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P18266

- GSK3B_RAT

UniProt

P18266 - GSK3B_RAT

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
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    • History
      Entry version 153 (01 Oct 2014)
      Sequence version 1 (01 Nov 1990)
      Previous versions | rss
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    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

    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

    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 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

    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

    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.
    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

    « Hide

    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

    Experimental Info

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

    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: October 1, 2014
    This is version 153 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