Q9WV60 (GSK3B_MOUSE) Reviewed, UniProtKB/Swiss-Prot
Last modified April 16, 2014. Version 147. History...
Names and origin
|Protein names||Recommended name:|
Glycogen synthase kinase-3 beta
Short name=GSK-3 beta
Serine/threonine-protein kinase GSK3B
|Organism||Mus musculus (Mouse) [Reference proteome]|
|Taxonomic identifier||10090 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus|
|Sequence length||420 AA.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
Constitutively active protein kinase that acts as a negative regulator in the hormonal control of glucose homeostasis, Wnt signaling and regulation of transcription factors and microtubules, by phosphorylating and inactivating glycogen synthase (GYS1 or GYS2), EIF2B, CTNNB1/beta-catenin, APC, AXIN1, DPYSL2/CRMP2, JUN, NFATC1/NFATC, MAPT/TAU and MACF1. Requires primed phosphorylation of the majority of its substrates. In skeletal muscle, contributes to insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity and hence glycogen synthesis. May also mediate the development of insulin resistance by regulating activation of transcription factors. Regulates protein synthesis by controlling the activity of initiation factor 2B (EIF2BE/EIF2B5) in the same manner as glycogen synthase. In Wnt signaling, GSK3B forms a multimeric complex with APC, AXIN1 and CTNNB1/beta-catenin and phosphorylates the N-terminus of CTNNB1 leading to its degradation mediated by ubiquitin/proteasomes. Phosphorylates JUN at sites proximal to its DNA-binding domain, thereby reducing its affinity for DNA. Phosphorylates NFATC1/NFATC on conserved serine residues promoting NFATC1/NFATC nuclear export, shutting off NFATC1/NFATC gene regulation, and thereby opposing the action of calcineurin. Phosphorylates MAPT/TAU on 'Thr-548', decreasing significantly MAPT/TAU ability to bind and stabilize microtubules. Plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex. Phosphorylates MACF1, inhibiting its binding to microtubules which is critical for its role in bulge stem cell migration and skin wound repair. Probably regulates NF-kappa-B (NFKB1) at the transcriptional level and is required for the NF-kappa-B-mediated anti-apoptotic response to TNF-alpha (TNF/TNFA). Negatively regulates replication in pancreatic beta-cells, resulting in apoptosis, loss of beta-cells. Through phosphorylation of the anti-apoptotic protein MCL1, may control cell apoptosis in response to growth factors deprivation. Phosphorylates MUC1 in breast cancer cells, decreasing the interaction of MUC1 with CTNNB1/beta-catenin. Is necessary for the establishment of neuronal polarity and axon outgrowth. Phosphorylates MARK2, leading to inhibit its activity. Phosphorylates SIK1 at 'Thr-182', leading to sustain its activity. Phosphorylates ZC3HAV1 which enhances its antiviral activity. Phosphorylates SFPQ at 'Thr-679' upon T-cell activation. Phosphorylates SNAI1, leading to its BTRC-triggered ubiquitination and proteasomal degradation. Phosphorylates NR1D1 st 'Ser-55' and 'Ser-59' and stabilizes it by protecting it from proteasomal degradation. Regulates the circadian clock via phosphorylation of the major clock components including ARNTL/BMAL1, CLOCK and PER2. Phosphorylates CLOCK AT 'Ser-427' and targets it for proteasomal degradation. Phosphorylates ARNTL/BMAL1 at 'Ser-17' and 'Ser-21' and primes it for ubiquitination and proteasomal degradation. Phosphorylates OGT at 'Ser-3' or 'Ser-4' which positively regulates its activity. Ref.3 Ref.6 Ref.7 Ref.8 Ref.10 Ref.13 Ref.14 Ref.15 Ref.16 Ref.17
ATP + [tau protein] = ADP + [tau protein] phosphate.
ATP + a protein = ADP + a phosphoprotein.
Activated by phosphorylation at Tyr-216. In response to insulin, inhibited by phosphorylation at Ser-9 by PKB/AKT1 and RPS6KA3; phosphorylation at this site causes a conformational change, preventing access of substrates to the active site. Inhibited by lithium.
Monomer. Interacts with DAB2IP (via C2 domain); the interaction stimulates GSK3B kinase activation. Interacts (via C2 domain) with PPP2CA By similarity. Interacts with CABYR, MMP2, MUC1, NIN and PRUNE By similarity. Interacts with AXIN1; the interaction mediates hyperphosphorylation of CTNNB1 leading to its ubiquitination and destruction. Interacts with and phosphorylates SNAI1. Interacts with DNM1L (via a C-terminal domain) By similarity. Interacts with ARRB2 and DISC1. Found in a complex composed of MACF1, APC, AXIN1, CTNNB1 and GSK3B By similarity. Interacts with SGK3. Interacts with the CLOCK-ARNTL/BMAL1 heterodimer By similarity. Interacts with AXIN1 and ZBED3. Interacts with the ARNTL/BMAL1. Ref.5 Ref.11 Ref.12 Ref.14
Cytoplasm By similarity. Nucleus By similarity. Cell membrane By similarity. Note: The phosphorylated form shows localization to cytoplasm and cell membrane. The MEMO1-RHOA-DIAPH1 signaling pathway controls localization of the phosphorylated form to the cell membrane By similarity.
Phosphorylated by AKT1 and ILK1. Upon insulin-mediated signaling, the activated PKB/AKT1 protein kinase phosphorylates and desactivates GSK3B, resulting in the dephosphorylation and activation of GYS1. Activated by phosphorylation at Tyr-216. Phosphorylation of Ser-9 in the hippocampus peaks at CT0, whereas in the liver it peaks at CT12. Ref.16 Ref.17
Mono-ADP-ribosylation by PARP10 negatively regulates kinase activity By similarity.
Embryonic lethality at E16 due to hepatocyte apoptosis. Ref.3
Contains 1 protein kinase domain.
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 420||420||Glycogen synthase kinase-3 beta||PRO_0000085981|
|Domain||56 – 340||285||Protein kinase|
|Nucleotide binding||62 – 70||9||ATP By similarity|
|Active site||181||1||Proton acceptor By similarity|
|Binding site||85||1||ATP By similarity|
Amino acid modifications
|Modified residue||9||1||Phosphoserine; by PKB/AKT1, RPS6KA3 and SGK3 Ref.16 Ref.17|
|Modified residue||216||1||Phosphotyrosine By similarity|
|Modified residue||389||1||Phosphoserine Ref.4|
|Mutagenesis||9||1||S → A: Loss of phosphorylation; No inhibition of activity and constitutively active. Ref.6 Ref.16|
|Mutagenesis||85||1||K → R: Inhibits interaction with AXIN1 and ZBED3. Ref.12|
|||"Testicular expression and hormonal control of glycogen synthase kinase 3, a homologue of yeast RIM11."|
Salameh W.A., Guo T.B., Chan K.C., Mitchell A.P.
Submitted (FEB-2000) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
|||"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."|
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Strain: Czech II and FVB/N.
Tissue: Mammary gland.
|||"Requirement for glycogen synthase kinase-3beta in cell survival and NF-kappaB activation."|
Hoeflich K.P., Luo J., Rubie E.A., Tsao M.S., Jin O., Woodgett J.R.
Nature 406:86-90(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, DISRUPTION PHENOTYPE.
|||"Phosphoproteomic analysis of the developing mouse brain."|
Ballif B.A., Villen J., Beausoleil S.A., Schwartz D., Gygi S.P.
Mol. Cell. Proteomics 3:1093-1101(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-389, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Embryonic brain.
|||"An Akt/beta-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior."|
Beaulieu J.-M., Sotnikova T.D., Marion S., Lefkowitz R.J., Gainetdinov R.R., Caron M.G.
Cell 122:261-273(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH ARRB2.
|||"Role that phosphorylation of GSK3 plays in insulin and Wnt signalling defined by knockin analysis."|
McManus E.J., Sakamoto K., Armit L.J., Ronaldson L., Shpiro N., Marquez R., Alessi D.R.
EMBO J. 24:1571-1583(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, MUTAGENESIS OF SER-9.
|||"Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1."|
Maurer U., Charvet C., Wagman A.S., Dejardin E., Green D.R.
Mol. Cell 21:749-760(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN MCL1 PHOSPHORYLATION.
|||"GSK3 alpha and GSK3 beta are necessary for axon formation."|
Garrido J.J., Simon D., Varea O., Wandosell F.
FEBS Lett. 581:1579-1586(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN AXON FORMATION.
|||"Large-scale phosphorylation analysis of mouse liver."|
Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.
Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
|||"Genetic deficiency of glycogen synthase kinase-3beta corrects diabetes in mouse models of insulin resistance."|
Tanabe K., Liu Z., Patel S., Doble B.W., Li L., Cras-Meneur C., Martinez S.C., Welling C.M., White M.F., Bernal-Mizrachi E., Woodgett J.R., Permutt M.A.
PLoS Biol. 6:E37-E37(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN REGULATION OF PANCREATIC BETA-CELLS.
|||"Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3beta/beta-catenin signaling."|
Mao Y., Ge X., Frank C.L., Madison J.M., Koehler A.N., Doud M.K., Tassa C., Berry E.M., Soda T., Singh K.K., Biechele T., Petryshen T.L., Moon R.T., Haggarty S.J., Tsai L.H.
Cell 136:1017-1031(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH DISC1.
|||"Identification of zinc-finger BED domain-containing 3 (Zbed3) as a novel Axin-interacting protein that activates Wnt/beta-catenin signaling."|
Chen T., Li M., Ding Y., Zhang L.S., Xi Y., Pan W.J., Tao D.L., Wang J.Y., Li L.
J. Biol. Chem. 284:6683-6689(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH AXIN1 AND ZBED3, MUTAGENESIS OF LYS-85.
|||"DYRK1A and glycogen synthase kinase 3beta, a dual-kinase mechanism directing proteasomal degradation of CRY2 for circadian timekeeping."|
Kurabayashi N., Hirota T., Sakai M., Sanada K., Fukada Y.
Mol. Cell. Biol. 30:1757-1768(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
|||"Regulation of BMAL1 protein stability and circadian function by GSK3beta-mediated phosphorylation."|
Sahar S., Zocchi L., Kinoshita C., Borrelli E., Sassone-Corsi P.
PLoS ONE 5:E8561-E8561(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH ARNTL/BMAL1.
|||"Skin stem cells orchestrate directional migration by regulating microtubule-ACF7 connections through GSK3beta."|
Wu X., Shen Q.T., Oristian D.S., Lu C.P., Zheng Q., Wang H.W., Fuchs E.
Cell 144:341-352(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
|||"ZNRF1 promotes Wallerian degeneration by degrading AKT to induce GSK3B-dependent CRMP2 phosphorylation."|
Wakatsuki S., Saitoh F., Araki T.
Nat. Cell Biol. 13:1415-1423(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF DPYSL2, PHOSPHORYLATION AT SER-9, MUTAGENESIS OF SER-9.
|||"Glucose sensor O-GlcNAcylation coordinates with phosphorylation to regulate circadian clock."|
Kaasik K., Kivimae S., Allen J.J., Chalkley R.J., Huang Y., Baer K., Kissel H., Burlingame A.L., Shokat K.M., Ptacek L.J., Fu Y.H.
Cell Metab. 17:291-302(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, PHOSPHORYLATION AT SER-9.
|+||Additional computationally mapped references.|
|AF156099 mRNA. Translation: AAD39258.2.|
BC006936 mRNA. Translation: AAH06936.1.
BC060743 mRNA. Translation: AAH60743.1.
|RefSeq||NP_062801.1. NM_019827.6. |
3D structure databases
|SMR||Q9WV60. Positions 23-386. |
Protein-protein interaction databases
|BioGrid||208115. 20 interactions.|
|IntAct||Q9WV60. 17 interactions.|
Protocols and materials databases
Genome annotation databases
|Ensembl||ENSMUST00000023507; ENSMUSP00000023507; ENSMUSG00000022812. |
|UCSC||uc007zen.1. mouse. |
|MGI||MGI:1861437. Gsk3b. |
Enzyme and pathway databases
|Reactome||REACT_188804. Cell Cycle. |
Gene expression databases
Family and domain databases
|InterPro||IPR011009. Kinase-like_dom. |
|Pfam||PF00069. Pkinase. 1 hit. |
|SMART||SM00220. S_TKc. 1 hit. |
|SUPFAM||SSF56112. SSF56112. 1 hit. |
|PROSITE||PS00107. PROTEIN_KINASE_ATP. 1 hit. |
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
|ChiTaRS||GSK3B. mouse. |
|Accession||Primary (citable) accession number: Q9WV60|
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|