Glycogen synthase kinase-3 alpha - Homo sapiens (Human)

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P49840 (GSK3A_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified January 25, 2012. Version 119. History...

Clusters with 100%, 90%, 50% identity |

Documents (7) |

Third-party data

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Names·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Cross-refs·Entry info·Documents Customize order

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)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	483 AA.
Sequence status	Complete.
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 transctiption 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.8
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.8
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.7 Ref.9 Ref.10 Ref.11 Ref.12 Ref.13 Ref.14 Ref.18
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.17).
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	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 cardiac left ventricle morphogenesis Inferred from sequence or structural similarity. Source: BHF-UCL fibroblast growth factor receptor signaling pathway Traceable author statement. Source: Reactome glycogen metabolic process Inferred from electronic annotation. Source: UniProtKB-KW insulin receptor signaling pathway Inferred from sequence or structural similarity. 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. Source: UniProtKB negative regulation of canonical Wnt receptor signaling pathway Traceable author statement Ref.17. 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. Source: BHF-UCL negative regulation of glycogen (starch) synthase activity Traceable author statement Ref.17. Source: UniProtKB negative regulation of glycogen biosynthetic process Traceable author statement Ref.17. Source: UniProtKB negative regulation of insulin receptor signaling pathway Inferred from mutant phenotype. Source: BHF-UCL negative regulation of type B pancreatic cell development Traceable author statement Ref.17. Source: UniProtKB nerve growth factor receptor signaling pathway Traceable author statement. Source: Reactome nervous system development Inferred from electronic annotation. Source: UniProtKB-KW 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. 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.17. Source: UniProtKB cytosol Traceable author statement. Source: BHF-UCL
Molecular function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW protein kinase A catalytic subunit binding Inferred from physical interaction. Source: BHF-UCL protein serine/threonine kinase activity Inferred from direct assay. Source: BHF-UCL tau-protein kinase activity Traceable author statement Ref.17. Source: UniProtKB
Complete GO annotation...

Binary interactions

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

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 483

483

Glycogen synthase kinase-3 alpha

PRO_0000085978

Regions

Domain

119 – 403

285

Protein kinase

Nucleotide binding

125 – 133

ATP By similarity

Compositional bias

3 – 83

Gly-rich

Sites

Active site

244

Proton acceptor By similarity

Binding site

148

ATP By similarity

Amino acid modifications

Modified residue

Phosphoserine Ref.13 Ref.18

Modified residue

Phosphothreonine Ref.18

Modified residue

Phosphoserine Ref.18

Modified residue

Phosphoserine; by PKB/AKT1 Ref.10 Ref.14 Ref.18

Modified residue

Phosphoserine Ref.18

Modified residue

Phosphoserine Ref.18

Modified residue

Phosphoserine Ref.18

Modified residue

Phosphoserine Ref.18

Modified residue

Phosphoserine Ref.13 Ref.18

Modified residue

Phosphoserine Ref.18

Modified residue

Phosphothreonine Ref.18

Modified residue

Phosphoserine Ref.18

Modified residue

279

Phosphotyrosine Ref.7 Ref.9 Ref.10 Ref.11 Ref.12 Ref.14

Modified residue

282

Phosphoserine Ref.14

Modified residue

480

Phosphothreonine Ref.18

Natural variations

Natural variant

109

Q → E.
Corresponds to variant rs35978177 [ dbSNP | Ensembl ].

VAR_051625

Natural variant

461

L → F. Ref.20
Corresponds to variant rs35454502 [ dbSNP | Ensembl ].

VAR_040539

Experimental info

Sequence conflict

449

A → S in AAA62432. Ref.1

Sequences

Sequence

Length

Mass (Da)

Tools

P49840 [UniParc].

Last modified December 1, 2000. Version 2.
Checksum: F18C012C03B7D786
Show »

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

« Hide

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. Lucas S.M. Nature 428:529-535(2004) [PubMed: 15057824] [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: 15489334] [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: 10868943] [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: 12761548] [Abstract] Cited for: ASSOCIATION WITH ALZHEIMER DISEASE, FUNCTION.
[7]	"Immunoaffinity profiling of tyrosine phosphorylation in cancer cells." Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H., Zha X.-M., Polakiewicz R.D., Comb M.J. Nat. Biotechnol. 23:94-101(2005) [PubMed: 15592455] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-279, MASS SPECTROMETRY.
[8]	"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: 17229088] [Abstract] Cited for: FUNCTION IN WNT SIGNALING, INTERACTION WITH AXIN1 AND CTNNB1/BETA-CATENIN.
[9]	"Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer." Rikova K., Guo A., Zeng Q., Possemato A., Yu J., Haack H., Nardone J., Lee K., Reeves C., Li Y., Hu Y., Tan Z., Stokes M., Sullivan L., Mitchell J., Wetzel R., Macneill J., Ren J.M. Comb M.J. Cell 131:1190-1203(2007) [PubMed: 18083107] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-279, MASS SPECTROMETRY. Tissue: Lung carcinoma.
[10]	"Proteomics analysis of protein kinases by target class-selective prefractionation and tandem mass spectrometry." Wissing J., Jaensch L., Nimtz M., Dieterich G., Hornberger R., Keri G., Wehland J., Daub H. Mol. Cell. Proteomics 6:537-547(2007) [PubMed: 17192257] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-21 AND TYR-279, MASS SPECTROMETRY. Tissue: Leukemic T-cell.
[11]	"Multiple reaction monitoring for robust quantitative proteomic analysis of cellular signaling networks." Wolf-Yadlin A., Hautaniemi S., Lauffenburger D.A., White F.M. Proc. Natl. Acad. Sci. U.S.A. 104:5860-5865(2007) [PubMed: 17389395] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-279, MASS SPECTROMETRY. Tissue: Mammary epithelium.
[12]	"Phosphoproteome of resting human platelets." Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J., Schuetz C., Walter U., Gambaryan S., Sickmann A. J. Proteome Res. 7:526-534(2008) [PubMed: 18088087] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-279, MASS SPECTROMETRY. Tissue: Platelet.
[13]	"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: 18691976] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-2 AND SER-72, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[14]	"Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach." Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S. Anal. Chem. 81:4493-4501(2009) [PubMed: 19413330] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-21; TYR-279 AND SER-282, MASS SPECTROMETRY. Tissue: Embryonic kidney.
[15]	"Glycogen synthase kinase-3: properties, functions, and regulation." Ali A., Hoeflich K.P., Woodgett J.R. Chem. Rev. 101:2527-2540(2001) [PubMed: 11749387] [Abstract] Cited for: REVIEW ON FUNCTION AND ENZYME REGULATION.
[16]	"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: 17478001] [Abstract] Cited for: REVIEW ON FUNCTION.
[17]	"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: 19366350] [Abstract] Cited for: REVIEW ON FUNCTION AND ENZYME REGULATION.
[18]	"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: 19369195] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-2; THR-19; SER-20; SER-21; SER-39; SER-41; SER-63; SER-65; SER-72; SER-77; THR-84; SER-97 AND THR-480, MASS SPECTROMETRY.
[19]	"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: 21269460] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[20]	"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. Stratton M.R. Nature 446:153-158(2007) [PubMed: 17344846] [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.

SMR

P49840. Positions 99-444.

ModBase

Search...

Protein-protein interaction databases

IntAct

P49840. 23 interactions.

MINT

MINT-1688290.

STRING

P49840.

PTM databases

PhosphoSite

P49840.

Polymorphism databases

DMDM

12644292.

Proteomic databases

PeptideAtlas

P49840.

PRIDE

P49840.

Protocols and materials databases

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.

H-InvDB

HIX0015173.

HGNC

HGNC:4616. GSK3A.

HPA

CAB004422.
HPA028423.

MIM

606784. gene.

neXtProt

NX_P49840.

PharmGKB

PA29008.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG04955.

HOGENOM

HBG755340.

HOVERGEN

HBG014652.

InParanoid

P49840.

OMA

VMAELIL.

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_15380. Diabetes pathways.

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.
IPR017442. Se/Thr_kinase-like_dom.
IPR008271. Ser/Thr_kinase_AS.
IPR002290. Ser/Thr_kinase_dom.
[Graphical view]

K08822.

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

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:	January 25, 2012
This is version 119 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.

Relevant documents

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

Human chromosome 19

Human chromosome 19: entries, gene names and cross-references to MIM

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

SIMILARITY comments

Index of protein domains and families

Names·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Cross-refs·Entry info·Documents

Preferred order of sections

Names and origin

Protein attributes

General annotation (Comments)

Ontologies

Binary interactions

With

Entry

#Exp.

IntAct

Notes

Sequence annotation (Features)

Molecule processing

Regions

Sites

Amino acid modifications

Natural variations

Experimental info

Sequences

References

Cross-references

Sequence databases

3D structure databases

Protein-protein interaction databases

PTM databases

Polymorphism databases

Proteomic databases

Protocols and materials databases

Genome annotation databases

Organism-specific databases

Phylogenomic databases

Enzyme and pathway databases

Gene expression databases

Family and domain databases

Other

Entry information

Relevant documents