P18266 (GSK3B_RAT) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Glycogen synthase kinase-3 beta
Short name=GSK-3 beta
EC=2.7.11.26

Alternative name(s):
Factor A
Short name=FA
Serine/threonine-protein kinase GSK3B
EC=2.7.11.1

Gene names

Name:

Gsk3b

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	420 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 transcription factors and microtubules, by phosphorylating and inactivating glycogen synthase (GYS1 or GYS2), EIF2B, CTNNB1/beta-catenin, APC, AXIN1, DPYSL2/CRMP2, JUN, NFATC1/NFATC, MAPT/TAU and MACF1. Requires primed phosphorylation of the majority of its substrates. In skeletal muscle, contributes to insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity and hence glycogen synthesis. May also mediate the development of insulin resistance by regulating activation of transcription factors. Regulates protein synthesis by controlling the activity of initiation factor 2B (EIF2BE/EIF2B5) in the same manner as glycogen synthase. In Wnt signaling, GSK3B forms a multimeric complex with APC, AXIN1 and CTNNB1/beta-catenin and phosphorylates the N-terminus of CTNNB1 leading to its degradation mediated by ubiquitin/proteasomes. Phosphorylates JUN at sites proximal to its DNA-binding domain, thereby reducing its affinity for DNA. Phosphorylates NFATC1/NFATC on conserved serine residues promoting NFATC1/NFATC nuclear export, shutting off NFATC1/NFATC gene regulation, and thereby opposing the action of calcineurin. Phosphorylates MAPT/TAU on 'Thr-548', decreasing significantly MAPT/TAU ability to bind and stabilize microtubules. Plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex. Phosphorylates MACF1, inhibiting its binding to microtubules which is critical for its role in bulge stem cell migration and skin wound repair. Probably regulates NF-kappa-B (NFKB1) at the transcriptional level and is required for the NF-kappa-B-mediated anti-apoptotic response to TNF-alpha (TNF/TNFA). Negatively regulates replication in pancreatic beta-cells, resulting in apoptosis, loss of beta-cells. Phosphorylates MUC1 in breast cancer cells, decreasing the interaction of MUC1 with CTNNB1/beta-catenin. Is necessary for the establishment of neuronal polarity and axon outgrowth. Phosphorylates MARK2, leading to inhibit its activity. Phosphorylates SIK1 at 'Thr-182', leading to sustain its activity. Phosphorylates ZC3HAV1 which enhances its antiviral activity. Phosphorylates SFPQ upon T-cell activation. Phosphorylates SNAI1, leading to its BTRC-triggered ubiquitination and proteasomal degradation. Ref.4 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-216. In response to insulin, inhibited by phosphorylation at Ser-9 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 By similarity. Interacts with ARRB2, AXIN1, CABYR, DISC1, MMP2, MUC1, NIN, PRUNE and ZBED3 By similarity. Interacts with AXIN1; the interaction mediates hyperphosphorylation of CTNNB1 leading to its ubiquitination and destruction. Interacts with and phosphorylates SNAI1. Interacts with DNM1L (via a C-terminal domain) By similarity. Found in a complex composed of MACF1, APC, AXIN1, CTNNB1 and GSK3B. Interacts with SGK3 By similarity. Ref.4 Ref.5
Subcellular location	Cytoplasm By similarity. Nucleus By similarity. Membrane. Cell membrane By similarity. Note: The phosphorylated form shows localization to cytoplasm and cell membrane. The MEMO1-RHOA-DIAPH1 signaling pathway controls localization of the phosphorylated form to the cell membrane By similarity. Ref.5
Post-translational modification	Phosphorylated by AKT1 and ILK1. Upon insulin-mediated signaling, the activated PKB/AKT1 and RPS6KA3 protein kinases phosphorylate and desactivate GSK3B, resulting in the dephosphorylation and activation of GYS1. Activated by phosphorylation at Tyr-216 By similarity. Ref.3
Miscellaneous	Simultaneous silencing of GSK3A and GSK3B by RNAi stimulates replication and promotes survival of INS-1E pancreatic beta cells (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 Differentiation Glycogen metabolism Neurogenesis Wnt signaling pathway
Cellular component	Cell membrane Cytoplasm Membrane Nucleus
Ligand	ATP-binding Nucleotide-binding
Molecular function	Developmental protein Kinase Serine/threonine-protein kinase Signal transduction inhibitor Transferase
PTM	Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	ER overload response Inferred from electronic annotation. Source: Compara axonogenesis Inferred from electronic annotation. Source: Compara canonical Wnt receptor signaling pathway involved in positive regulation of apoptotic process Inferred from electronic annotation. Source: Compara cell migration Inferred from electronic annotation. Source: Compara circadian rhythm Inferred from sequence or structural similarity. Source: UniProtKB epithelial to mesenchymal transition Inferred from sequence or structural similarity. Source: UniProtKB establishment of cell polarity Inferred from direct assay PubMed 12610628. Source: RGD fat cell differentiation Inferred from electronic annotation. Source: Compara glycogen metabolic process Inferred from electronic annotation. Source: UniProtKB-KW hippocampus development Inferred from electronic annotation. Source: Compara hypermethylation of CpG island Inferred from electronic annotation. Source: Compara induction of apoptosis Inferred from direct assay PubMed 12808104. Source: RGD intracellular signal transduction Inferred from electronic annotation. Source: Compara myoblast fusion Inferred from electronic annotation. Source: Compara negative regulation of MAP kinase activity Inferred from mutant phenotype PubMed 17182785. Source: RGD negative regulation of NFAT protein import into nucleus Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of apoptotic process Inferred from electronic annotation. Source: Compara negative regulation of dendrite morphogenesis Inferred from mutant phenotype PubMed 17182785. Source: RGD negative regulation of protein binding Inferred from electronic annotation. Source: Compara negative regulation of protein complex assembly Inferred from electronic annotation. Source: Compara negative regulation of transcription, DNA-dependent Inferred from direct assay PubMed 12808104. Source: RGD organ morphogenesis Inferred from electronic annotation. Source: Compara peptidyl-serine phosphorylation Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of Rac GTPase activity Inferred from electronic annotation. Source: Compara positive regulation of cell-matrix adhesion 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 protein binding Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of protein complex assembly Inferred from electronic annotation. Source: Compara positive regulation of protein export from nucleus Inferred from electronic annotation. Source: Compara positive regulation of stem cell differentiation Inferred from electronic annotation. Source: Compara positive regulation of transcription from RNA polymerase II promoter Inferred from electronic annotation. Source: Compara protein export from nucleus Inferred from electronic annotation. Source: Compara protein localization to microtubule Inferred from electronic annotation. Source: Compara re-entry into mitotic cell cycle Inferred from electronic annotation. Source: Compara regulation of gene expression by genetic imprinting Inferred from electronic annotation. Source: Compara regulation of microtubule-based process Inferred from sequence or structural similarity. Source: UniProtKB regulation of neuronal synaptic plasticity Inferred from mutant phenotype PubMed 17329210. Source: RGD response to drug Inferred from expression pattern PubMed 19359144. Source: RGD response to lithium ion Inferred from expression pattern PubMed 19359144. Source: RGD superior temporal gyrus development Inferred from electronic annotation. Source: Compara
Cellular_component	beta-catenin destruction complex Inferred from direct assay PubMed 10228155. Source: BHF-UCL centrosome Inferred from electronic annotation. Source: Compara cytosol Inferred from direct assay PubMed 17329210. Source: RGD dendritic shaft Inferred from electronic annotation. Source: Compara dendritic spine Inferred from direct assay PubMed 17329210. Source: RGD growth cone Inferred from electronic annotation. Source: Compara membrane raft Inferred from direct assay PubMed 16735023. Source: RGD neuronal cell body Inferred from electronic annotation. Source: Compara nucleus Inferred from sequence or structural similarity. Source: UniProtKB perinuclear region of cytoplasm Inferred from electronic annotation. Source: Compara plasma membrane Inferred from electronic annotation. Source: UniProtKB-SubCell ribonucleoprotein complex Inferred from electronic annotation. Source: Compara
Molecular_function	ATP binding Inferred from direct assay PubMed 16879317PubMed 17329210. Source: RGD protein serine/threonine kinase activity Inferred from direct assay PubMed 11035810Ref.4. Source: BHF-UCL tau protein binding Inferred from direct assay PubMed 16735023. Source: RGD tau-protein kinase activity Inferred from direct assay PubMed 16735023. Source: RGD
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 420	420	Glycogen synthase kinase-3 beta		PRO_0000085982
Regions
	Domain	56 – 340	285	Protein kinase
	Nucleotide binding	62 – 70	9	ATP By similarity
Sites
	Active site	181	1	Proton acceptor By similarity
	Binding site	85	1	ATP By similarity
Amino acid modifications
	Modified residue	7	1	Phosphothreonine By similarity
	Modified residue	9	1	Phosphoserine; by PKB/AKT1, RPS6KA3 and SGK3 By similarity
	Modified residue	215	1	Phosphoserine By similarity
	Modified residue	216	1	Phosphotyrosine Ref.3
	Modified residue	219	1	Phosphoserine By similarity
	Modified residue	389	1	Phosphoserine By similarity
	Modified residue	395	1	Phosphothreonine By similarity
Experimental info
	Mutagenesis	9	1	S → A: Loss of phosphorylation; No inhibition of activity. Ref.7
	Mutagenesis	216	1	Y → F: Loss of phosphorylation and strong reduction of activity. Ref.3
	Sequence conflict	240	1	M → V in CAA52020. Ref.2

Sequences

	Sequence		Length	Mass (Da)
	P18266 [UniParc]. Last modified November 1, 1990. Version 1. Checksum: 2F473FCAB89B4398	FASTA	420	46,742
	10 20 30 40 50 60 MSGRPRTTSF AESCKPVQQP SAFGSMKVSR DKDGSKVTTV VATPGQGPDR PQEVSYTDTK 70 80 90 100 110 120 VIGNGSFGVV YQAKLCDSGE LVAIKKVLQD KRFKNRELQI MRKLDHCNIV RLRYFFYSSG 130 140 150 160 170 180 EKKDEVYLNL VLDYVPETVY RVARHYSRAK QTLPVIYVKL YMYQLFRSLA YIHSFGICHR 190 200 210 220 230 240 DIKPQNLLLD PDTAVLKLCD FGSAKQLVRG EPNVSYICSR YYRAPELIFG ATDYTSSIDM 250 260 270 280 290 300 WSAGCVLAEL LLGQPIFPGD SGVDQLVEII KVLGTPTREQ IREMNPNYTE FKFPQIKAHP 310 320 330 340 350 360 WTKVFRPRTP PEAIALCSRL LEYTPTARLT PLEACAHSFF DELRDPNVKL PNGRDTPALF 370 380 390 400 410 420 NFTTQELSSN PPLATILIPP HARIQAAASP PANATAASDT NAGDRGQTNN AASASASNST

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]	"Glycogen synthase kinase 3 beta is identical to tau protein kinase I generating several epitopes of paired helical filaments." Ishiguro K., Shiratsuchi A., Sato S., Omori A., Arioka M., Kobayashi S., Uchida T., Imahori K. FEBS Lett. 325:167-172(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Strain: Sprague-Dawley. Tissue: Brain cortex.
[3]	"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-216, MUTAGENESIS OF TYR-216.
[4]	"Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3beta and beta-catenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin." Ikeda S., Kishida S., Yamamoto H., Murai H., Koyama S., Kikuchi A. EMBO J. 17:1371-1384(1998) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH CTNNB1/BETA-CATENIN.
[5]	"The role of microtubule actin cross-linking factor 1 (MACF1) in the Wnt signaling pathway." Chen H.J., Lin C.M., Lin C.S., Perez-Olle R., Leung C.L., Liem R.K. Genes Dev. 20:1933-1945(2006) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION, IDENTIFICATION IN A COMPLEX WITH MACF1; APC; AXIN1 AND CTNNB1.
[6]	"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.
[7]	"Glycogen synthase kinase (GSK) 3beta directly phosphorylates Serine 212 in the regulatory loop and inhibits microtubule affinity-regulating kinase (MARK) 2." Timm T., Balusamy K., Li X., Biernat J., Mandelkow E., Mandelkow E.M. J. Biol. Chem. 283:18873-18882(2008) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF MARK2, MUTAGENESIS OF SER-9.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	X53428 mRNA. Translation: CAA37519.1. X73653 mRNA. Translation: CAA52020.1.
IPI	IPI00324168.
PIR	TVRTKB. S14708.
RefSeq	NP_114469.1. NM_032080.1.
UniGene	Rn.10426.
3D structure databases
ProteinModelPortal	P18266.
SMR	P18266. Positions 23-386.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP-40957N.
MINT	MINT-121872.
STRING	10116.ENSRNOP00000003867.
PTM databases
PhosphoSite	P18266.
Proteomic databases
PaxDb	P18266.
PRIDE	P18266.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSRNOT00000003867; ENSRNOP00000003867; ENSRNOG00000002833.
GeneID	84027.
KEGG	rno:84027.
UCSC	RGD:70982. rat.
Organism-specific databases
CTD	2932.
RGD	70982. Gsk3b.
Phylogenomic databases
eggNOG	COG0515.
GeneTree	ENSGT00520000055635.
HOGENOM	HOG000233017.
HOVERGEN	HBG014652.
InParanoid	P18266.
KO	K03083.
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
Genevestigator	P18266.
GermOnline	ENSRNOG00000002833. Rattus norvegicus.
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	P18266.
ChEMBL	CHEMBL3669.
NextBio	616603.

Entry information

Entry name

GSK3B_RAT

Accession

Primary (citable) accession number: P18266

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1990
Last sequence update:	November 1, 1990
Last modified:	May 1, 2013
This is version 139 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program