P18265 (GSK3A_RAT) 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):
Factor A
Short name=FA
Serine/threonine-protein kinase GSK3A
EC=2.7.11.1

Gene names

Name:

Gsk3a

Organism

Rattus norvegicus (Rat) [Reference proteome]

Taxonomic identifier

10116 [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 › Rattus

Protein attributes

Sequence length	483 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 By similarity. Ref.3
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 By similarity.
Subunit structure	Monomer. Interacts with ARRB2, AXIN1 and CTNNB1/beta-catenin By similarity.
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 By similarity. Ref.2
Miscellaneous	Simultaneous silencing of GSK3A and GSK3B by RNAi stimulates replication and promotes survival of INS-1E pancreatic beta cells (Ref.3).
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 electronic annotation. Source: Compara cell migration Inferred from electronic annotation. Source: Compara cellular response to lithium ion Inferred from electronic annotation. Source: Compara cellular response to organic cyclic compound Inferred from electronic annotation. Source: Compara glycogen metabolic process Inferred from electronic annotation. Source: UniProtKB-KW hypermethylation of CpG island Inferred from electronic annotation. Source: Compara insulin receptor signaling pathway Inferred from electronic annotation. Source: Compara negative regulation of TOR signaling cascade Inferred from electronic annotation. Source: Compara negative regulation of cell growth involved in cardiac muscle cell development Inferred from electronic annotation. Source: Compara nervous system development Inferred from electronic annotation. Source: UniProtKB-KW positive regulation of adrenergic receptor signaling pathway Inferred from electronic annotation. Source: Compara positive regulation of cAMP biosynthetic process Inferred from electronic annotation. Source: Compara positive regulation of glycogen (starch) synthase activity Inferred from electronic annotation. Source: Compara positive regulation of heart contraction Inferred from electronic annotation. Source: Compara positive regulation of peptidyl-serine phosphorylation Inferred from electronic annotation. Source: Compara positive regulation of peptidyl-threonine phosphorylation Inferred from electronic annotation. Source: Compara positive regulation of transcription from RNA polymerase II promoter Inferred from electronic annotation. Source: Compara regulation of gene expression by genetic imprinting Inferred from electronic annotation. Source: Compara regulation of systemic arterial blood pressure Inferred from electronic annotation. Source: Compara signal transduction Non-traceable author statement Ref.1. Source: RGD
Cellular_component	cytosol Traceable author statement. Source: Reactome
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW protein serine/threonine kinase activity Inferred from direct assay PubMed 11035810. Source: BHF-UCL 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 – 483	482	Glycogen synthase kinase-3 alpha		PRO_0000085979
Regions
	Domain	119 – 403	285	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 By similarity
	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 Ref.2

Sequences

	Sequence		Length	Mass (Da)
	P18265 [UniParc]. Last modified November 1, 1990. Version 1. Checksum: A98DC1C5C7F7B716	FASTA	483	51,027
	10 20 30 40 50 60 MSGGGPSGGG PGGSGRARTS SFAEPGGGGG GGGGGPGGSA SGPGGTGGGK ASVGAMGGGV 70 80 90 100 110 120 GASSSGGGPS GSGGGGSGGP GAGTSFPPPG VKLGRDSGKV TTVVATLGQG PERSQEVAYT 130 140 150 160 170 180 DIKVIGNGSF GVVYQARLAE TRELVAIKKV LQDKRFKNRE LQIMRKLDHC NIVRLRYFFY 190 200 210 220 230 240 SSGEKKDELY LNLVLEYVPE TVYRVARHFT KAKLIIPIIY VKVYMYQLFR 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 RTPPEAIALC SSLLEYTPSS RLSPLEACAH SFFDELRSLG TQLPNNRPLP 430 440 450 460 470 480 PLFNFSPGEL SIQPSLNAIL IPPHLRSPSG PATLTSSSQA LTETQTGQDW QAPDATPTLT NSS

References

[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]	"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-279.
[3]	"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.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	X53427 mRNA. Translation: CAA37518.1.
IPI	IPI00189904.
PIR	TVRTKA. S14707.
RefSeq	NP_059040.1. NM_017344.1.
UniGene	Rn.36807.
3D structure databases
ProteinModelPortal	P18265.
SMR	P18265. Positions 99-446.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP-1072N.
STRING	10116.ENSRNOP00000027677.
PTM databases
PhosphoSite	P18265.
Proteomic databases
PaxDb	P18265.
PRIDE	P18265.
Protocols and materials databases
DNASU	50686.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
GeneID	50686.
KEGG	rno:50686.
UCSC	RGD:620351. rat.
Organism-specific databases
CTD	2931.
RGD	620351. Gsk3a.
Phylogenomic databases
eggNOG	COG0515.
HOGENOM	HOG000233017.
HOVERGEN	HBG014652.
InParanoid	P18265.
KO	K08822.
OrthoDB	EOG4WH8KZ.
Enzyme and pathway databases
BRENDA	2.7.11.26. 5301.
Reactome	REACT_109781. Immune System. REACT_110573. Disease. REACT_111984. Signal Transduction.
Gene expression databases
ArrayExpress	P18265.
Genevestigator	P18265.
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
ChEMBL	CHEMBL1075224.
NextBio	610536.

Entry information

Entry name

GSK3A_RAT

Accession

Primary (citable) accession number: P18265

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1990
Last sequence update:	November 1, 1990
Last modified:	April 3, 2013
This is version 115 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program