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Protein

Glycogen synthase kinase-3 beta

Gene

Gsk3b

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

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. Through phosphorylation of the anti-apoptotic protein MCL1, may control cell apoptosis in response to growth factors deprivation. 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. Phosphorylates NR1D1 st 'Ser-55' and 'Ser-59' and stabilizes it by protecting it from proteasomal degradation. Regulates the circadian clock via phosphorylation of the major clock components including ARNTL/BMAL1, CLOCK and PER2. Phosphorylates CLOCK AT 'Ser-427' and targets it for proteasomal degradation. Phosphorylates ARNTL/BMAL1 at 'Ser-17' and 'Ser-21' and primes it for ubiquitination and proteasomal degradation. Phosphorylates OGT at 'Ser-3' or 'Ser-4' which positively regulates its activity.3 Publications

Miscellaneous

Simultaneous silencing of GSK3A and GSK3B by RNAi stimulates replication and promotes survival of INS-1E pancreatic beta cells.1 Publication

Catalytic activityi

ATP + [tau protein] = ADP + [tau protein] phosphate.
ATP + a protein = ADP + a phosphoprotein.

Enzyme regulationi

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.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei85ATPPROSITE-ProRule annotation1
Active sitei181Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi62 – 70ATPPROSITE-ProRule annotation9

GO - Molecular functioni

  • ATP binding Source: RGD
  • kinase activity Source: RGD
  • protein serine/threonine kinase activity Source: BHF-UCL
  • tau protein binding Source: RGD
  • tau-protein kinase activity Source: RGD

GO - Biological processi

  • aging Source: RGD
  • cellular response to amyloid-beta Source: ARUK-UCL
  • cellular response to dopamine Source: RGD
  • cellular response to erythropoietin Source: RGD
  • cellular response to hydrogen peroxide Source: RGD
  • cellular response to interleukin-3 Source: UniProtKB
  • cellular response to iron(II) ion Source: RGD
  • cellular response to lithium ion Source: RGD
  • cellular response to mechanical stimulus Source: RGD
  • circadian rhythm Source: UniProtKB
  • epithelial to mesenchymal transition Source: UniProtKB
  • establishment of cell polarity Source: RGD
  • establishment or maintenance of cell polarity Source: RGD
  • extrinsic apoptotic signaling pathway in absence of ligand Source: UniProtKB
  • glycogen metabolic process Source: UniProtKB-KW
  • maintenance of cell polarity Source: ARUK-UCL
  • negative regulation of calcineurin-NFAT signaling cascade Source: UniProtKB
  • negative regulation of dendrite development Source: RGD
  • negative regulation of dendrite morphogenesis Source: RGD
  • negative regulation of dopaminergic neuron differentiation Source: RGD
  • negative regulation of MAP kinase activity Source: RGD
  • negative regulation of neuron death Source: UniProtKB
  • negative regulation of neuron migration Source: RGD
  • negative regulation of nitric-oxide synthase activity Source: RGD
  • negative regulation of protein acetylation Source: ARUK-UCL
  • negative regulation of protein localization to nucleus Source: BHF-UCL
  • negative regulation of smooth muscle cell apoptotic process Source: RGD
  • neuron projection development Source: UniProtKB
  • neuron projection retraction Source: ARUK-UCL
  • peptidyl-serine phosphorylation Source: UniProtKB
  • positive regulation of apoptotic process Source: RGD
  • positive regulation of DNA biosynthetic process Source: RGD
  • positive regulation of excitatory postsynaptic potential Source: RGD
  • positive regulation of mitochondrial membrane potential Source: RGD
  • positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway Source: UniProtKB
  • positive regulation of neuron apoptotic process Source: RGD
  • positive regulation of protein binding Source: UniProtKB
  • positive regulation of protein catabolic process Source: RGD
  • positive regulation of smooth muscle cell proliferation Source: RGD
  • protein phosphorylation Source: BHF-UCL
  • regulation of axon extension Source: RGD
  • regulation of axonogenesis Source: RGD
  • regulation of dendrite morphogenesis Source: RGD
  • regulation of microtubule-based process Source: UniProtKB
  • regulation of microtubule cytoskeleton organization Source: ARUK-UCL
  • regulation of neuronal synaptic plasticity Source: RGD
  • response to activity Source: RGD
  • response to angiotensin Source: RGD
  • response to drug Source: RGD
  • response to epinephrine Source: RGD
  • response to estradiol Source: RGD
  • response to insulin Source: RGD
  • response to insulin-like growth factor stimulus Source: RGD
  • response to L-glutamate Source: RGD
  • response to lithium ion Source: RGD
  • response to ultrasound Source: RGD
  • Wnt signaling pathway Source: UniProtKB-KW

Keywordsi

Molecular functionDevelopmental protein, Kinase, Serine/threonine-protein kinase, Signal transduction inhibitor, Transferase
Biological processBiological rhythms, Carbohydrate metabolism, Differentiation, Glycogen metabolism, Neurogenesis, Wnt signaling pathway
LigandATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.11.26 5301

Names & Taxonomyi

Protein namesi
Recommended name:
Glycogen synthase kinase-3 beta (EC:2.7.11.26)
Short name:
GSK-3 beta
Alternative name(s):
Factor A
Short name:
FA
Serine/threonine-protein kinase GSK3B (EC:2.7.11.1)
Gene namesi
Name:Gsk3b
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Unplaced

Organism-specific databases

RGDi70982 Gsk3b

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Membrane, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi9S → A: Loss of phosphorylation; No inhibition of activity. 1 Publication1
Mutagenesisi216Y → F: Loss of phosphorylation and strong reduction of activity. 1 Publication1

Chemistry databases

ChEMBLiCHEMBL3669

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000859821 – 420Glycogen synthase kinase-3 betaAdd BLAST420

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei9Phosphoserine; by PKB/AKT1, RPS6KA3 and SGK3By similarity1
Modified residuei216Phosphotyrosine1 Publication1
Modified residuei389PhosphoserineCombined sources1

Post-translational modificationi

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). Inactivated by phosphorylation at Ser-9 (By similarity).By similarity
Mono-ADP-ribosylation by PARP10 negatively regulates kinase activity.By similarity

Keywords - PTMi

ADP-ribosylation, Phosphoprotein

Proteomic databases

PaxDbiP18266
PRIDEiP18266

PTM databases

iPTMnetiP18266
PhosphoSitePlusiP18266

Interactioni

Subunit structurei

Monomer. Interacts with DAB2IP (via C2 domain); the interaction stimulates GSK3B kinase activation. Interacts (via C2 domain) with PPP2CA (By similarity). Interacts with ARRB2, AXIN1, CABYR, DISC1, MMP2, MUC1, NIN, PRUNE1 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. Interacts with the CLOCK-ARNTL/BMAL1 heterodimer. Interacts with the ARNTL/BMAL1 (By similarity). Interacts with CTNND2 (By similarity). The complex composed, at least, of APC, CTNNB1 and GSK3B interacts with JPT1; the interaction requires the inactive form of GSK3B (phosphorylated at 'Ser-9') (By similarity). Forms a complex composed of PRKAR2A or PRKAR2B, GSK3B and GSKIP through GSKIP interaction; facilitates PKA-induced phosphorylation and regulates GSK3B activity. Interacts with GSK3B; induces GSK3B-mediated phosphorylation of GSKIP (By similarity).By similarity

GO - Molecular functioni

  • tau protein binding Source: RGD

Protein-protein interaction databases

BioGridi249893, 9 interactors
CORUMiP18266
DIPiDIP-40957N
IntActiP18266, 1 interactor
MINTiP18266
STRINGi10116.ENSRNOP00000003867

Chemistry databases

BindingDBiP18266

Structurei

3D structure databases

ProteinModelPortaliP18266
SMRiP18266
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini56 – 340Protein kinasePROSITE-ProRule annotationAdd BLAST285

Sequence similaritiesi

Phylogenomic databases

eggNOGiKOG0658 Eukaryota
COG0515 LUCA
HOGENOMiHOG000233017
HOVERGENiHBG014652
InParanoidiP18266
KOiK03083
PhylomeDBiP18266
TreeFamiTF101104

Family and domain databases

InterProiView protein in InterPro
IPR033573 GSK3B
IPR011009 Kinase-like_dom_sf
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR008271 Ser/Thr_kinase_AS
PANTHERiPTHR24057:SF8 PTHR24057:SF8, 1 hit
PfamiView protein in Pfam
PF00069 Pkinase, 1 hit
SMARTiView protein in SMART
SM00220 S_TKc, 1 hit
SUPFAMiSSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS00107 PROTEIN_KINASE_ATP, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00108 PROTEIN_KINASE_ST, 1 hit

Sequencei

Sequence statusi: Complete.

P18266-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MSGRPRTTSF AESCKPVQQP SAFGSMKVSR DKDGSKVTTV VATPGQGPDR
60 70 80 90 100
PQEVSYTDTK VIGNGSFGVV YQAKLCDSGE LVAIKKVLQD KRFKNRELQI
110 120 130 140 150
MRKLDHCNIV RLRYFFYSSG EKKDEVYLNL VLDYVPETVY RVARHYSRAK
160 170 180 190 200
QTLPVIYVKL YMYQLFRSLA YIHSFGICHR DIKPQNLLLD PDTAVLKLCD
210 220 230 240 250
FGSAKQLVRG EPNVSYICSR YYRAPELIFG ATDYTSSIDM WSAGCVLAEL
260 270 280 290 300
LLGQPIFPGD SGVDQLVEII KVLGTPTREQ IREMNPNYTE FKFPQIKAHP
310 320 330 340 350
WTKVFRPRTP PEAIALCSRL LEYTPTARLT PLEACAHSFF DELRDPNVKL
360 370 380 390 400
PNGRDTPALF NFTTQELSSN PPLATILIPP HARIQAAASP PANATAASDT
410 420
NAGDRGQTNN AASASASNST
Length:420
Mass (Da):46,742
Last modified:November 1, 1990 - v1
Checksum:i2F473FCAB89B4398
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti240M → V in CAA52020 (PubMed:7686508).Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X53428 mRNA Translation: CAA37519.1
X73653 mRNA Translation: CAA52020.1
PIRiS14708 TVRTKB
RefSeqiNP_114469.1, NM_032080.1
UniGeneiRn.10426

Genome annotation databases

GeneIDi84027
KEGGirno:84027
UCSCiRGD:70982 rat

Similar proteinsi

Entry informationi

Entry nameiGSK3B_RAT
AccessioniPrimary (citable) accession number: P18266
Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 1, 1990
Last sequence update: November 1, 1990
Last modified: May 23, 2018
This is version 187 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families
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Main funding by: National Institutes of Health