Q2NL51 (GSK3A_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	490 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence 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. May be involved in the regulation of replication in pancreatic beta-cells. Is necessary for the establishment of neuronal polarity and axon outgrowth. Ref.4 Ref.5 Ref.6
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.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 process	Carbohydrate metabolism Glycogen metabolism Neurogenesis Wnt signaling pathway
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Signal transduction inhibitor Transferase
PTM	Acetylation Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	Wnt receptor 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 lithium ion Inferred from direct assay PubMed 15673614. Source: MGI cellular response to organic cyclic compound Inferred from direct assay PubMed 12055200. Source: MGI 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 cascade 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 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 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_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW protein serine/threonine kinase activity Inferred from direct assay PubMed 17986005. Source: MGI tau-protein kinase activity Inferred from electronic annotation. Source: EC
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Initiator methionine	1	1	Removed By similarity
	Chain	2 – 490	489	Glycogen synthase kinase-3 alpha		PRO_0000280395
Regions
	Domain	119 – 404	286	Protein kinase
	Nucleotide binding	125 – 133	9	ATP By similarity
	Compositional bias	3 – 83	81	Gly-rich
Sites
	Active site	244	1	Proton acceptor By similarity
	Binding site	148	1	ATP By similarity
Amino acid modifications
	Modified residue	2	1	N-acetylserine By similarity
	Modified residue	2	1	Phosphoserine By similarity
	Modified residue	21	1	Phosphoserine; by PKB/AKT1 Ref.4
	Modified residue	72	1	Phosphoserine By similarity
	Modified residue	77	1	Phosphoserine By similarity
	Modified residue	97	1	Phosphoserine By similarity
	Modified residue	279	1	Phosphotyrosine By similarity
Experimental info
	Mutagenesis	21	1	S → A: Loss of phosphorylation; No inhibition of activity and constitutively active. Ref.4

Sequences

	Sequence		Length	Mass (Da)
	Q2NL51 [UniParc]. Last modified March 20, 2007. Version 2. Checksum: 739CDD86BBFB497B	FASTA	490	51,661
	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

References

	« Hide 'large scale' referencesShow '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. , 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]	"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.
[6]	"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.
IPI	IPI00648141.
RefSeq	NP_001026837.1. NM_001031667.1.
UniGene	Mm.294664.
3D structure databases
ProteinModelPortal	Q2NL51.
SMR	Q2NL51. Positions 99-447.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q2NL51. 1 interaction.
STRING	10090.ENSMUSP00000071654.
PTM databases
PhosphoSite	Q2NL51.
Proteomic databases
PaxDb	Q2NL51.
PRIDE	Q2NL51.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000071739; ENSMUSP00000071654; ENSMUSG00000057177.
GeneID	606496.
KEGG	mmu:606496.
UCSC	uc009frx.1. mouse.
Organism-specific databases
CTD	2931.
MGI	MGI:2152453. Gsk3a.
Phylogenomic databases
eggNOG	COG0515.
GeneTree	ENSGT00520000055635.
HOGENOM	HOG000233017.
HOVERGEN	HBG014652.
InParanoid	Q2NL51.
KO	K08822.
OMA	FDELRCP.
OrthoDB	EOG4WH8KZ.
Gene expression databases
ArrayExpress	Q2NL51.
Bgee	Q2NL51.
CleanEx	MM_GSK3A.
Genevestigator	Q2NL51.
Family and domain databases
InterPro	IPR011009. Kinase-like_dom. IPR000719. Prot_kinase_cat_dom. IPR017441. Protein_kinase_ATP_BS. IPR002290. Ser/Thr_dual-sp_kinase_dom. IPR008271. Ser/Thr_kinase_AS. [Graphical view]
Pfam	PF00069. Pkinase. 1 hit. [Graphical view]
SMART	SM00220. S_TKc. 1 hit. [Graphical view]
SUPFAM	SSF56112. Kinase_like. 1 hit.
PROSITE	PS00107. PROTEIN_KINASE_ATP. 1 hit. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00108. PROTEIN_KINASE_ST. 1 hit. [Graphical view]
ProtoNet	Search...
Other
NextBio	414454.
PMAP-CutDB	Q2NL51.
SOURCE	Search...

Entry information

Entry name

GSK3A_MOUSE

Accession

Primary (citable) accession number: Q2NL51

Entry history

Integrated into UniProtKB/Swiss-Prot:	March 20, 2007
Last sequence update:	March 20, 2007
Last modified:	May 1, 2013
This is version 70 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program