GSK3B
entrez
2932
canonical
uniprot
P49841
canonical
ensembl
ENSG00000082701
resolver
ensp
ENSP00000264235
resolver
ensp
ENSP00000324806
resolver
ensp
ENSP00000497956
resolver
ensp
ENSP00000569324
resolver
enst
ENST00000650344
resolver
genesymbol
GSK3B
resolver
hgnc
HGNC:4617
resolver
uniprot
A0A3B3ITW1
resolver
uniprot
D3DN88
resolver
uniprot
D3DN89
resolver
uniprot
Q6FI27
resolver
uniprot
Q9BWH3
resolver
uniprot
Q9UL47
resolver
uniprot_entry
A0A3B3ITW1_HUMAN
resolver
uniprot_entry
GSK3B_HUMAN
resolver
uniprot_entry
Q6FI27_HUMAN
resolver
uniprot_sec
D3DN88
resolver
uniprot_sec
D3DN89
resolver
uniprot_sec
Q9BWH3
resolver
uniprot_sec
Q9UL47
resolver
activity_regulation
ACTIVITY 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 IL22 treatment which also triggers phosphorylation at Ser-9, promoting inactivation (By similarity). Inhibited by lithium. {ECO:0000250|UniProtKB:Q9WV60, ECO:0000269|PubMed:11749387, ECO:0000269|PubMed:12554650, ECO:0000269|PubMed:19366350, ECO:0000269|PubMed:8524413}.
uniprot
proteins
amino_acid_sequence
MSGRPRTTSFAESCKPVQQPSAFGSMKVSRDKDGSKVTTVVATPGQGPDRPQEVSYTDTKVIGNGSFGVVYQAKLCDSGELVAIKKVLQDKRFKNRELQIMRKLDHCNIVRLRYFFYSSGEKKDEVYLNLVLDYVPETVYRVARHYSRAKQTLPVIYVKLYMYQLFRSLAYIHSFGICHRDIKPQNLLLDPDTAVLKLCDFGSAKQLVRGEPNVSYICSRYYRAPELIFGATDYTSSIDVWSAGCVLAELLLGQPIFPGDSGVDQLVEIIKVLGTPTREQIREMNPNYTEFKFPQIKAHPWTKVFRPRTPPEAIALCSRLLEYTPTARLTPLEACAHSFFDELRDPNVKLPNGRDTPALFNFTTQELSSNPPLATILIPPHARIQAAASTPTNATAASDANTGDRGQTNNAASASASNST
uniprot
proteins
ec_number
2.7.11.1
uniprot
proteins
ec_number
2.7.11.26
uniprot
proteins
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 (PubMed:11430833, PubMed:12554650, PubMed:14690523, PubMed:16484495, PubMed:1846781, PubMed:20937854, PubMed:9072970). Requires primed phosphorylation of the majority of its substrates (PubMed:11430833, PubMed:16484495). In skeletal muscle, contributes to insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity and hence glycogen synthesis (PubMed:8397507). May also mediate the development of insulin resistance by regulating activation of transcription factors (PubMed:8397507). Regulates protein synthesis by controlling the activity of initiation factor 2B (EIF2BE/EIF2B5) in the same manner as glycogen synthase (PubMed:8397507). 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:12554650). Phosphorylates JUN at sites proximal to its DNA-binding domain, thereby reducing its affinity for DNA (PubMed:1846781). 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 (PubMed:9072970). Phosphorylates MAPT/TAU on 'Thr-548', decreasing significantly MAPT/TAU ability to bind and stabilize microtubules (PubMed:14690523). MAPT/TAU is the principal component of neurofibrillary tangles in Alzheimer disease (PubMed:14690523). Plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex (PubMed:20937854). Phosphorylates MACF1, inhibiting its binding to microtubules which is critical for its role in bulge stem cell migration and skin wound repair (By similarity). Probably regulates NF-kappa-B (NFKB1) at the transcriptional level and is required for the NF-kappa-B-mediated anti-apoptotic response to TNF (TNF/TNFA) (By similarity). Negatively regulates replication in pancreatic beta-cells, resulting in apoptosis, loss of beta-cells and diabetes (By similarity). 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 (PubMed:9819408). Is necessary for the establishment of neuronal polarity and axon outgrowth (PubMed:20067585). Phosphorylates MARK2, leading to inhibition of its activity (By similarity). Phosphorylates SIK1 at 'Thr-182', leading to sustainment of its activity (PubMed:18348280). Phosphorylates ZC3HAV1 which enhances its antiviral activity (PubMed:22514281). Phosphorylates SNAI1, leading to its ubiquitination and proteasomal degradation (PubMed:15448698, PubMed:15647282, PubMed:25827072, PubMed:29059170). Phosphorylates SFPQ at 'Thr-687' upon T-cell activation (PubMed:20932480). 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 BMAL1, CLOCK and PER2 (PubMed:19946213, PubMed:28903391). Phosphorylates FBXL2 at 'Thr-404' and primes it for ubiquitination by the SCF(FBXO3) complex and proteasomal degradation (By similarity). Phosphorylates CLOCK AT 'Ser-427' and targets it for proteasomal degradation (PubMed:19946213). Phosphorylates BMAL1 at 'Ser-17' and 'Ser-21' and primes it for ubiquitination and proteasomal degradation (PubMed:28903391). Phosphorylates OGT at 'Ser-3' or 'Ser-4' which positively regulates its activity. Phosphorylates MYCN in neuroblastoma cells which may promote its degradation (PubMed:24391509). Regulates the circadian rhythmicity of hippocampal long-term potentiation and BMAL1 and PER2 expression (By similarity). Acts as a regulator of autophagy by mediating phosphorylation of KAT5/TIP60 under starvation conditions, activating KAT5/TIP60 acetyltransferase activity and promoting acetylation of key autophagy regulators, such as ULK1 and RUBCNL/Pacer (PubMed:30704899). 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 (PubMed:18846110). Phosphorylates E2F1, promoting the interaction between E2F1 and USP11, stabilizing E2F1 and promoting its activity (PubMed:17050006, PubMed:28992046). Phosphorylates mTORC2 complex component RICTOR at 'Ser-1235' in response to endoplasmic stress, inhibiting mTORC2 (PubMed:21343617). Phosphorylates mTORC2 complex component RICTOR at 'Thr-1695' which facilitates FBXW7-mediated ubiquitination and subsequent degradation of RICTOR (PubMed:25897075). Acts as a negative regulator of smoothened signaling by mediating phosphorylation of GLI2 and GLI3 in absence of smoothened, promoting their processing by the SCF(BTRC) complex (PubMed:16705181). Phosphorylates FXR1, promoting FXR1 ubiquitination by the SCF(FBXO4) complex and FXR1 degradation by the proteasome (By similarity). Phosphorylates interleukin-22 receptor subunit IL22RA1, preventing its proteasomal degradation (By similarity). Phosphorylates and inhibits the CTP synthase and protein-asparagine deamidase activities of CTPS1 (PubMed:17681942). Phosphorylates DSP at multiple sequential serine residues in the C-terminus tail, promoting its recruitment to developing desmosome cell-cell junctions (PubMed:25733715). {ECO:0000250|UniProtKB:P18266, ECO:0000250|UniProtKB:Q9WV60, ECO:0000269|PubMed:11430833, ECO:0000269|PubMed:12554650, ECO:0000269|PubMed:14690523, ECO:0000269|PubMed:15448698, ECO:0000269|PubMed:15647282, ECO:0000269|PubMed:16484495, ECO:0000269|PubMed:16705181, ECO:0000269|PubMed:17050006, ECO:0000269|PubMed:17681942, ECO:0000269|PubMed:18348280, ECO:0000269|PubMed:1846781, ECO:0000269|PubMed:18846110, ECO:0000269|PubMed:19946213, ECO:0000269|PubMed:20067585, ECO:0000269|PubMed:20932480, ECO:0000269|PubMed:20937854, ECO:0000269|PubMed:21343617, ECO:0000269|PubMed:22514281, ECO:0000269|PubMed:24391509, ECO:0000269|PubMed:25733715, ECO:0000269|PubMed:25827072, ECO:0000269|PubMed:25897075, ECO:0000269|PubMed:28903391, ECO:0000269|PubMed:28992046, ECO:0000269|PubMed:29059170, ECO:0000269|PubMed:30704899, ECO:0000269|PubMed:8397507, ECO:0000269|PubMed:9072970, ECO:0000269|PubMed:9819408}.
uniprot
proteins
mass_dalton
46744
uniprot
proteins
mutagenesis
MUTAGEN 9; /note="S->A: Loss of phosphorylation; abolished inhibition of activity, leading to constitutively active."; /evidence="ECO:0000269|PubMed:17050006, ECO:0000269|PubMed:28992046, ECO:0000269|PubMed:7980435"; MUTAGEN 14; /note="C->A: Significantly reduced palmitoylation."; /evidence="ECO:0000269|PubMed:35606353"; MUTAGEN 85..86; /note="KK->AA: Abolished serine/threonine-protein kinase activity."; /evidence="ECO:0000269|PubMed:17050006"; MUTAGEN 96; /note="R->A: Prevents the phosphorylation of phosphate-primed glycogen synthase."; /evidence="ECO:0000269|PubMed:11430833"; MUTAGEN 128; /note="L->A: Abolishes activity toward AXIN1."; /evidence="ECO:0000269|PubMed:11430833
uniprot
proteins
post_translational_modification
PTM: Phosphorylated by AKT1 and ILK1. Upon insulin-mediated signaling, the activated PKB/AKT1 protein kinase phosphorylates and deactivates GSK3B, resulting in the dephosphorylation and activation of GYS1. Activated by phosphorylation at Tyr-216 (PubMed:25169422). Inactivated by phosphorylation at Ser-9 (Probable). Phosphorylated in a circadian manner in the hippocampus (By similarity). {ECO:0000250|UniProtKB:Q9WV60, ECO:0000269|PubMed:12054501, ECO:0000269|PubMed:12554650, ECO:0000269|PubMed:16484495, ECO:0000269|PubMed:20937854, ECO:0000269|PubMed:21029237, ECO:0000269|PubMed:25169422, ECO:0000269|PubMed:8250835, ECO:0000305|PubMed:25169422}.; PTM: Mono-ADP-ribosylation by PARP10 negatively regulates kinase activity. {ECO:0000269|PubMed:23332125}.; PTM: Palmitoylated. Palmitoylation by ZDHHC4 prevents AKT1-mediated phosphorylation. {ECO:0000269|PubMed:35606353}.
uniprot
proteins
protein_family
CMGC Ser/Thr protein kinase family
uniprot
proteins
protein_family
GSK-3 subfamily
uniprot
proteins
protein_family
Protein kinase superfamily
uniprot
proteins
pubmed
10486203
uniprot
proteins
pubmed
10523816
uniprot
proteins
pubmed
10868943
uniprot
proteins
pubmed
11004522
uniprot
proteins
pubmed
11430833
uniprot
proteins
pubmed
11440715
uniprot
proteins
pubmed
11738041
uniprot
proteins
pubmed
11749387
uniprot
proteins
pubmed
12054501
uniprot
proteins
pubmed
12554650
uniprot
proteins
pubmed
14690523
uniprot
proteins
pubmed
15448698
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
15647282
uniprot
proteins
pubmed
15752768
uniprot
proteins
pubmed
16428445
uniprot
proteins
pubmed
16484495
uniprot
proteins
pubmed
16705181
uniprot
proteins
pubmed
16981698
uniprot
proteins
pubmed
17050006
uniprot
proteins
pubmed
17318175
uniprot
proteins
pubmed
17478001
uniprot
proteins
pubmed
17681942
uniprot
proteins
pubmed
18348280
uniprot
proteins
pubmed
1846781
uniprot
proteins
pubmed
18669648
uniprot
proteins
pubmed
18691976
uniprot
proteins
pubmed
18846110
uniprot
proteins
pubmed
19366350
uniprot
proteins
pubmed
19369195
uniprot
proteins
pubmed
19493954
uniprot
proteins
pubmed
19690332
uniprot
proteins
pubmed
19706605
uniprot
proteins
pubmed
19946213
uniprot
proteins
pubmed
20007971
uniprot
proteins
pubmed
20067585
uniprot
proteins
pubmed
20068231
uniprot
proteins
pubmed
20080667
uniprot
proteins
pubmed
20932480
uniprot
proteins
pubmed
20937854
uniprot
proteins
pubmed
21029237
uniprot
proteins
pubmed
21269460
uniprot
proteins
pubmed
21343617
uniprot
proteins
pubmed
22514281
uniprot
proteins
pubmed
22539723
uniprot
proteins
pubmed
23186163
uniprot
proteins
pubmed
23332125
uniprot
proteins
pubmed
24275569
uniprot
proteins
pubmed
24391509
uniprot
proteins
pubmed
25169422
uniprot
proteins
pubmed
25733715
uniprot
proteins
pubmed
25827072
uniprot
proteins
pubmed
25897075
uniprot
proteins
pubmed
25920809
uniprot
proteins
pubmed
27484798
uniprot
proteins
pubmed
28829046
uniprot
proteins
pubmed
28903391
uniprot
proteins
pubmed
28992046
uniprot
proteins
pubmed
29059170
uniprot
proteins
pubmed
30704899
uniprot
proteins
pubmed
31073040
uniprot
proteins
pubmed
34058472
uniprot
proteins
pubmed
34764205
uniprot
proteins
pubmed
35606353
uniprot
proteins
pubmed
7980435
uniprot
proteins
pubmed
8250835
uniprot
proteins
pubmed
8397507
uniprot
proteins
pubmed
8524413
uniprot
proteins
pubmed
9072970
uniprot
proteins
pubmed
9731200
uniprot
proteins
pubmed
9736715
uniprot
proteins
pubmed
9819408
uniprot
proteins
sequence_length
420
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:21029237, ECO:0000269|PubMed:25169422, ECO:0000269|PubMed:25733715, ECO:0000269|PubMed:35606353}. Nucleus {ECO:0000269|PubMed:15448698, ECO:0000269|PubMed:21029237}. Cell membrane {ECO:0000269|PubMed:20937854}. Note=The phosphorylated form shows localization to cytoplasm and cell membrane (PubMed:20937854). The MEMO1-RHOA-DIAPH1 signaling pathway controls localization of the phosphorylated form to the cell membrane (PubMed:20937854). {ECO:0000269|PubMed:20937854}.
uniprot
proteins