P49840 (GSK3A_HUMAN) 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

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

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. 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. 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 ARRB2 By similarity. Interacts with AXIN1 and CTNNB1/beta-catenin. Ref.7
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.
Miscellaneous	Higher expression and activity of GSK3A are found in the skeletal muscle (vastus lateralis) of patients with type 2 diabetes (Ref.5). Several potent GSK3 (GSK3A and GSK3B) inhibitors have been identified and characterized in preclinical models for treatments of type 2 diabetes (Ref.12).
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
Coding sequence diversity	Polymorphism
Disease	Alzheimer disease Diabetes mellitus
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Signal transduction inhibitor Transferase
PTM	Acetylation Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	Wnt receptor signaling pathway Inferred from electronic annotation. Source: UniProtKB-KW activation of signaling protein activity involved in unfolded protein response Traceable author statement. Source: Reactome cardiac left ventricle morphogenesis Inferred from sequence or structural similarity. Source: BHF-UCL epidermal growth factor receptor signaling pathway Traceable author statement. Source: Reactome fibroblast growth factor receptor signaling pathway Traceable author statement. Source: Reactome glycogen metabolic process Inferred from electronic annotation. Source: UniProtKB-KW innate immune response Traceable author statement. Source: Reactome insulin receptor signaling pathway Inferred from sequence or structural similarity PubMed 18285345. Source: BHF-UCL negative regulation of TOR signaling cascade Inferred from sequence or structural similarity. Source: BHF-UCL negative regulation of UDP-glucose catabolic process Inferred by curator PubMed 11035810. Source: UniProtKB negative regulation of canonical Wnt receptor signaling pathway Traceable author statement Ref.12. Source: UniProtKB negative regulation of cell growth involved in cardiac muscle cell development Inferred from sequence or structural similarity. Source: BHF-UCL negative regulation of glucose import Inferred from mutant phenotype PubMed 17569761. Source: BHF-UCL negative regulation of glycogen (starch) synthase activity Traceable author statement Ref.12. Source: UniProtKB negative regulation of glycogen biosynthetic process Traceable author statement Ref.12. Source: UniProtKB negative regulation of insulin receptor signaling pathway Inferred from mutant phenotype PubMed 17569761. Source: BHF-UCL negative regulation of type B pancreatic cell development Traceable author statement Ref.12. Source: UniProtKB nervous system development Inferred from electronic annotation. Source: UniProtKB-KW neurotrophin TRK receptor signaling pathway Traceable author statement. Source: Reactome phosphatidylinositol-mediated signaling Traceable author statement. Source: Reactome positive regulation of adrenergic receptor signaling pathway Inferred from sequence or structural similarity. Source: BHF-UCL positive regulation of cAMP biosynthetic process Inferred from sequence or structural similarity. Source: BHF-UCL positive regulation of glycogen (starch) synthase activity Inferred from sequence or structural similarity. Source: BHF-UCL positive regulation of heart contraction Inferred from sequence or structural similarity. Source: BHF-UCL positive regulation of protein catabolic process Non-traceable author statement PubMed 19759537. Source: BHF-UCL regulation of systemic arterial blood pressure Inferred from sequence or structural similarity. Source: BHF-UCL
Cellular_component	beta-catenin destruction complex Traceable author statement Ref.12. Source: UniProtKB cytosol Traceable author statement PubMed 11035810. Source: BHF-UCL
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 Traceable author statement Ref.12. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
DEAF1	O75398	2	EBI-1044067,EBI-718185
HSP90AB1	P08238	2	EBI-1044067,EBI-352572

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Initiator methionine	1	1	Removed Ref.13
	Chain	2 – 483	482	Glycogen synthase kinase-3 alpha		PRO_0000085978
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 Ref.13
	Modified residue	2	1	Phosphoserine Ref.10 Ref.13
	Modified residue	21	1	Phosphoserine; by PKB/AKT1
	Modified residue	72	1	Phosphoserine Ref.10
	Modified residue	77	1	Phosphoserine Ref.13
	Modified residue	97	1	Phosphoserine Ref.13
	Modified residue	279	1	Phosphotyrosine By similarity
Natural variations
	Natural variant	109	1	Q → E. Corresponds to variant rs35978177 [ dbSNP | Ensembl ].		VAR_051625
	Natural variant	461	1	L → F. Ref.16 Corresponds to variant rs35454502 [ dbSNP | Ensembl ].		VAR_040539
Experimental info
	Sequence conflict	449	1	A → S in AAA62432. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	P49840 [UniParc]. Last modified December 1, 2000. Version 2. Checksum: F18C012C03B7D786	FASTA	483	50,981
	10 20 30 40 50 60 MSGGGPSGGG PGGSGRARTS SFAEPGGGGG GGGGGPGGSA SGPGGTGGGK ASVGAMGGGV 70 80 90 100 110 120 GASSSGGGPG 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 KAKLTIPILY 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 SFFDELRCLG TQLPNNRPLP 430 440 450 460 470 480 PLFNFSAGEL SIQPSLNAIL IPPHLRSPAG TTTLTPSSQA LTETPTSSDW QSTDATPTLT NSS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Glycogen synthase kinase 3 and dorsoventral patterning in Xenopus embryos." He X., Saint-Jeannet J.P., Woodgett J.R., Varmus H.E., Dawid I.B. Submitted (MAR-1995) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Foreskin.
[2]	"Isolation of cDNA clones for human glycogen synthase kinase 3alpha." Hoshino T., Kondo K., Ishiguro K., Takashima A., Imahori K. Submitted (NOV-1997) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Brain.
[3]	"The DNA sequence and biology of human chromosome 19." Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S., Carrano A.V. , Caoile C., Chan Y.M., Christensen M., Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E., Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M., Rubin E.M., Lucas S.M. Nature 428:529-535(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	"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]. Tissue: Eye and Pancreas.
[5]	"Potential role of glycogen synthase kinase-3 in skeletal muscle insulin resistance of type 2 diabetes." Nikoulina S.E., Ciaraldi T.P., Mudaliar S., Mohideen P., Carter L., Henry R.R. Diabetes 49:263-271(2000) [PubMed] [Europe PMC] [Abstract] Cited for: ASSOCIATION WITH DIABETES MELLITUS.
[6]	"GSK-3alpha regulates production of Alzheimer's disease amyloid-beta peptides." Phiel C.J., Wilson C.A., Lee V.M., Klein P.S. Nature 423:435-439(2003) [PubMed] [Europe PMC] [Abstract] Cited for: ASSOCIATION WITH ALZHEIMER DISEASE, FUNCTION.
[7]	"GSK3alpha exhibits beta-catenin and tau directed kinase activities that are modulated by Wnt." Asuni A.A., Hooper C., Reynolds C.H., Lovestone S., Anderton B.H., Killick R. Eur. J. Neurosci. 24:3387-3392(2006) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN WNT SIGNALING, INTERACTION WITH AXIN1 AND CTNNB1/BETA-CATENIN.
[8]	"Glycogen synthase kinase-3: properties, functions, and regulation." Ali A., Hoeflich K.P., Woodgett J.R. Chem. Rev. 101:2527-2540(2001) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON FUNCTION AND ENZYME REGULATION.
[9]	"The role of GSK3 in glucose homeostasis and the development of insulin resistance." Lee J., Kim M.S. Diabetes Res. Clin. Pract. 77:S49-S57(2007) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON FUNCTION.
[10]	"Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle." Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M. Mol. Cell 31:438-448(2008) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-2 AND SER-72, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[11]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. Tissue: Cervix carcinoma.
[12]	"Glycogen synthase kinase 3: more than a namesake." Rayasam G.V., Tulasi V.K., Sodhi R., Davis J.A., Ray A. Br. J. Pharmacol. 156:885-898(2009) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON FUNCTION AND ENZYME REGULATION.
[13]	"Large-scale proteomics analysis of the human kinome." Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., Mann M., Daub H. Mol. Cell. Proteomics 8:1751-1764(2009) [PubMed] [Europe PMC] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-2; SER-77 AND SER-97, MASS SPECTROMETRY, CLEAVAGE OF INITIATOR METHIONINE.
[14]	"Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions." Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K. Sci. Signal. 2:RA46-RA46(2009) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. Tissue: Leukemic T-cell.
[15]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[16]	"Patterns of somatic mutation in human cancer genomes." Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R. Nature 446:153-158(2007) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT [LARGE SCALE ANALYSIS] PHE-461.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

L40027 mRNA. Translation: AAA62432.1.
D63424 mRNA. Translation: BAA23608.1.
AC006486 Genomic DNA. Translation: AAD11986.1.
BC027984 mRNA. Translation: AAH27984.1.
BC051865 mRNA. Translation: AAH51865.1.

IPI

IPI00292228.

RefSeq

NP_063937.2. NM_019884.2.

UniGene

Hs.466828.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2DFM	model	-	A	98-449	[»]

ProteinModelPortal

P49840.

ModBase

Search...

Protein-protein interaction databases

IntAct

P49840. 26 interactions.

MINT

MINT-1688290.

STRING

9606.ENSP00000222330.

PTM databases

PhosphoSite

P49840.

Polymorphism databases

DMDM

12644292.

Proteomic databases

PaxDb

P49840.

PeptideAtlas

P49840.

PRIDE

P49840.

Protocols and materials databases

DNASU

2931.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000222330; ENSP00000222330; ENSG00000105723.
ENST00000453535; ENSP00000412663; ENSG00000105723.

GeneID

2931.

KEGG

hsa:2931.

UCSC

uc002otb.1. human.

Organism-specific databases

CTD

2931.

GeneCards

GC19M042734.

HGNC

HGNC:4616. GSK3A.

HPA

CAB004422.
HPA028423.

MIM

606784. gene.

neXtProt

NX_P49840.

PharmGKB

PA29008.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0515.

HOGENOM

HOG000233017.

HOVERGEN

HBG014652.

InParanoid

P49840.

KO

K08822.

OMA

FDELRCP.

OrthoDB

EOG4WH8KZ.

PhylomeDB

P49840.

Enzyme and pathway databases

Pathway_Interaction_DB

wnt_canonical_pathway. Canonical Wnt signaling pathway.
pi3kciaktpathway. Class I PI3K signaling events mediated by Akt.
foxm1pathway. FOXM1 transcription factor network.

Reactome

REACT_111102. Signal Transduction.
REACT_116125. Disease.
REACT_6900. Immune System.

SignaLink

P49840.

Gene expression databases

ArrayExpress

P49840.

Bgee

P49840.

CleanEx

HS_GSK3A.

Genevestigator

P49840.

GermOnline

ENSG00000105723. Homo sapiens.

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

BindingDB

P49840.

ChEMBL

CHEMBL2850.

ChiTaRS

GSK3A. human.

GenomeRNAi

2931.

NextBio

11615.

SOURCE

Search...

Entry information

Entry name

GSK3A_HUMAN

Accession

Primary (citable) accession number: P49840
Secondary accession number(s): O14959

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1996
Last sequence update:	December 1, 2000
Last modified:	May 29, 2013
This is version 132 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.