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P18266 (GSK3B_RAT) Reviewed, UniProtKB/Swiss-Prot

Last modified June 11, 2014. Version 151. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (1) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Glycogen synthase kinase-3 beta

Short name=GSK-3 beta
EC=2.7.11.26
Alternative name(s):
Factor A
Short name=FA
Serine/threonine-protein kinase GSK3B
EC=2.7.11.1
Gene names
Name:Gsk3b
OrganismRattus norvegicus (Rat) [Reference proteome]
Taxonomic identifier10116 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus

Protein attributes

Sequence length420 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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. Ref.4 Ref.6 Ref.7

Catalytic activity

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

ATP + a protein = ADP + a phosphoprotein.

Enzyme regulation

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.

Subunit structure

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. Ref.4 Ref.5

Subcellular location

Cytoplasm By similarity. Nucleus By similarity. Membrane. 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. Ref.5

Post-translational modification

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. Ref.3

Mono-ADP-ribosylation by PARP10 negatively regulates kinase activity By similarity.

Miscellaneous

Simultaneous silencing of GSK3A and GSK3B by RNAi stimulates replication and promotes survival of INS-1E pancreatic beta cells (Ref.6).

Sequence similarities

Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. GSK-3 subfamily.

Contains 1 protein kinase domain.

Ontologies

Keywords
   Biological processBiological rhythms
Carbohydrate metabolism
Differentiation
Glycogen metabolism
Neurogenesis
Wnt signaling pathway
   Cellular componentCell membrane
Cytoplasm
Membrane
Nucleus
   LigandATP-binding
Nucleotide-binding
   Molecular functionDevelopmental protein
Kinase
Serine/threonine-protein kinase
Signal transduction inhibitor
Transferase
   PTMADP-ribosylation
Phosphoprotein
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processER overload response

Inferred from electronic annotation. Source: Ensembl

axonogenesis

Inferred from electronic annotation. Source: Ensembl

canonical Wnt signaling pathway involved in positive regulation of apoptotic process

Inferred from electronic annotation. Source: Ensembl

cell migration

Inferred from electronic annotation. Source: Ensembl

cellular response to interleukin-3

Inferred from sequence or structural similarity. Source: UniProtKB

cellular response to mechanical stimulus

Inferred from direct assay PubMed 20042609. Source: RGD

circadian rhythm

Inferred from sequence or structural similarity. Source: UniProtKB

epithelial to mesenchymal transition

Inferred from sequence or structural similarity. Source: UniProtKB

establishment of cell polarity

Inferred from direct assay PubMed 12610628. Source: RGD

establishment or maintenance of cell polarity

Inferred from direct assay PubMed 12610628. Source: RGD

extrinsic apoptotic signaling pathway in absence of ligand

Inferred from sequence or structural similarity. Source: UniProtKB

fat cell differentiation

Inferred from electronic annotation. Source: Ensembl

glycogen metabolic process

Inferred from electronic annotation. Source: UniProtKB-KW

hippocampus development

Inferred from electronic annotation. Source: Ensembl

hypermethylation of CpG island

Inferred from electronic annotation. Source: Ensembl

intracellular signal transduction

Inferred from electronic annotation. Source: Ensembl

myoblast fusion

Inferred from electronic annotation. Source: Ensembl

negative regulation of MAP kinase activity

Inferred from mutant phenotype PubMed 17182785. Source: RGD

negative regulation of NFAT protein import into nucleus

Inferred from sequence or structural similarity. Source: UniProtKB

negative regulation of apoptotic process

Inferred from electronic annotation. Source: Ensembl

negative regulation of cardiac muscle hypertrophy

Inferred from electronic annotation. Source: Ensembl

negative regulation of dendrite morphogenesis

Inferred from mutant phenotype PubMed 17182785. Source: RGD

negative regulation of protein binding

Inferred from electronic annotation. Source: Ensembl

negative regulation of protein complex assembly

Inferred from electronic annotation. Source: Ensembl

organ morphogenesis

Inferred from electronic annotation. Source: Ensembl

peptidyl-serine phosphorylation

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of Rac GTPase activity

Inferred from electronic annotation. Source: Ensembl

positive regulation of apoptotic process

Inferred from direct assay PubMed 12393899. Source: RGD

positive regulation of cell-matrix adhesion

Inferred from electronic annotation. Source: Ensembl

positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of peptidyl-serine phosphorylation

Inferred from electronic annotation. Source: Ensembl

positive regulation of peptidyl-threonine phosphorylation

Inferred from electronic annotation. Source: Ensembl

positive regulation of protein binding

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of protein complex assembly

Inferred from electronic annotation. Source: Ensembl

positive regulation of protein export from nucleus

Inferred from electronic annotation. Source: Ensembl

positive regulation of stem cell differentiation

Inferred from electronic annotation. Source: Ensembl

positive regulation of transcription from RNA polymerase II promoter

Inferred from electronic annotation. Source: Ensembl

protein export from nucleus

Inferred from electronic annotation. Source: Ensembl

protein localization to microtubule

Inferred from electronic annotation. Source: Ensembl

protein phosphorylation

Inferred from direct assay PubMed 11035810. Source: BHF-UCL

re-entry into mitotic cell cycle

Inferred from electronic annotation. Source: Ensembl

regulation of gene expression by genetic imprinting

Inferred from electronic annotation. Source: Ensembl

regulation of microtubule-based process

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of neuronal synaptic plasticity

Inferred from mutant phenotype PubMed 17329210. Source: RGD

response to drug

Inferred from expression pattern PubMed 19359144. Source: RGD

response to lithium ion

Inferred from expression pattern PubMed 19359144. Source: RGD

superior temporal gyrus development

Inferred from electronic annotation. Source: Ensembl

   Cellular_componentbeta-catenin destruction complex

Inferred from direct assay PubMed 10228155. Source: BHF-UCL

centrosome

Inferred from electronic annotation. Source: Ensembl

cytoplasm

Inferred from sequence or structural similarity. Source: UniProtKB

cytosol

Inferred from direct assay PubMed 17329210. Source: RGD

dendritic shaft

Inferred from electronic annotation. Source: Ensembl

dendritic spine

Inferred from direct assay PubMed 17329210. Source: RGD

growth cone

Inferred from electronic annotation. Source: Ensembl

membrane

Inferred from direct assay Ref.5. Source: UniProtKB

membrane raft

Inferred from direct assay PubMed 16735023. Source: RGD

neuronal cell body

Inferred from electronic annotation. Source: Ensembl

nucleus

Inferred from sequence or structural similarity. Source: UniProtKB

perinuclear region of cytoplasm

Inferred from electronic annotation. Source: Ensembl

plasma membrane

Inferred from electronic annotation. Source: UniProtKB-SubCell

protein complex

Inferred from direct assay PubMed 17329210. Source: RGD

ribonucleoprotein complex

Inferred from electronic annotation. Source: Ensembl

   Molecular_functionATP binding

Inferred from direct assay PubMed 16879317PubMed 17329210. Source: RGD

integrin binding

Inferred from physical interaction PubMed 18677563. Source: RGD

ionotropic glutamate receptor binding

Inferred from physical interaction PubMed 17329210. Source: RGD

kinase activity

Inferred from sequence or structural similarity. Source: UniProtKB

protein binding

Inferred from physical interaction PubMed 10228155Ref.4. Source: BHF-UCL

protein kinase binding

Inferred from physical interaction PubMed 16478782. Source: RGD

protein serine/threonine kinase activity

Inferred from direct assay PubMed 11035810Ref.4. Source: BHF-UCL

tau protein binding

Inferred from direct assay PubMed 16735023. Source: RGD

tau-protein kinase activity

Inferred from direct assay PubMed 16735023. Source: RGD

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 420420Glycogen synthase kinase-3 beta
PRO_0000085982

Regions

Domain56 – 340285Protein kinase
Nucleotide binding62 – 709ATP By similarity

Sites

Active site1811Proton acceptor By similarity
Binding site851ATP By similarity

Amino acid modifications

Modified residue91Phosphoserine; by PKB/AKT1, RPS6KA3 and SGK3 By similarity
Modified residue2161Phosphotyrosine Ref.3
Modified residue3891Phosphoserine By similarity

Experimental info

Mutagenesis91S → A: Loss of phosphorylation; No inhibition of activity. Ref.7
Mutagenesis2161Y → F: Loss of phosphorylation and strong reduction of activity. Ref.3
Sequence conflict2401M → V in CAA52020. Ref.2

Sequences

Sequence LengthMass (Da)Tools
P18266 [UniParc].

Last modified November 1, 1990. Version 1.
Checksum: 2F473FCAB89B4398

FASTA42046,742
        10         20         30         40         50         60 
MSGRPRTTSF AESCKPVQQP SAFGSMKVSR DKDGSKVTTV VATPGQGPDR PQEVSYTDTK 

        70         80         90        100        110        120 
VIGNGSFGVV YQAKLCDSGE LVAIKKVLQD KRFKNRELQI MRKLDHCNIV RLRYFFYSSG 

       130        140        150        160        170        180 
EKKDEVYLNL VLDYVPETVY RVARHYSRAK QTLPVIYVKL YMYQLFRSLA YIHSFGICHR 

       190        200        210        220        230        240 
DIKPQNLLLD PDTAVLKLCD FGSAKQLVRG EPNVSYICSR YYRAPELIFG ATDYTSSIDM 

       250        260        270        280        290        300 
WSAGCVLAEL LLGQPIFPGD SGVDQLVEII KVLGTPTREQ IREMNPNYTE FKFPQIKAHP 

       310        320        330        340        350        360 
WTKVFRPRTP PEAIALCSRL LEYTPTARLT PLEACAHSFF DELRDPNVKL PNGRDTPALF 

       370        380        390        400        410        420 
NFTTQELSSN PPLATILIPP HARIQAAASP PANATAASDT NAGDRGQTNN AASASASNST 

« Hide

References

[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.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
X53428 mRNA. Translation: CAA37519.1.
X73653 mRNA. Translation: CAA52020.1.
PIRTVRTKB. S14708.
RefSeqNP_114469.1. NM_032080.1.
UniGeneRn.10426.

3D structure databases

ProteinModelPortalP18266.
SMRP18266. Positions 23-386.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid249893. 9 interactions.
DIPDIP-40957N.
IntActP18266. 1 interaction.
MINTMINT-121872.
STRING10116.ENSRNOP00000003867.

Chemistry

BindingDBP18266.
ChEMBLCHEMBL3669.

PTM databases

PhosphoSiteP18266.

Proteomic databases

PaxDbP18266.
PRIDEP18266.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSRNOT00000003867; ENSRNOP00000003867; ENSRNOG00000002833.
GeneID84027.
KEGGrno:84027.
UCSCRGD:70982. rat.

Organism-specific databases

CTD2932.
RGD70982. Gsk3b.

Phylogenomic databases

eggNOGCOG0515.
GeneTreeENSGT00520000055635.
HOGENOMHOG000233017.
HOVERGENHBG014652.
InParanoidP18266.
KOK03083.
OrthoDBEOG7TF78V.
PhylomeDBP18266.
TreeFamTF101104.

Enzyme and pathway databases

BRENDA2.7.11.26. 5301.
ReactomeREACT_206767. Disease.
REACT_212996. Signal Transduction.
REACT_227097. Immune System.

Gene expression databases

GenevestigatorP18266.

Family and domain databases

InterProIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMSSF56112. SSF56112. 1 hit.
PROSITEPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio616603.
PROP18266.

Entry information

Entry nameGSK3B_RAT
AccessionPrimary (citable) accession number: P18266
Entry history
Integrated into UniProtKB/Swiss-Prot: November 1, 1990
Last sequence update: November 1, 1990
Last modified: June 11, 2014
This is version 151 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families