P49841

Background

Protein Name
Glycogen synthase kinase-3 beta
Gene Name
GSK3B
Organism
Homo sapiens

Annotations

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. 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. 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. 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 and diabetes. 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 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 (PubMed:24391509).

Mapping Statistics

Site
Maximum Consensus Site Population
Minimum Consensus Site Population
Median Consensus Site Population
EDI 21 2 14.0
MT3 17 2 4.0
PIF 13 6 12.0
ATP 24 1 16.0
DEF 9 3 5.0
DRS 30 2 7.0
AAS 12 12 12.0
MPP 22 2 15.0
DFG 13 1 4.0
LBP 4 2 2.0
CMP 10 2 5.0
PDIG 23 2 5.0
PMP 6 4 5.0

Mapping Results

PDB ID
Maximum Consensus Site Population
EDI site
MT3 site
PIF site
ATP site
DEF site
DRS site
AAS site
MPP site
DFG site
LBP site
CMP site
PDIG site
PMP site
Total Druggable Structures per Site 21 2 0 45 0 19 0 6 0 0 0 4 0
1GNG 16 4 13 16 0 7 0 0 0 0 7 0 0
1H8F 14 3 0 18 0 10 0 0 0 0 5 4 0
1I09 15 4 0 21 0 8 0 16 4 0 0 5 0
1J1B 13 10 0 20 0 7 0 0 0 0 0 5 0
1J1C 14 5 0 18 0 7 0 0 2 0 0 4 0
1O9U 16 0 0 17 0 23 0 0 5 0 0 0 0
1PYX 15 4 0 17 0 7 0 15 2 0 0 4 0
1Q3D 15 5 0 17 0 16 0 0 2 0 0 17 0
1Q3W 15 9 0 17 0 17 0 17 0 0 0 6 0
1Q4L 11 17 0 17 0 6 0 0 0 0 0 13 0
1Q5K 16 8 12 16 0 8 0 8 0 0 0 12 0
1Q41 8 3 0 22 0 20 0 16 0 4 0 4 0
1R0E 13 13 0 24 6 8 0 0 0 2 3 0 0
1UV5 2 0 0 17 0 7 0 0 0 2 0 3 0
2JLD 15 11 0 22 0 8 0 0 0 0 5 23 0
2O5K 0 0 0 19 0 30 0 0 0 0 6 3 0
2OW3 14 0 0 16 0 13 0 0 0 0 10 6 0
3DU8 17 11 0 17 0 11 0 0 2 0 0 17 0
3F7Z 17 14 0 18 0 6 0 0 0 3 0 8 0
3F88 15 0 0 16 0 9 0 0 9 0 0 6 0
3GB2 9 16 0 21 0 12 0 0 0 0 0 0 0
3I4B 10 12 0 18 9 12 0 0 0 0 0 7 0
3L1S 4 15 0 18 0 19 0 0 0 0 0 10 0
3M1S 14 3 12 19 0 19 0 8 0 0 0 16 0
3PUP 10 0 0 14 0 18 0 10 13 0 6 4 0
3Q3B 13 13 0 16 0 15 0 0 8 0 0 8 0
3SAY 17 0 0 17 0 18 0 0 0 0 0 6 0
3SD0 14 3 0 16 7 13 0 0 0 0 0 6 0
3ZDI 5 4 0 15 0 9 0 0 0 0 2 5 0
3ZRK 18 5 0 16 0 16 0 0 0 0 0 3 0
3ZRL 17 3 0 17 0 16 0 0 0 0 0 5 6
3ZRM 17 10 7 18 0 24 0 13 0 2 0 7 4
4ACC 14 3 0 9 0 18 0 0 0 0 0 11 0
4ACD 15 4 0 12 0 21 0 0 0 0 0 9 0
4ACG 16 3 0 9 6 18 0 0 1 0 0 11 0
4ACH 16 3 0 9 0 21 0 0 0 0 0 9 0
4AFJ 17 15 0 19 0 4 0 16 0 0 0 4 0
4B7T 14 2 0 9 6 5 0 0 0 0 0 0 0
4DIT 0 11 0 3 0 14 12 0 0 0 0 0 0
4IQ6 0 0 0 18 0 8 0 22 0 0 0 7 0
4J1R 20 0 0 21 0 24 0 0 3 0 0 0 0
4J71 18 0 0 24 0 21 0 0 0 0 0 2 0
4NM0 6 2 0 22 4 5 0 0 0 0 6 2 0
4NM3 10 4 0 16 5 7 0 0 2 0 0 0 0
4NM5 18 2 0 23 5 7 0 0 3 0 0 0 0
4NM7 18 4 0 22 5 24 0 0 0 0 0 0 0
4PTC 0 0 0 19 7 15 0 0 0 0 4 6 0
4PTE 3 2 0 17 5 7 0 0 0 0 0 7 0
4PTG 19 2 0 16 0 5 0 0 7 0 0 6 0
5F94 18 4 0 20 0 9 0 0 0 0 0 3 0
5F95 16 0 0 18 0 3 0 0 0 0 0 6 0
5HLN 21 0 6 17 0 6 0 16 0 0 0 5 0
5HLP 19 0 12 16 0 10 0 0 0 0 0 4 0
AFP49841 0 0 0 0 0 0 0 15 7 0 0 0 0