GSK3B

Glycogen synthase kinase 3 beta
PDB rendering based on 1gng.
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​
Identifiers
Symbol	GSK3B
External IDs	OMIM: 605004 MGI: 1861437 HomoloGene: 55629 ChEMBL: 262 GeneCards: GSK3B Gene
EC number	2.7.11.1, 2.7.11.26
Gene ontology Molecular function • RNA polymerase II transcription factor binding • p53 binding • protein serine/threonine kinase activity • protein binding • ATP binding • beta-catenin binding • kinase activity • protein kinase binding • ubiquitin protein ligase binding • protein kinase A catalytic subunit binding • tau-protein kinase activity • NF-kappaB binding Cellular component • nucleus • nucleoplasm • cytoplasm • centrosome • cytosol • plasma membrane • growth cone • ribonucleoprotein complex • beta-catenin destruction complex • neuronal cell body • dendritic shaft • perinuclear region of cytoplasm • neuronal postsynaptic density Biological process • re-entry into mitotic cell cycle • epithelial to mesenchymal transition • positive regulation of cell-matrix adhesion • glycogen metabolic process • regulation of gene expression by genetic imprinting • protein phosphorylation • protein export from nucleus • ER overload response • epidermal growth factor receptor signaling pathway • axon guidance • myoblast fusion • circadian rhythm • fibroblast growth factor receptor signaling pathway • organ morphogenesis • negative regulation of cardiac muscle hypertrophy • positive regulation of peptidyl-threonine phosphorylation • negative regulation of neuron projection development • negative regulation of neuron maturation • cell migration • peptidyl-serine phosphorylation • hippocampus development • negative regulation of protein complex assembly • positive regulation of protein complex assembly • negative regulation of protein binding • positive regulation of protein binding • positive regulation of proteasomal ubiquitin-dependent protein catabolic process • regulation of microtubule-based process • positive regulation of peptidyl-serine phosphorylation • cellular response to heat • protein localization to microtubule • intracellular signal transduction • cellular response to interleukin-3 • Fc-epsilon receptor signaling pathway • negative regulation of apoptotic process • positive regulation of GTPase activity • hypermethylation of CpG island • canonical Wnt signaling pathway involved in positive regulation of apoptotic process • innate immune response • fat cell differentiation • negative regulation of glycogen biosynthetic process • positive regulation of protein catabolic process • positive regulation of axon extension • positive regulation of transcription from RNA polymerase II promoter • protein autophosphorylation • positive regulation of protein export from nucleus • neurotrophin TRK receptor signaling pathway • phosphatidylinositol-mediated signaling • negative regulation of NFAT protein import into nucleus • canonical Wnt signaling pathway • intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress • superior temporal gyrus development • negative regulation of canonical Wnt signaling pathway • positive regulation of canonical Wnt signaling pathway • extrinsic apoptotic signaling pathway in absence of ligand • regulation of cellular response to heat • negative regulation of protein localization to nucleus • positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway • negative regulation of type B pancreatic cell development • negative regulation of glycogen (starch) synthase activity • positive regulation of stem cell differentiation Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	2932	56637
Ensembl	ENSG00000082701	ENSMUSG00000022812
UniProt	P49841	Q9WV60
RefSeq (mRNA)	NM_001146156	NM_019827
RefSeq (protein)	NP_001139628	NP_062801
Location (UCSC)	Chr 3: 119.82 – 120.09 Mb	Chr 16: 38.09 – 38.25 Mb
PubMed search

Glycogen synthase kinase 3 beta, also known as GSK3B, is an enzyme that in humans is encoded by the GSK3B gene.^[1][2] In mice, the enzyme is encoded by the GSK-3β gene.^[3] Abnormal regulation and expression of GSK3β is associated with an increased susceptibility towards bipolar disorder.^[4]

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.^[1] GSK3B is involved in energy metabolism, neuronal cell development, and body pattern formation.^[5][6]

Loss of function mutations

Homozygous disruption of the GSK-3β locus in mice results in embryonic lethality during mid-gestation.^[3] This lethality phenotype could be rescued by inhibition of tumor necrosis factor.^[3]

Interactions

GSK3B has been shown to interact with:

• AKAP11,^[7]
• AXIN1,^[8][9]
• AXIN2,^[10][11]
• AR,^[12]
• CTNNB1,^[13][14]
• DNM1L,^[15]
• MACF1^[16]
• MUC1,^[17][18]
• SMAD3^[19]
• NOTCH1,^[20]
• NOTCH2,^[21]
• P53,^[22]
• PRKAR2A,^[7]
• SGK3,^[23] and
• TSC2.^[8][24]

Overview of signal transduction pathways involved in apoptosis.

See also

• Glycogen synthase kinase 3

References

1. Stambolic V, Woodgett JR (Nov 1994). "Mitogen inactivation of glycogen synthase kinase-3 beta in intact cells via serine 9 phosphorylation". The Biochemical Journal 303 (Pt 3): 701–4. PMC 1137602. PMID 7980435.
2. Lau KF, Miller CC, Anderton BH, Shaw PC (Sep 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.
3. Hoeflich KP, Luo J, Rubie EA, Tsao MS, Jin O, Woodgett JR (2000). "Requirement for glycogen synthase kinase-3beta in cell survival and NF-kappaB activation". Nature 406 (6791): 86–90. doi:10.1038/35017574. PMID 10894547.
4. Luykx JJ, Boks MP, Terwindt AP, Bakker S, Kahn RS, Ophoff RA (Jun 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.
5. Plyte SE, Hughes K, Nikolakaki E, Pulverer BJ, Woodgett JR (Dec 1992). "Glycogen synthase kinase-3: functions in oncogenesis and development". Biochimica et Biophysica Acta 1114 (2-3): 147–62. doi:10.1016/0304-419X(92)90012-N. PMID 1333807.
6. "Entrez Gene: GSK3B glycogen synthase kinase 3 beta".
7. Tanji C, Yamamoto H, Yorioka N, Kohno N, Kikuchi K, Kikuchi A (Oct 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.
8. Mak BC, Takemaru K, Kenerson HL, Moon RT, Yeung RS (Feb 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.
9. Nakamura T, Hamada F, Ishidate T, Anai K, Kawahara K, Toyoshima K, Akiyama T (Jun 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.
10. von Kries JP, Winbeck G, Asbrand C, Schwarz-Romond T, Sochnikova N, Dell'Oro A, Behrens J, Birchmeier W (Sep 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.
11. Schwarz-Romond T, Asbrand C, Bakkers J, Kühl M, Schaeffer HJ, Huelsken J, Behrens J, Hammerschmidt M, Birchmeier W (Aug 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.
12. Wang L, Lin HK, Hu YC, Xie S, Yang L, Chang C (Jul 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.
13. Davies G, Jiang WG, Mason MD (Apr 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.
14. Kishida S, Yamamoto H, Hino S, Ikeda S, Kishida M, Kikuchi A (Jun 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.
15. Hong YR, Chen CH, Cheng DS, Howng SL, Chow CC (Aug 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.
16. Wu X, Shen QT, Oristian DS, Lu CP, Zheng Q, Wang HW, Fuchs E (Feb 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. PMID 21295697.
17. Li Y, Bharti A, Chen D, Gong J, Kufe D (Dec 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.
18. Li Y, Kuwahara H, Ren J, Wen G, Kufe D (Mar 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.
19. Guo X, Ramirez A, Waddell DS, Li Z, Liu X, Wang XF (Jan 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.
20. Foltz DR, Santiago MC, Berechid BE, Nye JS (Jun 2002). "Glycogen synthase kinase-3beta modulates notch signaling and stability". Current Biology 12 (12): 1006–11. doi:10.1016/S0960-9822(02)00888-6. PMID 12123574.
21. Espinosa L, Inglés-Esteve J, Aguilera C, Bigas A (Aug 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.
22. Watcharasit P, Bijur GN, Zmijewski JW, Song L, Zmijewska A, Chen X, Johnson GV, Jope RS (Jun 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. doi:10.1073/pnas.122062299. PMC 123001. PMID 12048243.
23. Dai F, Yu L, He H, Chen Y, Yu J, Yang Y, Xu Y, Ling W, Zhao S (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.
24. 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 (Sep 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.

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 (Dec 1992). "Glycogen synthase kinase-3: functions in oncogenesis and development". Biochimica et Biophysica Acta 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, Titani K, Ihara Y (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.
• 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.
• Nadri C, Kozlovsky N, Agam G (Sep 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 (Jan 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.