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Q2NL51

- GSK3A_MOUSE

UniProt

Q2NL51 - GSK3A_MOUSE

Protein

Glycogen synthase kinase-3 alpha

Gene

Gsk3a

Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 83 (01 Oct 2014)
      Sequence version 2 (20 Mar 2007)
      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), CTNNB1/beta-catenin, APC and AXIN1. Requires primed phosphorylation of the majority of its substrates. Contributes to insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity and hence glycogen synthesis. Regulates glycogen metabolism in liver, but not in muscle. May also mediate the development of insulin resistance by regulating activation of transcription factors. In Wnt signaling, regulates the level and transcriptional activity of nuclear CTNNB1/beta-catenin. Facilitates amyloid precursor protein (APP) processing and the generation of APP-derived amyloid plaques found in Alzheimer disease. May be involved in the regulation of replication in pancreatic beta-cells. Is necessary for the establishment of neuronal polarity and axon outgrowth. Through phosphorylation of the anti-apoptotic protein MCL1, may control cell apoptosis in response to growth factors deprivation.4 Publications

    Catalytic activityi

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

    Enzyme regulationi

    Activated by phosphorylation at Tyr-279. In response to insulin, inhibited by phosphorylation at Ser-21 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 sitei148 – 1481ATPPROSITE-ProRule annotation
    Active sitei244 – 2441Proton acceptorPROSITE-ProRule annotation

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Nucleotide bindingi125 – 1339ATPPROSITE-ProRule annotation

    GO - Molecular functioni

    1. ATP binding Source: UniProtKB-KW
    2. protein binding Source: UniProtKB
    3. protein kinase activity Source: MGI
    4. protein serine/threonine kinase activity Source: UniProtKB
    5. tau-protein kinase activity Source: UniProtKB-EC

    GO - Biological processi

    1. cardiac left ventricle morphogenesis Source: BHF-UCL
    2. cell migration Source: MGI
    3. cellular response to interleukin-3 Source: UniProtKB
    4. cellular response to lithium ion Source: MGI
    5. cellular response to organic cyclic compound Source: MGI
    6. extrinsic apoptotic signaling pathway in absence of ligand Source: UniProtKB
    7. glycogen metabolic process Source: UniProtKB-KW
    8. hypermethylation of CpG island Source: BHF-UCL
    9. insulin receptor signaling pathway Source: BHF-UCL
    10. negative regulation of cell growth involved in cardiac muscle cell development Source: BHF-UCL
    11. negative regulation of TOR signaling Source: BHF-UCL
    12. nervous system development Source: UniProtKB-KW
    13. positive regulation of adrenergic receptor signaling pathway Source: BHF-UCL
    14. positive regulation of cAMP biosynthetic process Source: BHF-UCL
    15. positive regulation of glycogen (starch) synthase activity Source: BHF-UCL
    16. positive regulation of heart contraction Source: BHF-UCL
    17. positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway Source: UniProtKB
    18. positive regulation of peptidyl-serine phosphorylation Source: MGI
    19. positive regulation of peptidyl-threonine phosphorylation Source: MGI
    20. positive regulation of transcription from RNA polymerase II promoter Source: BHF-UCL
    21. proteasome-mediated ubiquitin-dependent protein catabolic process Source: UniProtKB
    22. protein phosphorylation Source: UniProtKB
    23. regulation of gene expression by genetic imprinting Source: BHF-UCL
    24. regulation of systemic arterial blood pressure Source: BHF-UCL
    25. Wnt signaling pathway Source: UniProtKB-KW

    Keywords - Molecular functioni

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

    Keywords - Biological processi

    Carbohydrate metabolism, Glycogen metabolism, Neurogenesis, Wnt signaling pathway

    Keywords - Ligandi

    ATP-binding, Nucleotide-binding

    Enzyme and pathway databases

    ReactomeiREACT_106572. XBP1(S) activates chaperone genes.
    REACT_196588. Constitutive PI3K/AKT Signaling in Cancer.
    REACT_220918. AKT phosphorylates targets in the cytosol.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Glycogen synthase kinase-3 alpha (EC:2.7.11.26)
    Short name:
    GSK-3 alpha
    Alternative name(s):
    Serine/threonine-protein kinase GSK3A (EC:2.7.11.1)
    Gene namesi
    Name:Gsk3a
    OrganismiMus musculus (Mouse)
    Taxonomic identifieri10090 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
    ProteomesiUP000000589: Chromosome 7

    Organism-specific databases

    MGIiMGI:2152453. Gsk3a.

    Pathology & Biotechi

    Disruption phenotypei

    Enhanced glucose tolerance and insulin sensitivity, increased activity of hepatic glycogen synthase, elevated hepatic glycogen storage and reduced fat mass.1 Publication

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi21 – 211S → A: Loss of phosphorylation; No inhibition of activity and constitutively active. 1 Publication

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Initiator methioninei1 – 11RemovedBy similarity
    Chaini2 – 490489Glycogen synthase kinase-3 alphaPRO_0000280395Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei2 – 21N-acetylserineBy similarity
    Modified residuei2 – 21PhosphoserineBy similarity
    Modified residuei21 – 211Phosphoserine; by PKB/AKT11 Publication
    Modified residuei72 – 721PhosphoserineBy similarity
    Modified residuei77 – 771PhosphoserineBy similarity
    Modified residuei97 – 971PhosphoserineBy similarity
    Modified residuei279 – 2791PhosphotyrosineBy similarity

    Post-translational modificationi

    Phosphorylated by AKT1 at Ser-21: upon insulin-mediated signaling, the activated PKB/AKT1 protein kinase phosphorylates and desactivates GSK3A, resulting in the dephosphorylation and activation of GYS1. Activated by phosphorylation at Tyr-279.1 Publication

    Keywords - PTMi

    Acetylation, Phosphoprotein

    Proteomic databases

    MaxQBiQ2NL51.
    PaxDbiQ2NL51.
    PRIDEiQ2NL51.

    PTM databases

    PhosphoSiteiQ2NL51.

    Miscellaneous databases

    PMAP-CutDBQ2NL51.

    Expressioni

    Gene expression databases

    BgeeiQ2NL51.
    CleanExiMM_GSK3A.
    GenevestigatoriQ2NL51.

    Interactioni

    Subunit structurei

    Monomer. Interacts with AXIN1 and CTNNB1/beta-catenin By similarity. Interacts with ARRB2.By similarity1 Publication

    Protein-protein interaction databases

    BioGridi546781. 3 interactions.
    IntActiQ2NL51. 1 interaction.
    STRINGi10090.ENSMUSP00000071654.

    Structurei

    3D structure databases

    ProteinModelPortaliQ2NL51.
    SMRiQ2NL51. Positions 99-447.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini119 – 404286Protein kinasePROSITE-ProRule annotationAdd
    BLAST

    Compositional bias

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Compositional biasi3 – 8381Gly-richAdd
    BLAST

    Sequence similaritiesi

    Contains 1 protein kinase domain.PROSITE-ProRule annotation

    Phylogenomic databases

    eggNOGiCOG0515.
    GeneTreeiENSGT00520000055635.
    HOGENOMiHOG000233017.
    HOVERGENiHBG014652.
    InParanoidiQ2NL51.
    KOiK08822.
    OMAiFDELRCP.
    OrthoDBiEOG7TF78V.
    PhylomeDBiQ2NL51.
    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.

    Sequence processingi: The displayed sequence is further processed into a mature form.

    Q2NL51-1 [UniParc]FASTAAdd to Basket

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    MSGGGPSGGG PGGSGRARTS SFAEPGGGGG GGGGGPGGSA SGPGGTGGGK    50
    ASVGAMGGGV GASSSGGGPS GSGGGGSGGP GAGTSFPPPG VKLGRDSGKV 100
    TTVVATVGQG PERSQEVAYT DIKVIGNGSF GVVYQARLAE TRELVAIKKV 150
    LQDKRFKNRE LQIMRKLDHC NIVRLRYFFY SSGEKKDELY LNLVLEYVPE 200
    TVYRVARHFT KAKLITPIIY IKVYMYQLFR SLAYIHSQGV CHRDIKPQNL 250
    LVDPDTAVLK LCDFGSAKQL VRGEPNVSYI CSRYYRAPEL IFGATDYTSS 300
    IDVWSAGCVL AELLLGQPIF PGDSGVDQLV EIIKVLGTPT REQIREMNPN 350
    YTEFKFPQIK AHPWTKVFKS SKTPPEAIAL CSSLLEYTPS SRLSPLEACA 400
    HSFFDELRRL GAQLPNDRPL PPLFNFSPGE LSIQPSLNAI LIPPHLRSPA 450
    GPASPLTTSY NPSSQALTEA QTGQDWQPSD ATTATLASSS 490
    Length:490
    Mass (Da):51,661
    Last modified:March 20, 2007 - v2
    Checksum:i739CDD86BBFB497B
    GO

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AC156992 Genomic DNA. No translation available.
    BC111032 mRNA. Translation: AAI11033.1.
    CCDSiCCDS20976.1.
    RefSeqiNP_001026837.1. NM_001031667.1.
    UniGeneiMm.491101.

    Genome annotation databases

    EnsembliENSMUST00000071739; ENSMUSP00000071654; ENSMUSG00000057177.
    GeneIDi606496.
    KEGGimmu:606496.
    UCSCiuc009frx.1. mouse.

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AC156992 Genomic DNA. No translation available.
    BC111032 mRNA. Translation: AAI11033.1 .
    CCDSi CCDS20976.1.
    RefSeqi NP_001026837.1. NM_001031667.1.
    UniGenei Mm.491101.

    3D structure databases

    ProteinModelPortali Q2NL51.
    SMRi Q2NL51. Positions 99-447.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 546781. 3 interactions.
    IntActi Q2NL51. 1 interaction.
    STRINGi 10090.ENSMUSP00000071654.

    Chemistry

    ChEMBLi CHEMBL2176843.

    PTM databases

    PhosphoSitei Q2NL51.

    Proteomic databases

    MaxQBi Q2NL51.
    PaxDbi Q2NL51.
    PRIDEi Q2NL51.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENSMUST00000071739 ; ENSMUSP00000071654 ; ENSMUSG00000057177 .
    GeneIDi 606496.
    KEGGi mmu:606496.
    UCSCi uc009frx.1. mouse.

    Organism-specific databases

    CTDi 2931.
    MGIi MGI:2152453. Gsk3a.

    Phylogenomic databases

    eggNOGi COG0515.
    GeneTreei ENSGT00520000055635.
    HOGENOMi HOG000233017.
    HOVERGENi HBG014652.
    InParanoidi Q2NL51.
    KOi K08822.
    OMAi FDELRCP.
    OrthoDBi EOG7TF78V.
    PhylomeDBi Q2NL51.
    TreeFami TF101104.

    Enzyme and pathway databases

    Reactomei REACT_106572. XBP1(S) activates chaperone genes.
    REACT_196588. Constitutive PI3K/AKT Signaling in Cancer.
    REACT_220918. AKT phosphorylates targets in the cytosol.

    Miscellaneous databases

    NextBioi 414454.
    PMAP-CutDB Q2NL51.
    PROi Q2NL51.
    SOURCEi Search...

    Gene expression databases

    Bgeei Q2NL51.
    CleanExi MM_GSK3A.
    Genevestigatori Q2NL51.

    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. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
      Strain: C57BL/6J.
    2. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
      The MGC Project Team
      Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 227-490.
      Tissue: Eye.
    3. "An Akt/beta-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior."
      Beaulieu J.-M., Sotnikova T.D., Marion S., Lefkowitz R.J., Gainetdinov R.R., Caron M.G.
      Cell 122:261-273(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH ARRB2.
    4. "Role that phosphorylation of GSK3 plays in insulin and Wnt signalling defined by knockin analysis."
      McManus E.J., Sakamoto K., Armit L.J., Ronaldson L., Shpiro N., Marquez R., Alessi D.R.
      EMBO J. 24:1571-1583(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, MUTAGENESIS OF SER-21, PHOSPHORYLATION AT SER-21.
    5. "Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1."
      Maurer U., Charvet C., Wagman A.S., Dejardin E., Green D.R.
      Mol. Cell 21:749-760(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION IN MCL1 PHOSPHORYLATION.
    6. "GSK3 alpha and GSK3 beta are necessary for axon formation."
      Garrido J.J., Simon D., Varea O., Wandosell F.
      FEBS Lett. 581:1579-1586(2007) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION IN AXON FORMATION, TISSUE SPECIFICITY.
    7. "Glycogen synthase kinase 3alpha-specific regulation of murine hepatic glycogen metabolism."
      MacAulay K., Doble B.W., Patel S., Hansotia T., Sinclair E.M., Drucker D.J., Nagy A., Woodgett J.R.
      Cell Metab. 6:329-337(2007) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION IN HEPATIC GLYCOGEN METABOLISM, DISRUPTION PHENOTYPE.

    Entry informationi

    Entry nameiGSK3A_MOUSE
    AccessioniPrimary (citable) accession number: Q2NL51
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: March 20, 2007
    Last sequence update: March 20, 2007
    Last modified: October 1, 2014
    This is version 83 of the entry and version 2 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program

    Miscellaneousi

    Keywords - Technical termi

    Complete proteome, Reference proteome

    Documents

    1. MGD cross-references
      Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
    2. Human and mouse protein kinases
      Human and mouse protein kinases: classification and index
    3. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3