| IED ID | IndEnz0002002438 |
| Enzyme Type ID | protease002438 |
| Protein Name |
Glycogen synthase kinase-3 beta GSK-3 beta EC 2.7.11.26 Factor A FA Serine/threonine-protein kinase GSK3B EC 2.7.11.1 |
| Gene Name | Gsk3b |
| Organism | Rattus norvegicus (Rat) |
| Taxonomic Lineage | cellular organisms Eukaryota Opisthokonta Metazoa Eumetazoa Bilateria Deuterostomia Chordata Craniata Vertebrata Gnathostomata (jawed vertebrates) Teleostomi Euteleostomi Sarcopterygii Dipnotetrapodomorpha Tetrapoda Amniota Mammalia Theria Eutheria Boreoeutheria Euarchontoglires Glires (Rodents and rabbits) Rodentia Myomorpha (mice and others) Muroidea Muridae Murinae Rattus Rattus norvegicus (Rat) |
| Enzyme Sequence | MSGRPRTTSFAESCKPVQQPSAFGSMKVSRDKDGSKVTTVVATPGQGPDRPQEVSYTDTKVIGNGSFGVVYQAKLCDSGELVAIKKVLQDKRFKNRELQIMRKLDHCNIVRLRYFFYSSGEKKDEVYLNLVLDYVPETVYRVARHYSRAKQTLPVIYVKLYMYQLFRSLAYIHSFGICHRDIKPQNLLLDPDTAVLKLCDFGSAKQLVRGEPNVSYICSRYYRAPELIFGATDYTSSIDMWSAGCVLAELLLGQPIFPGDSGVDQLVEIIKVLGTPTREQIREMNPNYTEFKFPQIKAHPWTKVFRPRTPPEAIALCSRLLEYTPTARLTPLEACAHSFFDELRDPNVKLPNGRDTPALFNFTTQELSSNPPLATILIPPHARIQAAASPPANATAASDTNAGDRGQTNNAASASASNST |
| Enzyme Length | 420 |
| Uniprot Accession Number | P18266 |
| Absorption | |
| Active Site | ACT_SITE 181; /note="Proton acceptor"; /evidence="ECO:0000255|PROSITE-ProRule:PRU00159, ECO:0000255|PROSITE-ProRule:PRU10027" |
| Activity Regulation | ACTIVITY 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. |
| Binding Site | BINDING 85; /note=ATP; /evidence=ECO:0000255|PROSITE-ProRule:PRU00159 |
| Calcium Binding | |
| catalytic Activity | CATALYTIC ACTIVITY: Reaction=ATP + L-seryl-[tau protein] = ADP + H(+) + O-phospho-L-seryl-[tau protein]; Xref=Rhea:RHEA:12801, Rhea:RHEA-COMP:13701, Rhea:RHEA-COMP:13702, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.26; Evidence={ECO:0000250|UniProtKB:P49841}; CATALYTIC ACTIVITY: Reaction=ATP + L-threonyl-[tau protein] = ADP + H(+) + O-phospho-L-threonyl-[tau protein]; Xref=Rhea:RHEA:53904, Rhea:RHEA-COMP:13703, Rhea:RHEA-COMP:13704, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.26; Evidence={ECO:0000250|UniProtKB:P49841}; CATALYTIC ACTIVITY: Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-[protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1; Evidence={ECO:0000250|UniProtKB:P49841}; CATALYTIC ACTIVITY: Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.1; Evidence={ECO:0000250|UniProtKB:P49841}; |
| DNA Binding | |
| EC Number | 2.7.11.26; 2.7.11.1 |
| Enzyme Function | 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 (PubMed:9482734). In skeletal muscle, contributes to insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity and hence glycogen synthesis (By similarity). May also mediate the development of insulin resistance by regulating activation of transcription factors (By similarity). Regulates protein synthesis by controlling the activity of initiation factor 2B (EIF2BE/EIF2B5) in the same manner as glycogen synthase (By similarity). 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 (PubMed:9482734). 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. MAPT/TAU is the principal component of neurofibrillary tangles in Alzheimer disease. Plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex (By similarity). 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) (By similarity). Negatively regulates replication in pancreatic beta-cells, resulting in apoptosis, loss of beta-cells and diabetes (PubMed:17242403). Through phosphorylation of the anti-apoptotic protein MCL1, may control cell apoptosis in response to growth factors deprivation (By similarity). 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 (By similarity). Phosphorylates MARK2, leading to inhibit its activity (PubMed:18424437). Phosphorylates SIK1 at 'Thr-182', leading to sustain its activity. Phosphorylates ZC3HAV1 which enhances its antiviral activity. Phosphorylates SNAI1, leading to its BTRC-triggered ubiquitination and proteasomal degradation. Phosphorylates SFPQ at 'Thr-687' upon T-cell activation. 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. Phosphorylates MYCN in neuroblastoma cells which may promote its degradation (By similarity). Regulates the circadian rhythmicity of hippocampal long-term potentiation and ARNTL/BMLA1 and PER2 expression (By similarity). Acts as a regulator of autophagy by mediating phosphorylation of KAT5/TIP60 under starvation conditions, leading to activate KAT5/TIP60 acetyltransferase activity and promote acetylation of key autophagy regulators, such as ULK1 and RUBCNL/Pacer. Negatively regulates extrinsic apoptotic signaling pathway via death domain receptors. Promotes the formation of an anti-apoptotic complex, made of DDX3X, BRIC2 and GSK3B, at death receptors, including TNFRSF10B. The anti-apoptotic function is most effective with weak apoptotic signals and can be overcome by stronger stimulation (By similarity). Phosphorylates E2F1, promoting the interaction between E2F1 and USP11, leading to stabilize E2F1 and promote its activity (By similarity). {ECO:0000250|UniProtKB:P49841, ECO:0000250|UniProtKB:Q9WV60, ECO:0000269|PubMed:17242403, ECO:0000269|PubMed:18424437, ECO:0000269|PubMed:9482734}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | NP_BIND 62..70; /note=ATP; /evidence=ECO:0000255|PROSITE-ProRule:PRU00159 |
| Features | Active site (1); Binding site (1); Chain (1); Compositional bias (2); Domain (1); Modified residue (3); Mutagenesis (2); Nucleotide binding (1); Region (2); Sequence conflict (1) |
| Keywords | ADP-ribosylation;ATP-binding;Biological rhythms;Carbohydrate metabolism;Cell membrane;Cytoplasm;Developmental protein;Differentiation;Glycogen metabolism;Kinase;Membrane;Neurogenesis;Nucleotide-binding;Nucleus;Phosphoprotein;Reference proteome;Serine/threonine-protein kinase;Signal transduction inhibitor;Transferase;Wnt signaling pathway |
| Interact With | |
| Induction | |
| Subcellular Location | SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:P49841}. Nucleus {ECO:0000250|UniProtKB:P49841}. Membrane {ECO:0000269|PubMed:16815997}. Cell membrane {ECO:0000250|UniProtKB:P49841}. 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). {ECO:0000250|UniProtKB:P49841}. |
| Modified Residue | MOD_RES 9; /note="Phosphoserine; by PKB/AKT1, RPS6KA3 and SGK3"; /evidence="ECO:0000250|UniProtKB:P49841"; MOD_RES 216; /note="Phosphotyrosine"; /evidence="ECO:0000269|PubMed:8382613"; MOD_RES 389; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:22673903" |
| Post Translational Modification | PTM: 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). Phosphorylated in a circadian manner in the hippocampus (By similarity). {ECO:0000250|UniProtKB:P49841, ECO:0000250|UniProtKB:Q9WV60}.; PTM: Mono-ADP-ribosylation by PARP10 negatively regulates kinase activity. {ECO:0000250|UniProtKB:P49841}. |
| Signal Peptide | |
| Structure 3D | |
| Cross Reference PDB | - |
| Mapped Pubmed ID | 10228155; 10671552; 10910956; 10995469; 11035810; 11094086; 11403684; 11533051; 11978789; 12393899; 12421827; 12526086; 12551719; 12610628; 12644246; 12710887; 12721208; 12808104; 1346104; 15073173; 15522889; 15652487; 15741240; 15788447; 15877933; 15950778; 16041621; 16051512; 16181430; 16191209; 16478782; 16538228; 16557150; 16565311; 16611852; 16735023; 16765055; 16802321; 16810687; 16879317; 16902054; 16934435; 16996218; 17182785; 17329210; 17427960; 17570255; 17623045; 17686886; 17728459; 17952604; 17996850; 18005341; 18089761; 18268107; 18323734; 18367454; 18434357; 18445133; 18485099; 18660440; 18677563; 18840784; 18932008; 18983912; 19033378; 19218353; 19318234; 19359144; 19608791; 19652884; 19755525; 19815943; 19875195; 19887077; 20007479; 20042609; 20154265; 20180783; 20217242; 20362550; 20398714; 20433952; 20549454; 20708505; 20841359; 20926980; 21265094; 21457712; 21557011; 22212922; 22252247; 22561258; 22643085; 22761705; 22982863; 23022559; 23094836; 23321003; 23470087; 23554136; 23624080; 23864697; 24248537; 24349798; 24583037; 25234320; 25764078; 25938237; 26224839; 26300412; 26386043; 26591365; 26722385; 26888388; 26918336; 26970304; 26997328; 27026509; 27118553; 27125978; 27164497; 27208492; 27295130; 27854077; 27893738; 28061416; 28315454; 28440874; 28446231; 28468966; 28638224; 28731198; 28807209; 28810530; 29197866; 29224185; 29257340; 29298655; 29346712; 29555592; 29978610; 30188517; 30316051; 31026457; 31316348; 31362343; 31545438; 32783850; 32823945; 8250835; 8576078; |
| Motif | |
| Gene Encoded By | |
| Mass | 46,742 |
| Kinetics | |
| Metal Binding | |
| Rhea ID | RHEA:12801; RHEA:53904; RHEA:17989; RHEA:46608 |
| Cross Reference Brenda | 2.7.11.1;2.7.11.26; |