Q9WV60 (GSK3B_MOUSE) 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):
Serine/threonine-protein kinase GSK3B
EC=2.7.11.1

Gene names

Name:

Gsk3b

Organism

Mus musculus (Mouse)

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

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, 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. Ref.3 Ref.6 Ref.9 Ref.14 Ref.17
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 and RPS6KA3; 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 CABYR, MMP2, MUC1, NIN and PRUNE 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. Interacts with ARRB2 and DISC1. Found in a complex composed of MACF1, APC, AXIN1, CTNNB1 and GSK3B By similarity. Interacts with SGK3 By similarity. Ref.5 Ref.15
Subcellular location	Cytoplasm By similarity. Nucleus By similarity. 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 phosophorylated form to the cell membrane By similarity.
Post-translational modification	Phosphorylated by AKT1 and ILK1. Upon insulin-mediated signaling, the activated PKB/AKT1 protein kinase phosphorylates and desactivates GSK3B, resulting in the dephosphorylation and activation of GYS1. Activated by phosphorylation at Tyr-216 By similarity. Ref.4 Ref.7 Ref.8 Ref.10 Ref.11 Ref.12 Ref.13 Ref.16
Disruption phenotype	Embryonic lethality at E16 due to hepatocyte apoptosis. 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 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 direct assay. Source: MGI anti-apoptosis Inferred from mutant phenotype Ref.3. Source: MGI axonogenesis Inferred from genetic interaction. Source: MGI canonical Wnt receptor signaling pathway involved in positive regulation of apoptosis Inferred from mutant phenotype. Source: BHF-UCL cell migration Inferred from genetic interaction. Source: MGI cell proliferation Traceable author statement Ref.3. Source: MGI epithelial to mesenchymal transition Inferred from sequence or structural similarity. Source: UniProtKB fat cell differentiation Inferred from direct assay. Source: MGI glycogen metabolic process Inferred from electronic annotation. Source: UniProtKB-KW hypermethylation of CpG island Inferred from mutant phenotype. Source: BHF-UCL myoblast fusion Inferred from direct assay. Source: MGI negative regulation of NFAT protein import into nucleus Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of signal transduction Inferred from electronic annotation. Source: UniProtKB-KW organ morphogenesis Inferred from mutant phenotype Ref.3. Source: MGI peptidyl-serine phosphorylation Inferred from direct assay. Source: MGI positive regulation of peptidyl-serine phosphorylation Inferred from direct assay. Source: MGI positive regulation of peptidyl-threonine phosphorylation Inferred from direct assay. Source: MGI positive regulation of transcription from RNA polymerase II promoter Inferred from mutant phenotype. Source: BHF-UCL protein export from nucleus Inferred from direct assay. Source: MGI protein localization to microtubule Inferred from genetic interaction. Source: MGI re-entry into mitotic cell cycle Inferred from direct assay. Source: MGI regulation of gene expression by genetic imprinting Inferred from mutant phenotype. Source: BHF-UCL regulation of microtubule-based process Inferred from direct assay Ref.17. Source: UniProtKB
Cellular component	Axin-APC-beta-catenin-GSK3B complex Inferred from direct assay. Source: MGI cytosol Inferred from direct assay. Source: MGI dendritic shaft Inferred from direct assay. Source: MGI growth cone Inferred from direct assay. Source: MGI neuronal cell body Inferred from direct assay. Source: MGI nucleoplasm Traceable author statement. Source: Reactome plasma membrane Inferred from sequence or structural similarity. Source: UniProtKB soluble fraction Inferred from direct assay. Source: MGI
Molecular function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW beta-catenin binding Inferred from physical interaction. Source: MGI protein serine/threonine kinase activity Inferred from direct assay. Source: MGI tau-protein kinase activity Inferred from direct assay. Source: MGI
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
Epm2a	Q9WUA5	2	EBI-400793,EBI-1040928

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_0000085981
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 Ref.12
	Modified residue	9	1	Phosphoserine; by PKB/AKT1, RPS6KA3 and SGK3 By similarity
	Modified residue	25	1	Phosphoserine By similarity
	Modified residue	215	1	Phosphoserine Ref.11 Ref.16
	Modified residue	216	1	Phosphotyrosine Ref.7 Ref.8 Ref.10 Ref.11 Ref.12 Ref.13
	Modified residue	219	1	Phosphoserine Ref.10 Ref.12 Ref.13
	Modified residue	275	1	Phosphothreonine By similarity
	Modified residue	277	1	Phosphothreonine By similarity
	Modified residue	389	1	Phosphoserine Ref.4 Ref.11
	Modified residue	395	1	Phosphothreonine Ref.11
	Modified residue	398	1	Phosphoserine By similarity
	Modified residue	413	1	Phosphoserine By similarity
	Modified residue	415	1	Phosphoserine By similarity
	Modified residue	417	1	Phosphoserine By similarity
	Modified residue	419	1	Phosphoserine By similarity
Experimental info
	Mutagenesis	9	1	S → A: Loss of phosphorylation; No inhibition of activity and constitutively active. Ref.6

Sequences

	Sequence		Length	Mass (Da)
	Q9WV60 [UniParc]. Last modified May 1, 2000. Version 2. Checksum: 200C3FD1B38B4883	FASTA	420	46,710
	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 ATDYTSSIDV 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

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Testicular expression and hormonal control of glycogen synthase kinase 3, a homologue of yeast RIM11." Salameh W.A., Guo T.B., Chan K.C., Mitchell A.P. Submitted (FEB-2000) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Testis.
[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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Strain: Czech II and FVB/N. Tissue: Mammary gland.
[3]	"Requirement for glycogen synthase kinase-3beta in cell survival and NF-kappaB activation." Hoeflich K.P., Luo J., Rubie E.A., Tsao M.S., Jin O., Woodgett J.R. Nature 406:86-90(2000) [PubMed: 10894547] [Abstract] Cited for: FUNCTION, DISRUPTION PHENOTYPE.
[4]	"Phosphoproteomic analysis of the developing mouse brain." Ballif B.A., Villen J., Beausoleil S.A., Schwartz D., Gygi S.P. Mol. Cell. Proteomics 3:1093-1101(2004) [PubMed: 15345747] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-389, MASS SPECTROMETRY. Tissue: Embryonic brain.
[5]	"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: 16051150] [Abstract] Cited for: INTERACTION WITH ARRB2.
[6]	"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: 15791206] [Abstract] Cited for: FUNCTION, MUTAGENESIS OF SER-9.
[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-216, MASS SPECTROMETRY.
[8]	"Comprehensive identification of phosphorylation sites in postsynaptic density preparations." Trinidad J.C., Specht C.G., Thalhammer A., Schoepfer R., Burlingame A.L. Mol. Cell. Proteomics 5:914-922(2006) [PubMed: 16452087] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-216, MASS SPECTROMETRY. Tissue: Brain.
[9]	"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: 17391670] [Abstract] Cited for: FUNCTION IN AXON FORMATION.
[10]	"Quantitative time-resolved phosphoproteomic analysis of mast cell signaling." Cao L., Yu K., Banh C., Nguyen V., Ritz A., Raphael B.J., Kawakami Y., Kawakami T., Salomon A.R. J. Immunol. 179:5864-5876(2007) [PubMed: 17947660] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-216 AND SER-219, MASS SPECTROMETRY. Tissue: Mast cell.
[11]	"Qualitative and quantitative analyses of protein phosphorylation in naive and stimulated mouse synaptosomal preparations." Munton R.P., Tweedie-Cullen R., Livingstone-Zatchej M., Weinandy F., Waidelich M., Longo D., Gehrig P., Potthast F., Rutishauser D., Gerrits B., Panse C., Schlapbach R., Mansuy I.M. Mol. Cell. Proteomics 6:283-293(2007) [PubMed: 17114649] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-215; TYR-216; SER-389 AND THR-395, MASS SPECTROMETRY. Tissue: Brain cortex.
[12]	"Large-scale phosphorylation analysis of mouse liver." Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007) [PubMed: 17242355] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-7; TYR-216 AND SER-219, MASS SPECTROMETRY. Tissue: Liver.
[13]	"Large-scale identification and evolution indexing of tyrosine phosphorylation sites from murine brain." Ballif B.A., Carey G.R., Sunyaev S.R., Gygi S.P. J. Proteome Res. 7:311-318(2008) [PubMed: 18034455] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-216 AND SER-219, MASS SPECTROMETRY. Tissue: Brain.
[14]	"Genetic deficiency of glycogen synthase kinase-3beta corrects diabetes in mouse models of insulin resistance." Tanabe K., Liu Z., Patel S., Doble B.W., Li L., Cras-Meneur C., Martinez S.C., Welling C.M., White M.F., Bernal-Mizrachi E., Woodgett J.R., Permutt M.A. PLoS Biol. 6:E37-E37(2008) [PubMed: 18288891] [Abstract] Cited for: FUNCTION IN REGULATION OF PANCREATIC BETA-CELLS.
[15]	"Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3beta/beta-catenin signaling." Mao Y., Ge X., Frank C.L., Madison J.M., Koehler A.N., Doud M.K., Tassa C., Berry E.M., Soda T., Singh K.K., Biechele T., Petryshen T.L., Moon R.T., Haggarty S.J., Tsai L.H. Cell 136:1017-1031(2009) [PubMed: 19303846] [Abstract] Cited for: INTERACTION WITH DISC1.
[16]	"Large scale localization of protein phosphorylation by use of electron capture dissociation mass spectrometry." Sweet S.M., Bailey C.M., Cunningham D.L., Heath J.K., Cooper H.J. Mol. Cell. Proteomics 8:904-912(2009) [PubMed: 19131326] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-215, MASS SPECTROMETRY. Tissue: Embryonic fibroblast.
[17]	"Skin stem cells orchestrate directional migration by regulating microtubule-ACF7 connections through GSK3beta." Wu X., Shen Q.T., Oristian D.S., Lu C.P., Zheng Q., Wang H.W., Fuchs E. Cell 144:341-352(2011) [PubMed: 21295697] [Abstract] Cited for: FUNCTION.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AF156099 mRNA. Translation: AAD39258.2. BC006936 mRNA. Translation: AAH06936.1. BC060743 mRNA. Translation: AAH60743.1.
IPI	IPI00125319.
RefSeq	NP_062801.1. NM_019827.6.
UniGene	Mm.394930.
3D structure databases
ProteinModelPortal	Q9WV60.
SMR	Q9WV60. Positions 23-386.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q9WV60. 6 interactions.
STRING	Q9WV60.
PTM databases
PhosphoSite	Q9WV60.
Proteomic databases
PRIDE	Q9WV60.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000023507; ENSMUSP00000023507; ENSMUSG00000022812.
GeneID	56637.
KEGG	mmu:56637.
Organism-specific databases
CTD	2932.
MGI	MGI:1861437. Gsk3b.
Phylogenomic databases
GeneTree	ENSGT00520000055635.
HOVERGEN	HBG014652.
OrthoDB	EOG4WH8KZ.
PhylomeDB	Q9WV60.
Enzyme and pathway databases
Reactome	REACT_90332. Cell Cycle, Mitotic.
Gene expression databases
ArrayExpress	Q9WV60.
Bgee	Q9WV60.
CleanEx	MM_GSK3B.
Genevestigator	Q9WV60.
GermOnline	ENSMUSG00000022812. Mus musculus.
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]
KO	K03083.
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	313081.
PMAP-CutDB	Q9WV60.
SOURCE	Search...

Entry information

Entry name

GSK3B_MOUSE

Accession

Primary (citable) accession number: Q9WV60

Entry history

Integrated into UniProtKB/Swiss-Prot:	December 1, 2000
Last sequence update:	May 1, 2000
Last modified:	December 14, 2011
This is version 121 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program