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P18266

- GSK3B_RAT

UniProt

P18266 - GSK3B_RAT

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Protein

Glycogen synthase kinase-3 beta

Gene
Gsk3b
Organism
Rattus norvegicus (Rat)
Status
Reviewed - 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 – 851ATP By similarity
Active sitei181 – 1811Proton acceptor By similarity

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi62 – 709ATP By similarity

GO - Molecular functioni

  1. ATP binding Source: RGD
  2. integrin binding Source: RGD
  3. ionotropic glutamate receptor binding Source: RGD
  4. kinase activity Source: UniProtKB
  5. protein binding Source: BHF-UCL
  6. protein kinase binding Source: RGD
  7. protein serine/threonine kinase activity Source: BHF-UCL
  8. tau protein binding Source: RGD
  9. tau-protein kinase activity Source: RGD

GO - Biological processi

  1. axonogenesis Source: Ensembl
  2. canonical Wnt signaling pathway involved in positive regulation of apoptotic process Source: Ensembl
  3. cell migration Source: Ensembl
  4. cellular response to interleukin-3 Source: UniProtKB
  5. cellular response to mechanical stimulus Source: RGD
  6. circadian rhythm Source: UniProtKB
  7. epithelial to mesenchymal transition Source: UniProtKB
  8. ER overload response Source: Ensembl
  9. establishment of cell polarity Source: RGD
  10. establishment or maintenance of cell polarity Source: RGD
  11. extrinsic apoptotic signaling pathway in absence of ligand Source: UniProtKB
  12. fat cell differentiation Source: Ensembl
  13. glycogen metabolic process Source: UniProtKB-KW
  14. hippocampus development Source: Ensembl
  15. hypermethylation of CpG island Source: Ensembl
  16. intracellular signal transduction Source: Ensembl
  17. myoblast fusion Source: Ensembl
  18. negative regulation of apoptotic process Source: Ensembl
  19. negative regulation of cardiac muscle hypertrophy Source: Ensembl
  20. negative regulation of dendrite morphogenesis Source: RGD
  21. negative regulation of MAP kinase activity Source: RGD
  22. negative regulation of NFAT protein import into nucleus Source: UniProtKB
  23. negative regulation of protein binding Source: Ensembl
  24. negative regulation of protein complex assembly Source: Ensembl
  25. organ morphogenesis Source: Ensembl
  26. peptidyl-serine phosphorylation Source: UniProtKB
  27. positive regulation of apoptotic process Source: RGD
  28. positive regulation of cell-matrix adhesion Source: Ensembl
  29. positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway Source: UniProtKB
  30. positive regulation of peptidyl-serine phosphorylation Source: Ensembl
  31. positive regulation of peptidyl-threonine phosphorylation Source: Ensembl
  32. positive regulation of protein binding Source: UniProtKB
  33. positive regulation of protein complex assembly Source: Ensembl
  34. positive regulation of protein export from nucleus Source: Ensembl
  35. positive regulation of Rac GTPase activity Source: Ensembl
  36. positive regulation of stem cell differentiation Source: Ensembl
  37. positive regulation of transcription from RNA polymerase II promoter Source: Ensembl
  38. protein export from nucleus Source: Ensembl
  39. protein localization to microtubule Source: Ensembl
  40. protein phosphorylation Source: BHF-UCL
  41. re-entry into mitotic cell cycle Source: Ensembl
  42. regulation of gene expression by genetic imprinting Source: Ensembl
  43. regulation of microtubule-based process Source: UniProtKB
  44. regulation of neuronal synaptic plasticity Source: RGD
  45. response to drug Source: RGD
  46. response to lithium ion Source: RGD
  47. superior temporal gyrus development Source: Ensembl
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_198729. Constitutive PI3K/AKT Signaling in Cancer.
REACT_216489. Regulation of HSF1-mediated heat shock response.
REACT_216976. disassembly of the destruction complex and recruitment of AXIN to the membrane.

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: Chromosome 11

Organism-specific databases

RGDi70982. Gsk3b.

Subcellular locationi

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.1 Publication

GO - Cellular componenti

  1. beta-catenin destruction complex Source: BHF-UCL
  2. centrosome Source: Ensembl
  3. cytoplasm Source: UniProtKB
  4. cytosol Source: RGD
  5. dendritic shaft Source: Ensembl
  6. dendritic spine Source: RGD
  7. growth cone Source: Ensembl
  8. membrane Source: UniProtKB
  9. membrane raft Source: RGD
  10. neuronal cell body Source: Ensembl
  11. nucleus Source: UniProtKB
  12. perinuclear region of cytoplasm Source: Ensembl
  13. plasma membrane Source: UniProtKB-SubCell
  14. protein complex Source: RGD
  15. 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 SGK3 By similarity
Modified residuei216 – 2161Phosphotyrosine1 Publication
Modified residuei389 – 3891Phosphoserine By 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.1 Publication
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.2 Publications

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.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini56 – 340285Protein kinaseAdd
BLAST

Sequence similaritiesi

Phylogenomic databases

eggNOGiCOG0515.
GeneTreeiENSGT00520000055635.
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_dom.
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

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MSGRPRTTSF AESCKPVQQP SAFGSMKVSR DKDGSKVTTV VATPGQGPDR    50
PQEVSYTDTK VIGNGSFGVV YQAKLCDSGE LVAIKKVLQD KRFKNRELQI 100
MRKLDHCNIV RLRYFFYSSG EKKDEVYLNL VLDYVPETVY RVARHYSRAK 150
QTLPVIYVKL YMYQLFRSLA YIHSFGICHR DIKPQNLLLD PDTAVLKLCD 200
FGSAKQLVRG EPNVSYICSR YYRAPELIFG ATDYTSSIDM WSAGCVLAEL 250
LLGQPIFPGD SGVDQLVEII KVLGTPTREQ IREMNPNYTE FKFPQIKAHP 300
WTKVFRPRTP PEAIALCSRL LEYTPTARLT PLEACAHSFF DELRDPNVKL 350
PNGRDTPALF NFTTQELSSN PPLATILIPP HARIQAAASP PANATAASDT 400
NAGDRGQTNN AASASASNST 420
Length:420
Mass (Da):46,742
Last modified:November 1, 1990 - v1
Checksum:i2F473FCAB89B4398
GO

Sequence conflict

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti240 – 2401M → V in CAA52020. 1 Publication

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
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

EnsembliENSRNOT00000003867; ENSRNOP00000003867; ENSRNOG00000002833.
GeneIDi84027.
KEGGirno:84027.
UCSCiRGD:70982. rat.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
X53428 mRNA. Translation: CAA37519.1 .
X73653 mRNA. Translation: CAA52020.1 .
PIRi S14708. TVRTKB.
RefSeqi NP_114469.1. NM_032080.1.
UniGenei Rn.10426.

3D structure databases

ProteinModelPortali P18266.
SMRi P18266. Positions 23-386.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 249893. 9 interactions.
DIPi DIP-40957N.
IntActi P18266. 1 interaction.
MINTi MINT-121872.
STRINGi 10116.ENSRNOP00000003867.

Chemistry

BindingDBi P18266.
ChEMBLi CHEMBL3669.

PTM databases

PhosphoSitei P18266.

Proteomic databases

PaxDbi P18266.
PRIDEi P18266.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENSRNOT00000003867 ; ENSRNOP00000003867 ; ENSRNOG00000002833 .
GeneIDi 84027.
KEGGi rno:84027.
UCSCi RGD:70982. rat.

Organism-specific databases

CTDi 2932.
RGDi 70982. Gsk3b.

Phylogenomic databases

eggNOGi COG0515.
GeneTreei ENSGT00520000055635.
HOGENOMi HOG000233017.
HOVERGENi HBG014652.
InParanoidi P18266.
KOi K03083.
OrthoDBi EOG7TF78V.
PhylomeDBi P18266.
TreeFami TF101104.

Enzyme and pathway databases

BRENDAi 2.7.11.26. 5301.
Reactomei REACT_198729. Constitutive PI3K/AKT Signaling in Cancer.
REACT_216489. Regulation of HSF1-mediated heat shock response.
REACT_216976. disassembly of the destruction complex and recruitment of AXIN to the membrane.

Miscellaneous databases

NextBioi 616603.
PROi P18266.

Gene expression databases

Genevestigatori P18266.

Family and domain databases

InterProi IPR011009. 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 ]
Pfami PF00069. Pkinase. 1 hit.
[Graphical view ]
SMARTi SM00220. S_TKc. 1 hit.
[Graphical view ]
SUPFAMi SSF56112. SSF56112. 1 hit.
PROSITEi PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view ]
ProtoNeti Search...

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: September 3, 2014
This is version 152 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

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