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Protein

Glycogen synthase kinase-3 beta

Gene

Gsk3b

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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 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.3 Publications

Catalytic activityi

ATP + [tau protein] = ADP + [tau protein] phosphate.
ATP + a protein = ADP + a phosphoprotein.

Enzyme regulationi

Activated by phosphorylation at Tyr-216. In response to insulin, inhibited by phosphorylation at Ser-9 by PKB/AKT1; phosphorylation at this site causes a conformational change, preventing access of substrates to the active site. Inhibited by lithium.

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei85 – 851ATPPROSITE-ProRule annotation
Active sitei181 – 1811Proton acceptorPROSITE-ProRule annotation

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi62 – 709ATPPROSITE-ProRule annotation

GO - Molecular functioni

  • ATP binding Source: RGD
  • integrin binding Source: RGD
  • ionotropic glutamate receptor binding Source: RGD
  • kinase activity Source: UniProtKB
  • protein kinase binding Source: RGD
  • protein serine/threonine kinase activity Source: BHF-UCL
  • tau protein binding Source: RGD
  • tau-protein kinase activity Source: RGD
  • transcription factor binding Source: RGD

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Developmental protein, Kinase, Serine/threonine-protein kinase, Signal transduction inhibitor, Transferase

Keywords - Biological processi

Biological rhythms, Carbohydrate metabolism, Differentiation, Glycogen metabolism, Neurogenesis, Wnt signaling pathway

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.11.26. 5301.
ReactomeiREACT_280715. GLI3 is processed to GLI3R by the proteasome.
REACT_287195. Degradation of GLI2 by the proteasome.
REACT_289020. Degradation of beta-catenin by the destruction complex.
REACT_299983. Regulation of HSF1-mediated heat shock response.
REACT_301102. CRMPs in Sema3A signaling.
REACT_341833. disassembly of the destruction complex and recruitment of AXIN to the membrane.
REACT_345474. Beta-catenin phosphorylation cascade.
REACT_348904. AKT phosphorylates targets in the cytosol.

Names & Taxonomyi

Protein namesi
Recommended name:
Glycogen synthase kinase-3 beta (EC:2.7.11.26)
Short name:
GSK-3 beta
Alternative name(s):
Factor A
Short name:
FA
Serine/threonine-protein kinase GSK3B (EC:2.7.11.1)
Gene namesi
Name:Gsk3b
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
ProteomesiUP000002494 Componenti: Unplaced

Organism-specific databases

RGDi70982. Gsk3b.

Subcellular locationi

  • Cytoplasm By similarity
  • Nucleus By similarity
  • Membrane 1 Publication
  • 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).By similarity

GO - Cellular componenti

  • beta-catenin destruction complex Source: BHF-UCL
  • centrosome Source: Ensembl
  • cytoplasm Source: UniProtKB
  • cytosol Source: RGD
  • dendritic shaft Source: Ensembl
  • dendritic spine Source: RGD
  • growth cone Source: Ensembl
  • membrane Source: UniProtKB
  • membrane raft Source: RGD
  • neuronal cell body Source: Ensembl
  • nucleoplasm Source: Ensembl
  • nucleus Source: UniProtKB
  • perinuclear region of cytoplasm Source: Ensembl
  • plasma membrane Source: UniProtKB-SubCell
  • protein complex Source: RGD
  • ribonucleoprotein complex Source: Ensembl
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Membrane, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi9 – 91S → A: Loss of phosphorylation; No inhibition of activity. 1 Publication
Mutagenesisi216 – 2161Y → F: Loss of phosphorylation and strong reduction of activity. 1 Publication

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 420420Glycogen synthase kinase-3 betaPRO_0000085982Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei9 – 91Phosphoserine; by PKB/AKT1, RPS6KA3 and SGK3By similarity
Modified residuei216 – 2161Phosphotyrosine1 Publication
Modified residuei389 – 3891PhosphoserineBy similarity

Post-translational modificationi

Phosphorylated by AKT1 and ILK1. Upon insulin-mediated signaling, the activated PKB/AKT1 and RPS6KA3 protein kinases phosphorylate and desactivate GSK3B, resulting in the dephosphorylation and activation of GYS1. Activated by phosphorylation at Tyr-216 (By similarity).By similarity
Mono-ADP-ribosylation by PARP10 negatively regulates kinase activity.By similarity

Keywords - PTMi

ADP-ribosylation, Phosphoprotein

Proteomic databases

PaxDbiP18266.
PRIDEiP18266.

PTM databases

PhosphoSiteiP18266.

Expressioni

Gene expression databases

GenevestigatoriP18266.

Interactioni

Subunit structurei

Monomer. Interacts with DAB2IP (via C2 domain); the interaction stimulates GSK3B kinase activation. Interacts (via C2 domain) with PPP2CA (By similarity). Interacts with ARRB2, AXIN1, CABYR, DISC1, MMP2, MUC1, NIN, PRUNE and ZBED3 (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). Found in a complex composed of MACF1, APC, AXIN1, CTNNB1 and GSK3B. Interacts with SGK3. Interacts with the CLOCK-ARNTL/BMAL1 heterodimer. Interacts with the ARNTL/BMAL1 (By similarity).By similarity

Protein-protein interaction databases

BioGridi249893. 9 interactions.
DIPiDIP-40957N.
IntActiP18266. 1 interaction.
MINTiMINT-121872.
STRINGi10116.ENSRNOP00000003867.

Structurei

3D structure databases

ProteinModelPortaliP18266.
SMRiP18266. Positions 23-386.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini56 – 340285Protein kinasePROSITE-ProRule annotationAdd
BLAST

Sequence similaritiesi

Contains 1 protein kinase domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiCOG0515.
HOGENOMiHOG000233017.
HOVERGENiHBG014652.
InParanoidiP18266.
KOiK03083.
OrthoDBiEOG7TF78V.
PhylomeDBiP18266.
TreeFamiTF101104.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

P18266-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MSGRPRTTSF AESCKPVQQP SAFGSMKVSR DKDGSKVTTV VATPGQGPDR
60 70 80 90 100
PQEVSYTDTK VIGNGSFGVV YQAKLCDSGE LVAIKKVLQD KRFKNRELQI
110 120 130 140 150
MRKLDHCNIV RLRYFFYSSG EKKDEVYLNL VLDYVPETVY RVARHYSRAK
160 170 180 190 200
QTLPVIYVKL YMYQLFRSLA YIHSFGICHR DIKPQNLLLD PDTAVLKLCD
210 220 230 240 250
FGSAKQLVRG EPNVSYICSR YYRAPELIFG ATDYTSSIDM WSAGCVLAEL
260 270 280 290 300
LLGQPIFPGD SGVDQLVEII KVLGTPTREQ IREMNPNYTE FKFPQIKAHP
310 320 330 340 350
WTKVFRPRTP PEAIALCSRL LEYTPTARLT PLEACAHSFF DELRDPNVKL
360 370 380 390 400
PNGRDTPALF NFTTQELSSN PPLATILIPP HARIQAAASP PANATAASDT
410 420
NAGDRGQTNN AASASASNST
Length:420
Mass (Da):46,742
Last modified:November 1, 1990 - v1
Checksum:i2F473FCAB89B4398
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti240 – 2401M → V in CAA52020 (PubMed:7686508).Curated

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X53428 mRNA. Translation: CAA37519.1.
X73653 mRNA. Translation: CAA52020.1.
PIRiS14708. TVRTKB.
RefSeqiNP_114469.1. NM_032080.1.
UniGeneiRn.10426.

Genome annotation databases

GeneIDi84027.
KEGGirno:84027.
UCSCiRGD:70982. rat.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X53428 mRNA. Translation: CAA37519.1.
X73653 mRNA. Translation: CAA52020.1.
PIRiS14708. TVRTKB.
RefSeqiNP_114469.1. NM_032080.1.
UniGeneiRn.10426.

3D structure databases

ProteinModelPortaliP18266.
SMRiP18266. Positions 23-386.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi249893. 9 interactions.
DIPiDIP-40957N.
IntActiP18266. 1 interaction.
MINTiMINT-121872.
STRINGi10116.ENSRNOP00000003867.

Chemistry

BindingDBiP18266.
ChEMBLiCHEMBL3669.

PTM databases

PhosphoSiteiP18266.

Proteomic databases

PaxDbiP18266.
PRIDEiP18266.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

GeneIDi84027.
KEGGirno:84027.
UCSCiRGD:70982. rat.

Organism-specific databases

CTDi2932.
RGDi70982. Gsk3b.

Phylogenomic databases

eggNOGiCOG0515.
HOGENOMiHOG000233017.
HOVERGENiHBG014652.
InParanoidiP18266.
KOiK03083.
OrthoDBiEOG7TF78V.
PhylomeDBiP18266.
TreeFamiTF101104.

Enzyme and pathway databases

BRENDAi2.7.11.26. 5301.
ReactomeiREACT_280715. GLI3 is processed to GLI3R by the proteasome.
REACT_287195. Degradation of GLI2 by the proteasome.
REACT_289020. Degradation of beta-catenin by the destruction complex.
REACT_299983. Regulation of HSF1-mediated heat shock response.
REACT_301102. CRMPs in Sema3A signaling.
REACT_341833. disassembly of the destruction complex and recruitment of AXIN to the membrane.
REACT_345474. Beta-catenin phosphorylation cascade.
REACT_348904. AKT phosphorylates targets in the cytosol.

Miscellaneous databases

NextBioi616603.
PROiP18266.

Gene expression databases

GenevestigatoriP18266.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

  1. "Molecular cloning and expression of glycogen synthase kinase-3/factor A."
    Woodgett J.R.
    EMBO J. 9:2431-2438(1990) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA].
    Strain: Sprague-Dawley.
    Tissue: Brain.
  2. "Glycogen synthase kinase 3 beta is identical to tau protein kinase I generating several epitopes of paired helical filaments."
    Ishiguro K., Shiratsuchi A., Sato S., Omori A., Arioka M., Kobayashi S., Uchida T., Imahori K.
    FEBS Lett. 325:167-172(1993) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA].
    Strain: Sprague-Dawley.
    Tissue: Brain cortex.
  3. "Modulation of the glycogen synthase kinase-3 family by tyrosine phosphorylation."
    Hughes K., Nikolakaki E., Plyte S.E., Totty N.F., Woodgett J.R.
    EMBO J. 12:803-808(1993) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHOSPHORYLATION AT TYR-216, MUTAGENESIS OF TYR-216.
  4. "Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3beta and beta-catenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin."
    Ikeda S., Kishida S., Yamamoto H., Murai H., Koyama S., Kikuchi A.
    EMBO J. 17:1371-1384(1998) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, INTERACTION WITH CTNNB1/BETA-CATENIN.
  5. "The role of microtubule actin cross-linking factor 1 (MACF1) in the Wnt signaling pathway."
    Chen H.J., Lin C.M., Lin C.S., Perez-Olle R., Leung C.L., Liem R.K.
    Genes Dev. 20:1933-1945(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: SUBCELLULAR LOCATION, IDENTIFICATION IN A COMPLEX WITH MACF1; APC; AXIN1 AND CTNNB1.
  6. "Inhibition of GSK3 promotes replication and survival of pancreatic beta cells."
    Mussmann R., Geese M., Harder F., Kegel S., Andag U., Lomow A., Burk U., Onichtchouk D., Dohrmann C., Austen M.
    J. Biol. Chem. 282:12030-12037(2007) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN REGULATION OF PANCREATIC BETA-CELLS.
  7. "Glycogen synthase kinase (GSK) 3beta directly phosphorylates Serine 212 in the regulatory loop and inhibits microtubule affinity-regulating kinase (MARK) 2."
    Timm T., Balusamy K., Li X., Biernat J., Mandelkow E., Mandelkow E.M.
    J. Biol. Chem. 283:18873-18882(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN PHOSPHORYLATION OF MARK2, MUTAGENESIS OF SER-9.

Entry informationi

Entry nameiGSK3B_RAT
AccessioniPrimary (citable) accession number: P18266
Entry historyi
Integrated into UniProtKB/Swiss-Prot: November 1, 1990
Last sequence update: November 1, 1990
Last modified: May 27, 2015
This is version 160 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Miscellaneous

Simultaneous silencing of GSK3A and GSK3B by RNAi stimulates replication and promotes survival of INS-1E pancreatic beta cells.1 Publication

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.