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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)DescriptionActionsGraphical viewLength
Binding sitei85ATPPROSITE-ProRule annotation1
Active sitei181Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi62 – 70ATPPROSITE-ProRule annotation9

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

  • aging Source: RGD
  • cellular response to dopamine Source: RGD
  • cellular response to erythropoietin Source: RGD
  • cellular response to hydrogen peroxide Source: RGD
  • cellular response to interleukin-3 Source: UniProtKB
  • cellular response to iron(II) ion Source: RGD
  • cellular response to lithium ion Source: RGD
  • cellular response to mechanical stimulus Source: RGD
  • circadian rhythm Source: UniProtKB
  • epithelial to mesenchymal transition Source: UniProtKB
  • establishment of cell polarity Source: RGD
  • establishment or maintenance of cell polarity Source: RGD
  • extrinsic apoptotic signaling pathway in absence of ligand Source: UniProtKB
  • glycogen metabolic process Source: UniProtKB-KW
  • negative regulation of dendrite development Source: RGD
  • negative regulation of dendrite morphogenesis Source: RGD
  • negative regulation of dopaminergic neuron differentiation Source: RGD
  • negative regulation of MAP kinase activity Source: RGD
  • negative regulation of neuron migration Source: RGD
  • negative regulation of NFAT protein import into nucleus Source: UniProtKB
  • negative regulation of nitric-oxide synthase activity Source: RGD
  • negative regulation of protein localization to nucleus Source: BHF-UCL
  • negative regulation of smooth muscle cell apoptotic process Source: RGD
  • peptidyl-serine phosphorylation Source: UniProtKB
  • positive regulation of apoptotic process Source: RGD
  • positive regulation of DNA biosynthetic process Source: RGD
  • positive regulation of excitatory postsynaptic potential Source: RGD
  • positive regulation of mitochondrial membrane potential Source: RGD
  • positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway Source: UniProtKB
  • positive regulation of neuron apoptotic process Source: RGD
  • positive regulation of protein binding Source: UniProtKB
  • positive regulation of protein catabolic process Source: RGD
  • positive regulation of smooth muscle cell proliferation Source: RGD
  • protein phosphorylation Source: BHF-UCL
  • regulation of axon extension Source: RGD
  • regulation of axonogenesis Source: RGD
  • regulation of dendrite morphogenesis Source: RGD
  • regulation of microtubule-based process Source: UniProtKB
  • regulation of neuronal synaptic plasticity Source: RGD
  • response to activity Source: RGD
  • response to angiotensin Source: RGD
  • response to drug Source: RGD
  • response to epinephrine Source: RGD
  • response to estradiol Source: RGD
  • response to insulin Source: RGD
  • response to insulin-like growth factor stimulus Source: RGD
  • response to L-glutamate Source: RGD
  • response to lithium ion Source: RGD
  • response to ultrasound Source: RGD
  • Wnt signaling pathway Source: UniProtKB-KW
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.
ReactomeiR-RNO-198323. 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
Proteomesi
  • UP000002494 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

  • axon Source: RGD
  • beta-catenin destruction complex Source: BHF-UCL
  • cytoplasm Source: UniProtKB
  • cytosol Source: RGD
  • dendrite Source: RGD
  • dendritic spine Source: RGD
  • membrane Source: UniProtKB
  • membrane raft Source: RGD
  • microtubule Source: RGD
  • mitochondrion Source: RGD
  • nucleus Source: UniProtKB
  • plasma membrane Source: UniProtKB-SubCell
  • protein complex Source: RGD
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Membrane, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi9S → A: Loss of phosphorylation; No inhibition of activity. 1 Publication1
Mutagenesisi216Y → F: Loss of phosphorylation and strong reduction of activity. 1 Publication1

Chemistry databases

ChEMBLiCHEMBL3669.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000859821 – 420Glycogen synthase kinase-3 betaAdd BLAST420

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei9Phosphoserine; by PKB/AKT1, RPS6KA3 and SGK3By similarity1
Modified residuei216Phosphotyrosine1 Publication1
Modified residuei389PhosphoserineCombined sources1

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

iPTMnetiP18266.
PhosphoSitePlusiP18266.

Expressioni

Gene expression databases

BgeeiENSRNOG00000002833.

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). Interacts with CTNND2 (By similarity).By similarity

GO - Molecular functioni

  • integrin binding Source: RGD
  • ionotropic glutamate receptor binding Source: RGD
  • protein kinase binding Source: RGD
  • tau protein binding Source: RGD
  • transcription factor binding Source: RGD

Protein-protein interaction databases

BioGridi249893. 9 interactors.
DIPiDIP-40957N.
IntActiP18266. 1 interactor.
MINTiMINT-121872.
STRINGi10116.ENSRNOP00000003867.

Chemistry databases

BindingDBiP18266.

Structurei

3D structure databases

ProteinModelPortaliP18266.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini56 – 340Protein kinasePROSITE-ProRule annotationAdd BLAST285

Sequence similaritiesi

Contains 1 protein kinase domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiKOG0658. Eukaryota.
COG0515. LUCA.
HOGENOMiHOG000233017.
HOVERGENiHBG014652.
InParanoidiP18266.
KOiK03083.
PhylomeDBiP18266.
TreeFamiTF101104.

Family and domain databases

InterProiIPR033573. GSK3B.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PANTHERiPTHR24057:SF8. PTHR24057:SF8. 1 hit.
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)DescriptionActionsGraphical viewLength
Sequence conflicti240M → V in CAA52020 (PubMed:7686508).Curated1

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.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi249893. 9 interactors.
DIPiDIP-40957N.
IntActiP18266. 1 interactor.
MINTiMINT-121872.
STRINGi10116.ENSRNOP00000003867.

Chemistry databases

BindingDBiP18266.
ChEMBLiCHEMBL3669.

PTM databases

iPTMnetiP18266.
PhosphoSitePlusiP18266.

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

eggNOGiKOG0658. Eukaryota.
COG0515. LUCA.
HOGENOMiHOG000233017.
HOVERGENiHBG014652.
InParanoidiP18266.
KOiK03083.
PhylomeDBiP18266.
TreeFamiTF101104.

Enzyme and pathway databases

BRENDAi2.7.11.26. 5301.
ReactomeiR-RNO-198323. AKT phosphorylates targets in the cytosol.

Miscellaneous databases

PROiP18266.

Gene expression databases

BgeeiENSRNOG00000002833.

Family and domain databases

InterProiIPR033573. GSK3B.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PANTHERiPTHR24057:SF8. PTHR24057:SF8. 1 hit.
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...

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: November 2, 2016
This is version 174 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

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 one 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.