW, et al. (February 2011). "Skin stem cells orchestrate directional migration by regulating microtubule-ACF7 connections through GSK3β". Cell. 144 (3): 341–52. doi:10.1016/j.cell.2010.12.033. PMC 3050560. PMID 21295697.
25. Li Y, Bharti A, Chen D, Gong J, Kufe D (December 1998). "Interaction of glycogen synthase kinase 3beta with the DF3/MUC1 carcinoma-associated antigen and beta-catenin". Molecular and Cellular Biology. 18 (12): 7216–24. doi:10.1128/mcb.18.12.7216. PMC 109303. PMID 9819408.
26. Li Y, Kuwahara H, Ren J, Wen G, Kufe D (March 2001). "The c-Src tyrosine kinase regulates signaling of the human DF3/MUC1 carcinoma-associated antigen with GSK3 beta and beta-catenin". The Journal of Biological Chemistry. 276 (9): 6061–4. doi:10.1074/jbc.C000754200. PMID 11152665.
27. Guo X, Ramirez A, Waddell DS, Li Z, Liu X, Wang XF (January 2008). "Axin and GSK3- control Smad3 protein stability and modulate TGF- signaling". Genes & Development. 22 (1): 106–20. doi:10.1101/gad.1590908. PMC 2151009. PMID 18172167.
28. Foltz DR, Santiago MC, Berechid BE, Nye JS (June 2002). "Glycogen synthase kinase-3beta modulates notch signaling and stability". Current Biology. 12 (12): 1006–11. Bibcode:2002CBio...12.1006F. doi:10.1016/S0960-9822(02)00888-6. PMID 12123574. S2CID 15884556.
29. Espinosa L, Inglés-Esteve J, Aguilera C, Bigas A (August 2003). "Phosphorylation by glycogen synthase kinase-3 beta down-regulates Notch activity, a link for Notch and Wnt pathways". The Journal of Biological Chemistry. 278 (34): 32227–35. doi:10.1074/jbc.M304001200. PMID 12794074.
30. Watcharasit P, Bijur GN, Zmijewski JW, Song L, Zmijewska A, Chen X, et al. (June 2002). "Direct, activating interaction between glycogen synthase kinase-3beta and p53 after DNA damage". Proceedings of the National Academy of Sciences of the United States of America. 99 (12): 7951–5. Bibcode:2002PNAS...99.7951W. doi:10.1073/pnas.122062299. PMC 123001. PMID 12048243.
31. Dai F, Yu L, He H, Chen Y, Yu J, Yang Y, et al. (May 2002). "Human serum and glucocorticoid-inducible kinase-like kinase (SGKL) phosphorylates glycogen syntheses kinase 3 beta (GSK-3beta) at serine-9 through direct interaction". Biochemical and Biophysical Research Communications. 293 (4): 1191–6. doi:10.1016/S0006-291X(02)00349-2. PMID 12054501.
32. Inoki K, Ouyang H, Zhu T, Lindvall C, Wang Y, Zhang X, et al. (September 2006). "TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth". Cell. 126 (5): 955–68. doi:10.1016/j.cell.2006.06.055. PMID 16959574. S2CID 16047397.

Further reading

• Turenne GA, Price BD (2001). "Glycogen synthase kinase3 beta phosphorylates serine 33 of p53 and activates p53's transcriptional activity". BMC Cell Biology. 2: 12. doi:10.1186/1471-2121-2-12. PMC 35361. PMID 11483158.
• Plyte SE, Hughes K, Nikolakaki E, Pulverer BJ, Woodgett JR (December 1992). "Glycogen synthase kinase-3: functions in oncogenesis and development". Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 1114 (2–3): 147–62. doi:10.1016/0304-419X(92)90012-N. PMID 1333807.
• Morishima-Kawashima M, Hasegawa M, Takio K, Suzuki M, Yoshida H, Watanabe A, et al. (1995). "Hyperphosphorylation of tau in PHF". Neurobiology of Aging. 16 (3): 365–71, discussion 371–80. doi:10.1016/0197-4580(95)00027-C. PMID 7566346. S2CID 22471158.
• Jope RS, Bijur GN (2002). "Mood stabilizers, glycogen synthase kinase-3beta and cell survival". Molecular Psychiatry. 7 (Suppl 1): S35-45. doi:10.1038/sj.mp.4001017. PMID 11986994.
• Bhat RV, Budd SL (2003). "GSK3beta signalling: casting a wide net in Alzheimer's disease". Neuro-Signals. 11 (5): 251–61. doi:10.1159/000067423. PMID 12566926. S2CID 13650262.
• Wang W, Li M, Wang Y, Li Q, Deng G, Wan J, et al. (December 2016). "GSK-3β inhibitor TWS119 attenuates rtPA-induced hemorrhagic transformation and activates the Wnt/β-catenin signaling pathway after acute ischemic stroke in rats". Molecular Neurobiology. 53 (10): 7028–7036. doi:10.1007/s12035-015-9607-2. PMC 4909586. PMID 26671619.
• Nadri C, Kozlovsky N, Agam G (September 2003). "[Schizophrenia, neurodevelopment and glycogen synthase kinase-3]". Harefuah. 142 (8–9): 636–42, 644. PMID 14518171.
• Mulholland DJ, Dedhar S, Wu H, Nelson CC (January 2006). "PTEN and GSK3beta: key regulators of progression to androgen-independent prostate cancer". Oncogene. 25 (3): 329–37. doi:10.1038/sj.onc.1209020. PMID 16421604.

External links

• PDBe-KB provides an overview of all the structure information available in the PDB for Human Glycogen synthase kinase-3 beta (GSK3B)