Glycogen synthase kinase-3 beta explained

Glycogen synthase kinase-3 beta, (GSK-3 beta), is an enzyme that in humans is encoded by the GSK3B gene.^{[1] [2]} In mice, the enzyme is encoded by the Gsk3b gene. Abnormal regulation and expression of GSK-3 beta is associated with an increased susceptibility towards bipolar disorder.^[3]

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. GSK3B is involved in energy metabolism, neuronal cell development, and body pattern formation.^{[4] [5]} 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. This lethality phenotype could be rescued by inhibition of tumor necrosis factor.

Two SNPs at this gene, rs334558 (-50T/C) and rs3755557 (-1727A/T), are associated with efficacy of lithium treatment in bipolar disorder.^[6]

Signaling pathways

Pharmacological inhibition of ERK1/2 restores GSK-3 beta activity and protein synthesis levels in a model of tuberous sclerosis.^[7]

Interactions

GSK3B has been shown to interact with:

• KIAA1211L^[8]
• ATP2A2^[9]

• AKAP11,
• AXIN1,^[10]
• AXIN2,^{[11] [12]}
• AR,^[13]
• CTNNB1,^{[14] [15]}
• DNM1L,^[16]
• MACF1^[17]
• MUC1,^{[18] [19]}
• SMAD3^[20]
• NOTCH1,^[21]
• NOTCH2,^[22]
• P53,^[23]
• PRKAR2A,^[24]
• SGK3,^[25] and
• TSC2.^{[26] [27]}

See also

• Glycogen synthase kinase 3

Further reading

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

External links

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

Notes and References

1. Stambolic V, Woodgett JR . Mitogen inactivation of glycogen synthase kinase-3 beta in intact cells via serine 9 phosphorylation . The Biochemical Journal . 303 . Pt 3 . 701–4 . November 1994 . 7980435 . 1137602 . 10.1042/bj3030701 .
2. Lau KF, Miller CC, Anderton BH, Shaw PC . Molecular cloning and characterization of the human glycogen synthase kinase-3beta promoter . Genomics . 60 . 2 . 121–8 . September 1999 . 10486203 . 10.1006/geno.1999.5875 .
3. Luykx JJ, Boks MP, Terwindt AP, Bakker S, Kahn RS, Ophoff RA . The involvement of GSK3beta in bipolar disorder: integrating evidence from multiple types of genetic studies . European Neuropsychopharmacology . 20 . 6 . 357–68 . June 2010 . 20226637 . 10.1016/j.euroneuro.2010.02.008 . 43214075 .
4. Plyte SE, Hughes K, Nikolakaki E, Pulverer BJ, Woodgett JR . Glycogen synthase kinase-3: functions in oncogenesis and development . Biochimica et Biophysica Acta (BBA) - Reviews on Cancer . 1114 . 2–3 . 147–62 . December 1992 . 1333807 . 10.1016/0304-419X(92)90012-N .
5. Web site: Entrez Gene: GSK3B glycogen synthase kinase 3 beta.
6. Iwahashi K, Nishizawa D, Narita S, Numajiri M, Murayama O, Yoshihara E, Onozawa Y, Nagahori K, Fukamauchi F, Ikeda K, Ishigooka J . Haplotype analysis of GSK-3β gene polymorphisms in bipolar disorder lithium responders and nonresponders . Clinical Neuropharmacology . 37 . 4 . 108–10 . 2013 . 24992082 . 4206383 . 10.1097/WNF.0000000000000039 .
7. Pal R, Bondar VV, Adamski CJ, Rodney GG, Sardiello M . Inhibition of ERK1/2 Restores GSK3β Activity and Protein Synthesis Levels in a Model of Tuberous Sclerosis . Scientific Reports . 7 . 1 . 4174 . June 2017 . 28646232 . 5482840 . 10.1038/s41598-017-04528-5 . 2017NatSR...7.4174P .
8. Web site: EMBL European Bioinformatics Institute. EMBL-EBI. www.ebi.ac.uk.. en. 2017-04-26.
9. Gonnot F, Boulogne L, Brun C, Dia M, Gouriou Y, Bidaux G, Chouabe C, Crola Da Silva C, Ducreux S, Pillot B, Kaczmarczyk A, Leon C, Chanon S, Perret C, Sciandra F, Dargar T, Gache V, Farhat F, Sebbag L, Bochaton T, Thibault H, Ovize M, Paillard M, Gomez L . SERCA2 phosphorylation at serine 663 is a key regulator of Ca²⁺ homeostasis in heart diseases . Nature Communications . 14 . 1 . 3346 . June 2023 . 37291092 . 10250397 . 10.1038/s41467-023-39027-x .
10. Nakamura T, Hamada F, Ishidate T, Anai K, Kawahara K, Toyoshima K, Akiyama T . 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 . June 1998 . 9734785 . 10.1046/j.1365-2443.1998.00198.x . 10875463 . free .
11. von Kries JP, Winbeck G, Asbrand C, Schwarz-Romond T, Sochnikova N, Dell'Oro A, Behrens J, Birchmeier W . Hot spots in beta-catenin for interactions with LEF-1, conductin and APC . Nature Structural Biology . 7 . 9 . 800–7 . September 2000 . 10966653 . 10.1038/79039 . 40432152 .
12. Schwarz-Romond T, Asbrand C, Bakkers J, Kühl M, Schaeffer HJ, Huelsken J, Behrens J, Hammerschmidt M, Birchmeier W . 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 . August 2002 . 12183362 . 186448 . 10.1101/gad.230402 .
13. Wang L, Lin HK, Hu YC, Xie S, Yang L, Chang C . 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 . July 2004 . 15178691 . 10.1074/jbc.M313963200 . free .
14. Davies G, Jiang WG, Mason MD . 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 . April 2001 . 11251183 . 10.3892/ijo.18.4.843 .
15. Kishida S, Yamamoto H, Hino S, Ikeda S, Kishida M, Kikuchi A . 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 . June 1999 . 10330181 . 104400 . 10.1128/mcb.19.6.4414 .
16. Hong YR, Chen CH, Cheng DS, Howng SL, Chow CC . Human dynamin-like protein interacts with the glycogen synthase kinase 3beta . Biochemical and Biophysical Research Communications . 249 . 3 . 697–703 . August 1998 . 9731200 . 10.1006/bbrc.1998.9253 .
17. Wu X, Shen QT, Oristian DS, Lu CP, Zheng Q, Wang HW, Fuchs E . Skin stem cells orchestrate directional migration by regulating microtubule-ACF7 connections through GSK3β . Cell . 144 . 3 . 341–52 . February 2011 . 21295697 . 3050560 . 10.1016/j.cell.2010.12.033 .
18. Li Y, Bharti A, Chen D, Gong J, Kufe D . Interaction of glycogen synthase kinase 3beta with the DF3/MUC1 carcinoma-associated antigen and beta-catenin . Molecular and Cellular Biology . 18 . 12 . 7216–24 . December 1998 . 9819408 . 109303 . 10.1128/mcb.18.12.7216 .
19. Li Y, Kuwahara H, Ren J, Wen G, Kufe D . 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 . March 2001 . 11152665 . 10.1074/jbc.C000754200 . free .
20. Guo X, Ramirez A, Waddell DS, Li Z, Liu X, Wang XF . Axin and GSK3- control Smad3 protein stability and modulate TGF- signaling . Genes & Development . 22 . 1 . 106–20 . January 2008 . 18172167 . 2151009 . 10.1101/gad.1590908 .
21. Foltz DR, Santiago MC, Berechid BE, Nye JS . Glycogen synthase kinase-3beta modulates notch signaling and stability . Current Biology . 12 . 12 . 1006–11 . June 2002 . 12123574 . 10.1016/S0960-9822(02)00888-6 . 15884556 . free . 2002CBio...12.1006F .
22. Espinosa L, Inglés-Esteve J, Aguilera C, Bigas A . 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 . August 2003 . 12794074 . 10.1074/jbc.M304001200 . free .
23. Watcharasit P, Bijur GN, Zmijewski JW, Song L, Zmijewska A, Chen X, Johnson GV, Jope RS . 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 . June 2002 . 12048243 . 123001 . 10.1073/pnas.122062299 . 2002PNAS...99.7951W . free .
24. Tanji C, Yamamoto H, Yorioka N, Kohno N, Kikuchi K, Kikuchi A . 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 . October 2002 . 12147701 . 10.1074/jbc.M206210200 . free .
25. Dai F, Yu L, He H, Chen Y, Yu J, Yang Y, Xu Y, Ling W, Zhao S . 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 . May 2002 . 12054501 . 10.1016/S0006-291X(02)00349-2 .
26. Mak BC, Takemaru K, Kenerson HL, Moon RT, Yeung RS . The tuberin-hamartin complex negatively regulates beta-catenin signaling activity . The Journal of Biological Chemistry . 278 . 8 . 5947–51 . February 2003 . 12511557 . 10.1074/jbc.C200473200 . free .
27. Inoki K, Ouyang H, Zhu T, Lindvall C, Wang Y, Zhang X, Yang Q, Bennett C, Harada Y, Stankunas K, Wang CY, He X, MacDougald OA, You M, Williams BO, Guan KL . TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth . Cell . 126 . 5 . 955–68 . September 2006 . 16959574 . 10.1016/j.cell.2006.06.055 . 16047397 . free .