P18266 (GSK3B_RAT) Reviewed, UniProtKB/Swiss-Prot
Last modified June 11, 2014. Version 151. History...
Names and origin
|Protein names||Recommended name:|
Glycogen synthase kinase-3 beta
Short name=GSK-3 beta
Serine/threonine-protein kinase GSK3B
|Organism||Rattus norvegicus (Rat) [Reference proteome]|
|Taxonomic identifier||10116 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus|
|Sequence length||420 AA.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
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. Ref.4 Ref.6 Ref.7
ATP + [tau protein] = ADP + [tau protein] phosphate.
ATP + a protein = ADP + a phosphoprotein.
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.
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, 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. Interacts with the CLOCK-ARNTL/BMAL1 heterodimer. Interacts with the ARNTL/BMAL1 By similarity. Ref.4 Ref.5
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
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
Mono-ADP-ribosylation by PARP10 negatively regulates kinase activity By similarity.
Simultaneous silencing of GSK3A and GSK3B by RNAi stimulates replication and promotes survival of INS-1E pancreatic beta cells (Ref.6).
Contains 1 protein kinase domain.
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 420||420||Glycogen synthase kinase-3 beta||PRO_0000085982|
|Domain||56 – 340||285||Protein kinase|
|Nucleotide binding||62 – 70||9||ATP By similarity|
|Active site||181||1||Proton acceptor By similarity|
|Binding site||85||1||ATP By similarity|
Amino acid modifications
|Modified residue||9||1||Phosphoserine; by PKB/AKT1, RPS6KA3 and SGK3 By similarity|
|Modified residue||216||1||Phosphotyrosine Ref.3|
|Modified residue||389||1||Phosphoserine By similarity|
|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|
|||"Molecular cloning and expression of glycogen synthase kinase-3/factor A."|
EMBO J. 9:2431-2438(1990) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
|||"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].
Tissue: Brain cortex.
|||"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.
|||"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.
|||"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.
|||"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.
|||"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.|
|X53428 mRNA. Translation: CAA37519.1.|
X73653 mRNA. Translation: CAA52020.1.
|PIR||TVRTKB. S14708. |
|RefSeq||NP_114469.1. NM_032080.1. |
3D structure databases
|SMR||P18266. Positions 23-386. |
Protein-protein interaction databases
|BioGrid||249893. 9 interactions.|
|IntAct||P18266. 1 interaction.|
Protocols and materials databases
Genome annotation databases
|Ensembl||ENSRNOT00000003867; ENSRNOP00000003867; ENSRNOG00000002833. |
|UCSC||RGD:70982. rat. |
|RGD||70982. Gsk3b. |
Enzyme and pathway databases
|BRENDA||22.214.171.124. 5301. |
|Reactome||REACT_206767. Disease. |
REACT_212996. Signal Transduction.
REACT_227097. Immune System.
Gene expression databases
Family and domain databases
|InterPro||IPR011009. Kinase-like_dom. |
|Pfam||PF00069. Pkinase. 1 hit. |
|SMART||SM00220. S_TKc. 1 hit. |
|SUPFAM||SSF56112. SSF56112. 1 hit. |
|PROSITE||PS00107. PROTEIN_KINASE_ATP. 1 hit. |
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
|Accession||Primary (citable) accession number: P18266|
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|
Index of protein domains and families