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Q2NL51 (GSK3A_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 81. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | 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 alpha

Short name=GSK-3 alpha
EC=2.7.11.26
Alternative name(s):
Serine/threonine-protein kinase GSK3A
EC=2.7.11.1
Gene names
Name:Gsk3a
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length490 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
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), 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. Ref.4 Ref.5 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-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.

Subunit structure

Monomer. Interacts with AXIN1 and CTNNB1/beta-catenin By similarity. Interacts with ARRB2. Ref.3

Post-translational modification

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. Ref.4

Disruption phenotype

Enhanced glucose tolerance and insulin sensitivity, increased activity of hepatic glycogen synthase, elevated hepatic glycogen storage and reduced fat mass. Ref.7

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 processCarbohydrate metabolism
Glycogen metabolism
Neurogenesis
Wnt signaling pathway
   LigandATP-binding
Nucleotide-binding
   Molecular functionKinase
Serine/threonine-protein kinase
Signal transduction inhibitor
Transferase
   PTMAcetylation
Phosphoprotein
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processWnt signaling pathway

Inferred from electronic annotation. Source: UniProtKB-KW

cardiac left ventricle morphogenesis

Inferred from mutant phenotype PubMed 20516643. Source: BHF-UCL

cell migration

Inferred from genetic interaction PubMed 17986005. Source: MGI

cellular response to interleukin-3

Inferred from direct assay Ref.5. Source: UniProtKB

cellular response to lithium ion

Inferred from direct assay PubMed 15673614. Source: MGI

cellular response to organic cyclic compound

Inferred from direct assay PubMed 12055200. Source: MGI

extrinsic apoptotic signaling pathway in absence of ligand

Inferred from direct assay Ref.5. Source: UniProtKB

glycogen metabolic process

Inferred from electronic annotation. Source: UniProtKB-KW

hypermethylation of CpG island

Inferred from mutant phenotype PubMed 21047779. Source: BHF-UCL

insulin receptor signaling pathway

Inferred from direct assay PubMed 18285345. Source: BHF-UCL

negative regulation of TOR signaling

Inferred from mutant phenotype PubMed 20516643. Source: BHF-UCL

negative regulation of cell growth involved in cardiac muscle cell development

Inferred from mutant phenotype PubMed 20516643. Source: BHF-UCL

nervous system development

Inferred from electronic annotation. Source: UniProtKB-KW

positive regulation of adrenergic receptor signaling pathway

Inferred from mutant phenotype PubMed 20516643. Source: BHF-UCL

positive regulation of cAMP biosynthetic process

Inferred from mutant phenotype PubMed 20516643. Source: BHF-UCL

positive regulation of glycogen (starch) synthase activity

Inferred from mutant phenotype PubMed 20516643. Source: BHF-UCL

positive regulation of heart contraction

Inferred from mutant phenotype PubMed 20516643. Source: BHF-UCL

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

Inferred from direct assay Ref.5. Source: UniProtKB

positive regulation of peptidyl-serine phosphorylation

Inferred from direct assay PubMed 17986005. Source: MGI

positive regulation of peptidyl-threonine phosphorylation

Inferred from direct assay PubMed 17986005. Source: MGI

positive regulation of transcription from RNA polymerase II promoter

Inferred from mutant phenotype PubMed 21047779. Source: BHF-UCL

proteasome-mediated ubiquitin-dependent protein catabolic process

Inferred from direct assay Ref.5. Source: UniProtKB

protein phosphorylation

Inferred from mutant phenotype Ref.5. Source: UniProtKB

regulation of gene expression by genetic imprinting

Inferred from mutant phenotype PubMed 21047779. Source: BHF-UCL

regulation of systemic arterial blood pressure

Inferred from mutant phenotype PubMed 20516643. Source: BHF-UCL

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

protein binding

Inferred from physical interaction Ref.3. Source: UniProtKB

protein kinase activity

Inferred from direct assay PubMed 14730361. Source: MGI

protein serine/threonine kinase activity

Inferred from mutant phenotype Ref.5. Source: UniProtKB

tau-protein kinase activity

Inferred from electronic annotation. Source: UniProtKB-EC

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Initiator methionine11Removed By similarity
Chain2 – 490489Glycogen synthase kinase-3 alpha
PRO_0000280395

Regions

Domain119 – 404286Protein kinase
Nucleotide binding125 – 1339ATP By similarity
Compositional bias3 – 8381Gly-rich

Sites

Active site2441Proton acceptor By similarity
Binding site1481ATP By similarity

Amino acid modifications

Modified residue21N-acetylserine By similarity
Modified residue21Phosphoserine By similarity
Modified residue211Phosphoserine; by PKB/AKT1 Ref.4
Modified residue721Phosphoserine By similarity
Modified residue771Phosphoserine By similarity
Modified residue971Phosphoserine By similarity
Modified residue2791Phosphotyrosine By similarity

Experimental info

Mutagenesis211S → A: Loss of phosphorylation; No inhibition of activity and constitutively active. Ref.4

Sequences

Sequence LengthMass (Da)Tools
Q2NL51 [UniParc].

Last modified March 20, 2007. Version 2.
Checksum: 739CDD86BBFB497B

FASTA49051,661
        10         20         30         40         50         60 
MSGGGPSGGG PGGSGRARTS SFAEPGGGGG GGGGGPGGSA SGPGGTGGGK ASVGAMGGGV 

        70         80         90        100        110        120 
GASSSGGGPS GSGGGGSGGP GAGTSFPPPG VKLGRDSGKV TTVVATVGQG PERSQEVAYT 

       130        140        150        160        170        180 
DIKVIGNGSF GVVYQARLAE TRELVAIKKV LQDKRFKNRE LQIMRKLDHC NIVRLRYFFY 

       190        200        210        220        230        240 
SSGEKKDELY LNLVLEYVPE TVYRVARHFT KAKLITPIIY IKVYMYQLFR SLAYIHSQGV 

       250        260        270        280        290        300 
CHRDIKPQNL LVDPDTAVLK LCDFGSAKQL VRGEPNVSYI CSRYYRAPEL IFGATDYTSS 

       310        320        330        340        350        360 
IDVWSAGCVL AELLLGQPIF PGDSGVDQLV EIIKVLGTPT REQIREMNPN YTEFKFPQIK 

       370        380        390        400        410        420 
AHPWTKVFKS SKTPPEAIAL CSSLLEYTPS SRLSPLEACA HSFFDELRRL GAQLPNDRPL 

       430        440        450        460        470        480 
PPLFNFSPGE LSIQPSLNAI LIPPHLRSPA GPASPLTTSY NPSSQALTEA QTGQDWQPSD 

       490 
ATTATLASSS 

« Hide

References

« Hide 'large scale' references
[1]"Lineage-specific biology revealed by a finished genome assembly of the mouse."
Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S. expand/collapse author list , Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R., Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K., Eichler E.E., Ponting C.P.
PLoS Biol. 7:E1000112-E1000112(2009) [PubMed] [Europe PMC] [Abstract]
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.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AC156992 Genomic DNA. No translation available.
BC111032 mRNA. Translation: AAI11033.1.
CCDSCCDS20976.1.
RefSeqNP_001026837.1. NM_001031667.1.
UniGeneMm.491101.

3D structure databases

ProteinModelPortalQ2NL51.
SMRQ2NL51. Positions 99-447.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid546781. 3 interactions.
IntActQ2NL51. 1 interaction.
STRING10090.ENSMUSP00000071654.

Chemistry

ChEMBLCHEMBL2176843.

PTM databases

PhosphoSiteQ2NL51.

Proteomic databases

MaxQBQ2NL51.
PaxDbQ2NL51.
PRIDEQ2NL51.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000071739; ENSMUSP00000071654; ENSMUSG00000057177.
GeneID606496.
KEGGmmu:606496.
UCSCuc009frx.1. mouse.

Organism-specific databases

CTD2931.
MGIMGI:2152453. Gsk3a.

Phylogenomic databases

eggNOGCOG0515.
GeneTreeENSGT00520000055635.
HOGENOMHOG000233017.
HOVERGENHBG014652.
InParanoidQ2NL51.
KOK08822.
OMAFDELRCP.
OrthoDBEOG7TF78V.
PhylomeDBQ2NL51.
TreeFamTF101104.

Gene expression databases

BgeeQ2NL51.
CleanExMM_GSK3A.
GenevestigatorQ2NL51.

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

NextBio414454.
PMAP-CutDBQ2NL51.
PROQ2NL51.
SOURCESearch...

Entry information

Entry nameGSK3A_MOUSE
AccessionPrimary (citable) accession number: Q2NL51
Entry history
Integrated into UniProtKB/Swiss-Prot: March 20, 2007
Last sequence update: March 20, 2007
Last modified: July 9, 2014
This is version 81 of the entry and version 2 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

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot