GSK3B

Last updated
GSK3B
Protein GSK3B PDB 1gng.png
Available structures
PDB Ortholog search: PDBe RCSB
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
EC number 2.7.11.1
Gene location (Human)
Ideogram human chromosome 3.svg
Chr. Chromosome 3 (human) [1]
Human chromosome 3 ideogram.svg
HSR 1996 II 3.5e.svg
Red rectangle 2x18.png
Band 3q13.33Start119,821,323 bp [1]
End120,094,417 bp [1]
RNA expression pattern
PBB GE GSK3B 209945 s at fs.png
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
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: 38.09 – 38.25 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Glycogen synthase kinase 3 beta, also known as GSK3B, is an enzyme that in humans is encoded by the GSK3B gene. [5] [6] In mice, the enzyme is encoded by the GSK-3β gene. [7] Abnormal regulation and expression of GSK3β is associated with an increased susceptibility towards bipolar disorder. [8]

Enzyme class of biological molecules with catalytic activity

Enzymes are macromolecular biological catalysts that accelerate chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. Almost all metabolic processes in the cell need enzyme catalysis in order to occur at rates fast enough to sustain life. Metabolic pathways depend upon enzymes to catalyze individual steps. The study of enzymes is called enzymology and a new field of pseudoenzyme analysis has recently grown up, recognising that during evolution, some enzymes have lost the ability to carry out biological catalysis, which is often reflected in their amino acid sequences and unusual 'pseudocatalytic' properties.

Gene Basic physical and functional unit of heredity

In biology, a gene is a sequence of nucleotides in DNA or RNA that codes for a molecule that has a function. During gene expression, the DNA is first copied into RNA. The RNA can be directly functional or be the intermediate template for a protein that performs a function. The transmission of genes to an organism's offspring is the basis of the inheritance of phenotypic trait. These genes make up different DNA sequences called genotypes. Genotypes along with environmental and developmental factors determine what the phenotypes will be. Most biological traits are under the influence of polygenes as well as gene–environment interactions. Some genetic traits are instantly visible, such as eye color or number of limbs, and some are not, such as blood type, risk for specific diseases, or the thousands of basic biochemical processes that constitute life.

Bipolar disorder mental disorder that causes periods of depression and periods of abnormally elevated mood

Bipolar disorder, previously known as manic depression, is a mental disorder that causes periods of depression and periods of abnormally elevated mood. The elevated mood is significant and is known as mania, or hypomania if less severe and symptoms of psychosis are absent. During mania, an individual behaves or feels abnormally energetic, happy, or irritable. Individuals often make poorly thought out decisions with little regard to the consequences. The need for sleep is usually reduced during manic phases. During periods of depression, there may be crying, a negative outlook on life, and poor eye contact with others. The risk of suicide among those with the illness is high at greater than 6 percent over 20 years, while self-harm occurs in 30–40 percent. Other mental health issues such as anxiety disorders and substance use disorder are commonly associated with bipolar disorder.

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.

GSK-3

Glycogen synthase kinase 3 is a serine/threonine protein kinase that mediates the addition of phosphate molecules onto serine and threonine amino acid residues. First discovered in 1980 as a regulatory kinase for its namesake, Glycogen synthase, GSK-3 has since been identified as a kinase for over forty different proteins in a variety of different pathways. In mammals GSK-3 is encoded by two paralogous genes, GSK-3 alpha (GSK3A) and GSK-3 beta (GSK3B). GSK-3 has recently been the subject of much research because it has been implicated in a number of diseases, including Type II diabetes, Alzheimer's Disease, inflammation, cancer, and bipolar disorder.

Serine/threonine-specific protein kinase

A serine/threonine protein kinase is a kinase enzyme that phosphorylates the OH group of serine or threonine. At least 125 of the 500+ human protein kinases are serine/threonine kinases (STK).

Phosphorylation the process of introducing a phosphate group into a molecule, usually with the formation of a phosphoric ester, a phosphoric anhydride or a phosphoric amide.

In chemistry, phosphorylation of a molecule is the attachment of a phosphoryl group. Together with its counterpart, dephosphorylation, it is critical for many cellular processes in biology. Phosphorylation is especially important for protein function; for example, this modification activates almost half of the enzymes present in yeast, thereby regulating their function. Many proteins are phosphorylated temporarily, as are many sugars, lipids, and other biologically-relevant molecules.

Disease relevance

Homozygous disruption of the GSK-3β 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]

Lithium (medication) primarily used as a psychiatric medication

Lithium compounds, also known as lithium salts, are primarily used as a psychiatric medication. This includes the treatment of major depressive disorder that does not improve following the use of other antidepressants, and bipolar disorder. In these disorders, it reduces the risk of suicide. Lithium is taken by mouth.

Signaling pathways

Pharmacological inhibition of ERK1/2 restores GSK3β activity and protein synthesis levels in a model of tuberous sclerosis. [12]

MAPK3 protein-coding gene in the species Homo sapiens

Mitogen-activated protein kinase 3, also known as p44MAPK and ERK1, is an enzyme that in humans is encoded by the MAPK3 gene.

Tuberous sclerosis rare multisystem genetic disease that causes benign tumors to grow in the brain and on other vital organs

Tuberous sclerosis complex (TSC) is a rare multisystem autosomal dominant genetic disease that causes non-cancerous tumours to grow in the brain and on other vital organs such as the kidneys, heart, liver, eyes, lungs and skin. A combination of symptoms may include seizures, intellectual disability, developmental delay, behavioral problems, skin abnormalities, lung disease, and kidney disease.

Interactions

GSK3B has been shown to interact with:

AKAP11 protein-coding gene in the species Homo sapiens

A-kinase anchor protein 11 is an enzyme that in humans is encoded by the AKAP11 gene.

AXIN1 protein-coding gene in the species Homo sapiens

Axin-1 is a protein that in humans is encoded by the AXIN1 gene.

AXIN2 protein-coding gene in the species Homo sapiens

Axin-2 also known as axin-like protein (Axil) or axis inhibition protein 2 (AXIN2) or conductin is a protein that in humans is encoded by the AXIN2 gene.

Overview of signal transduction pathways involved in apoptosis. Signal transduction v1.png
Overview of signal transduction pathways involved in apoptosis.

See also

Related Research Articles

The Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt is a portmanteau created from the name Wingless and the name Int-1.

Adenomatous polyposis coli protein-coding gene in the species Homo sapiens

Adenomatous polyposis coli (APC) also known as deleted in polyposis 2.5 (DP2.5) is a protein that in humans is encoded by the APC gene. The APC protein is a negative regulator that controls beta-catenin concentrations and interacts with E-cadherin, which are involved in cell adhesion. Mutations in the APC gene may result in colorectal cancer.

Beta-catenin protein-coding gene in the species Homo sapiens

Catenin beta-1, also known as β-catenin, is a protein that in humans is encoded by the CTNNB1 gene.

Plakoglobin protein-coding gene in the species Homo sapiens

Plakoglobin, also known as junction plakoglobin or gamma-catenin, is a protein that in humans is encoded by the JUP gene. Plakoglobin is a member of the catenin protein family and homologous to β-catenin. Plakoglobin is a cytoplasmic component of desmosomes and adherens junctions structures located within intercalated discs of cardiac muscle that function to anchor sarcomeres and join adjacent cells in cardiac muscle. Mutations in plakoglobin are associated with arrhythmogenic right ventricular dysplasia.

GSK3A protein-coding gene in the species Homo sapiens

Glycogen synthase kinase-3 alpha is an enzyme that in humans is encoded by the GSK3A gene.

Tau-protein kinase

In enzymology, a tau-protein kinase is an enzyme that catalyzes the chemical reaction

DVL1 protein-coding gene in the species Homo sapiens

Segment polarity protein dishevelled homolog DVL-1 is a protein that in humans is encoded by the DVL1 gene.

SGK3 protein-coding gene in the species Homo sapiens

Serine/threonine-protein kinase Sgk3 is an enzyme that in humans is encoded by the SGK3 gene.

PRKD3 protein-coding gene in the species Homo sapiens

Serine/threonine-protein kinase D3 (PKD3) or PKC-nu is an enzyme that in humans is encoded by the PRKD3 gene.

LRP6 protein-coding gene in the species Homo sapiens

Low-density lipoprotein receptor-related protein 6 is a protein that in humans is encoded by the LRP6 gene. LRP6 is a key component of the LRP5/LRP6/Frizzled co-receptor group that is involved in canonical Wnt pathway.

WNT3A protein-coding gene in the species Homo sapiens

Protein Wnt-3a is a protein that in humans is encoded by the WNT3A gene.

NLK mammalian protein found in Homo sapiens

Serine/threonine protein kinase NLK is an enzyme that in humans is encoded by the NLK gene. Its name is an abbreviation for Nemo-Like Kinase, Nemo (nmo) being the Drosophila ortholog of the mammalian NLK gene. This enzyme is a member of the Mitogen-activated protein kinase (MAPK) family, although not explicitly designated as such. It is a highly divergent, atypical member of the MAPK group, lacking most features so characteristic of most mitogen-activated protein kinases. Its activation mechanism and downstream targets are still not well characterized.

DVL2 protein-coding gene in the species Homo sapiens

Segment polarity protein dishevelled homolog DVL-2 is a protein that in humans is encoded by the DVL2 gene.

FRAT1 protein-coding gene in the species Homo sapiens

Proto-oncogene FRAT1 is a protein that in humans is encoded by the FRAT1 gene.

FRAT2 protein-coding gene in the species Homo sapiens

GSK-3-binding protein FRAT2 is a protein that in humans is encoded by the FRAT2 gene.

ILKAP protein-coding gene in the species Homo sapiens

Integrin-linked kinase-associated serine/threonine phosphatase 2C is an enzyme that in humans is encoded by the ILKAP gene.

Dishevelled

Dishevelled (Dsh) is a family of proteins involved in canonical and non-canonical Wnt signalling pathways. Dsh is a cytoplasmic phosphoprotein that acts directly downstream of frizzled receptors. It takes its name from its initial discovery in flies, where a mutation in the dishevelled gene was observed to cause improper orientation of body and wing hairs. There are vertebrate homologs in zebrafish, Xenopus (Xdsh), mice and humans. Dsh relays complex Wnt signals in tissues and cells, in normal and abnormal contexts. It is thought to interact with the novel protein, SPATS1, when regulating the Wnt Signalling pathway.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000082701 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000022812 - Ensembl, May 2017
  3. "Human PubMed Reference:".
  4. "Mouse PubMed Reference:".
  5. 1 2 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. 1 2 3 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. doi:10.1038/35017574. PMID   10894547. Closed Access logo transparent.svg
  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.
  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. 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" Check |url= value (help). www.ebi.ac.uk. Retrieved 2017-04-26.
  14. 1 2 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.
  15. 1 2 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.
  16. Nakamura T, Hamada F, Ishidate T, Anai K, Kawahara K, Toyoshima K, Akiyama T (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.
  17. 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.
  18. 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.
  19. 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.
  20. 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.
  21. 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.
  22. 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.
  23. Wu X, Shen QT, Oristian DS, Lu CP, Zheng Q, Wang HW, Fuchs E (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.
  24. 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.
  25. 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.
  26. 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.
  27. 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. doi:10.1016/S0960-9822(02)00888-6. PMID   12123574.
  28. 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.
  29. 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.
  30. 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.
  31. 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.

Further reading