GSK3_beta

Protein GSK3_beta_*

Identifiers
glycogen synthase kinase 3 beta
HUGO:GSK3B, HGNC:4617, ENTREZ:2932, GENECARDS:GC03M119540, UNIPROT:P49841??
HUGO:GSK3B HGNC:4617 ENTREZ:2932 UNIPROT:P49841
HUGO:GSK3B
HUGO:GSK3B HGNC:4617 ENTREZ:2932 UNIPROT:P49841 GENECARDS:GSK3B REACTOME:404223 ATLASONC:GSK3BID40761ch3q13 WIKI:GSK3B

Maps_Modules
HMC:ACTIVATING_INVASION_AND_METASTASIS
EMT Senescence / EMT_REGULATORS
EMT Senescence / SENESCENCE
HMC:RESISTING_CELL_DEATH
HMC:DEREGULATING_CELLULAR_ENERGETICS
Regulated Cell Death / ANTIOXIDANT_RESPONSE
Regulated Cell Death / STARVATION_AUTOPHAGY
Regulated Cell Death / CASPASES
Regulated Cell Death / GLUCOSE_METABOLISM
Regulated Cell Death / MITOCHONDRIAL_METABOLISM
Regulated Cell Death / MOMP_REGULATION
HMC:AVOIDING_IMMUNE_DESTRUCTION
Innate Immunity / IMMUNOSTIMULATORY_CORE_PATHWAYS
HMC:EVADING_GROWTH_SUPPRESSORS
Survival / MAPK
Survival / HEDGEHOG
Survival / PI3K_AKT_MTOR
Survival / WNT_CANONICAL

References
PMID:15465828
GSK-3b plays a critical role in cell survival by phosphorylating nuclear factor-??B (NF-??B) p65 subunit, leading to NF-??B transactivation in hepatocytes
This phosphorylation negatively regulates basal p65 NF-kappaB activity.
PMID:15020233
MEK1/2 can phosphorylate tyrosine 216, which stimulates GSK3B kinase activity
U0126, a MEK1/2 inhibitor, inhibited tyrosine phosphorylation of GSK3B, suggesting that MEK1/2 was involved in the phosphorylation of Tyr216 in GSK3B
In vitro kinase interaction showed that GSK3B is phosphorylated by recombinant MEK1 at Y216
PMID:16944320
The enzymatic activity of GSK3 is enhanced by phosphorylation of tyrosine-216 in GSK3b
GSK3 is considered to be largely a cytosolic enzyme, but it is also associated with, or internalized in, subcellular compartments such as the nucleus, mitochondria, and growth cones
PMID:9832503
GSK3 is predominatly cytoplasmic during G1 phase of the celle cycle, but a significant fraction enters the nucleus during S phase, promoting its ability to phosphorylate cyclin D1 in the nucleus
Phosphorylation of cyclin D1 on a single threonine residue near the carboxyl terminus (Thr-286) positively regulates proteasomal degradation of D1
GSK3 phosphorylates cyclin D1 specifically on Thr-286, thereby triggering rapid cyclin D1 turnover.
PMID:14663202
GSK3B is highly activated in nuclei and mitochondria.
PMID:11967263
Tyr-216 phosphorylation is required for GSK-mediated down-regulation of b-catenin activity.
PMID:8524413
Inactiviation of GSK-3 occurs through Akt phosphorylation of serine 9 of GSK-3b.
This phosphorylation may be involved in later phases of neuronal apoptosis.
Mutation of Ser9 to Ala did not affect GSK-3 -mediated phosphorylation of b-catenin, whereas mutation of Tyr216 to Phe markedly reduced the in vivo phosphorylation of b-catenin.
PMID:16713974
GSK3B inhitits activation (DNA binding) of AP-1 factors.
GSK3B is activated downstrean of IFNG via PI3K pathway.
PMID:16007092
GSK3B inhibits CREB1 interaction with CBP and inhibits CREB1 dependent IL10 expression.
CREB1/CBP complex formation prevents binding CBP to RELA (p65) and inhibits downstream NF-kB signaling.
ERK phosphorylates GSK3B to facilitate phosphorylation of GSK3B by p90RSK (RSK) which leads to the inactivation of GSK3B. GSK3B docking to ERK and phosphorylation by ERK are required for inhibition of beta-catenin (CTNNB1) ubiquitination and therefore for its stabilisation. ERK GSK3B and p90RSK (RSK) are in the same complex.
PMID:16039586
PMID:12615961
PMID:20537194
glycogen synthase kinase 3

GSK3_beta_*@Nucleus

References
em_emtc_emtc_re270( EMT Senescence ):
PMID:16944320
The enzymatic activity of GSK3 is enhanced by phosphorylation of tyrosine-216 in GSK3b
GSK3 is considered to be largely a cytosolic enzyme, but it is also associated with, or internalized in, subcellular compartments such as the nucleus, mitochondria, and growth cones
PMID:9832503
GSK3 is predominatly cytoplasmic during G1 phase of the celle cycle, but a significant fraction enters the nucleus during S phase, promoting its ability to phosphorylate cyclin D1 in the nucleus
Phosphorylation of cyclin D1 on a single threonine residue near the carboxyl terminus (Thr-286) positively regulates proteasomal degradation of D1
GSK3 phosphorylates cyclin D1 specifically on Thr-286, thereby triggering rapid cyclin D1 turnover.
PMID:14663202
GSK3B is highly activated in nuclei and mitochondria.
em_emtc_emtc_re454( EMT Senescence ):
PMID:15459715
PMID:15448698
Dual regulation of Snail by GSK3B-mediated phosphorylation in control of EMT.
Snail is highly unstable, with a short half-life about 25 min.
GSK-3b binds to and phosphorylates Snail at two consensus motifs to dually regulate the function of this protein.
Phosphorylation of the first motif regulates its b-Trcp-mediated ubiquitination, whereas phosphorylation of the second motif controls its subcellular localization.
A variant of Snail (Snail-6SA), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce EMT
Inhibition of GSK-3b results in the upregulation of Snail and downregulation of E-cadherin in vivo
Thus, the inhibition of GSK-3b by many extracellular pathways suppresses the phosphorylation of Snail and hence induces the nuclear localization and protein stabilization of Snail, which leads to EMT.
em_emtc_emtc_re1347( EMT Senescence ):
PMID:21828089
Phosphorylation of NICD by GSK3B inhibits Ntch1/ICD-mediated induction of genes such as Hes1 but stabilizes Notch1/ICD.

GSK3_beta_*@Cytosol

References
em_emtc_emtc_re270( EMT Senescence ):
PMID:16944320
The enzymatic activity of GSK3 is enhanced by phosphorylation of tyrosine-216 in GSK3b
GSK3 is considered to be largely a cytosolic enzyme, but it is also associated with, or internalized in, subcellular compartments such as the nucleus, mitochondria, and growth cones
PMID:9832503
GSK3 is predominatly cytoplasmic during G1 phase of the celle cycle, but a significant fraction enters the nucleus during S phase, promoting its ability to phosphorylate cyclin D1 in the nucleus
Phosphorylation of cyclin D1 on a single threonine residue near the carboxyl terminus (Thr-286) positively regulates proteasomal degradation of D1
GSK3 phosphorylates cyclin D1 specifically on Thr-286, thereby triggering rapid cyclin D1 turnover.
PMID:14663202
GSK3B is highly activated in nuclei and mitochondria.
em_emtc_emtc_re455( EMT Senescence ):
PMID:15459715
PMID:15448698
Dual regulation of Snail by GSK3B-mediated phosphorylation in control of EMT.
Snail is highly unstable, with a short half-life about 25 min.
GSK-3b binds to and phosphorylates Snail at two consensus motifs to dually regulate the function of this protein.
Phosphorylation of the first motif regulates its b-Trcp-mediated ubiquitination, whereas phosphorylation of the second motif controls its subcellular localization.
A variant of Snail (Snail-6SA), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce EMT
Inhibition of GSK-3b results in the upregulation of Snail and downregulation of E-cadherin in vivo
Thus, the inhibition of GSK-3b by many extracellular pathways suppresses the phosphorylation of Snail and hence induces the nuclear localization and protein stabilization of Snail, which leads to EMT.
em_emtc_emtc_re458( EMT Senescence ):
PMID:7945242
PMID:8524413
AKT (PKB) phosphorylates GSK3B at Serine residue and inactivate GSK3B

GSK3_beta_*|Y_pho|active@Cytosol

References
em_emtc_emtc_re462( EMT Senescence ):
PMID:7542250
Whereas in the normal cells CTNNB1 (beta-catenin) is found in association with E-cadherin, p120 Cas is not. In the ras-transformed cells, the situation is reversed; tyrosine-phosphorylated p120 Cas, but not tyrosine-phosphorylated CTNNB1, now is detected in E-cadherin complexes.
The tyrosine-phosphorylated CTNNB1 also shows increased detergent solubility, suggesting a decreased association with the actin cytoskeleton.
decreased tyrosine phosphorylation of CTNNB1 is accompanied by increased interaction with both E-cadherin and the detergent insoluble cytoskeletal fraction
PMID:11967263
Tyr-216 phosphorylation in GSK3B is required for GSK-mediated down-regulation of b-catenin activity.
PMID:8666229
Xenopus GSK3 functions to destabilize b-catenin and thus decrease the amount of b-catenin available for signaling
em_emtc_emtc_re1007( EMT Senescence ):
PMID:10671552
PMID:11348595
PMID:17928543
in vitro phosphorylation of Cadherin at S834, 836, 842 significantly enhances the affinity with which beta-catenin binds cadherins.
GSK3B and CSNK2 (casein kinase II) have been shown to phosphorylate these sites in vitro.
em_emtc_emtc_re1012( EMT Senescence ):
PMID:10581160
PMID:17318175
PMID:10421629
Recruitment of CTNNB1 via the degradation complex of APC/AXIN1 is regulated by a series of ordered phosphorylation events.
Phosphorylation of AXIN1 by CSNK1 (casein kinase 1) and GSK3B can increase axin binding to CTNNB1.
PMID:8638126
PMID:11487578
PMID:15327768
AXIN1 also promotes phosphorylation of APC by CSNK1 and GSK3B.
Phosphorylated APC has higher affinity to CTNNB1.
PMID:12554650
Finally, these phosphorylation events allo CTNNB1 to be a more efficient substrate of both CSNK1 (at S45) and the GSK3B (at T41, S33, S37).
The affinity of phosphorylated APC to CTNNB1 is higher than that of phosphorylated AXIN1.
Therefore upon phosphorylation, APC can displace AXIN1 from CTNNB1, allowing AXIN1 to bind another molecule of CTNNB1.

GSK3_beta_*|S_pho@Cytosol

References
em_emtc_emtc_re458( EMT Senescence ):
PMID:7945242
PMID:8524413
AKT (PKB) phosphorylates GSK3B at Serine residue and inactivate GSK3B

GSK3_beta_*|S9_pho@Cytosol

Maps_Modules
HMC:RESISTING_CELL_DEATH
HMC:DEREGULATING_CELLULAR_ENERGETICS
Regulated Cell Death / ANTIOXIDANT_RESPONSE
Regulated Cell Death / STARVATION_AUTOPHAGY
Regulated Cell Death / CASPASES
Regulated Cell Death / GLUCOSE_METABOLISM
Regulated Cell Death / MITOCHONDRIAL_METABOLISM
Regulated Cell Death / MOMP_REGULATION

References
rc_re326:( Regulated Cell Death ) PMID:9065430

GSK3_beta_*@INNATE_IMMUNE_CELL_Cytosol

References
in_re1154( Innate Immunity ):
PMID:16713974
AKT kinases phosphorylate GSK3 proteins and inhibit its activity downstream of TLR signaling.
IFNG prevents this inactivation.
in_re1281( Innate Immunity ):
TLR activation of CREB by phosphorylation of serine-133 is dependent on p38.
GSK3B inhibits IL10 expression downstream of IFNG, probably via GREB1 inhibition.
PMID:16007092
GSK3B inhibits CREB1 interaction CBP and inhibits CREB1 dependent IL10 expression.

GSK3_beta_*|pho@INNATE_IMMUNE_CELL_Cytosol

References
in_re1154( Innate Immunity ):
PMID:16713974
AKT kinases phosphorylate GSK3 proteins and inhibit its activity downstream of TLR signaling.
IFNG prevents this inactivation.

GSK3_beta_*@Cytoplasm

References
su_mpk1_mpk1_re105( Survival ):
Phosphorylation of beta-catenin (CTNNB1) by GSK-3beta (GSK3B) causes its degradation
PMID:16039586
su_mpk1_mpk1_re109( Survival ):
ERK phosphorylates GSK3B to facilitate phosphorylation of GSK3B by p90RSK (RSK) which leads to the inactivation of GSK3B. GSK3B docking to ERK and phosphorylation by ERK are required for inhibition of beta-catenin (CTNNB1) ubiquitination and therefore for its stabilisation. ERK GSK3B and p90RSK (RSK) are in the same complex.
su_mpk1_mpk1_re110( Survival ):
A small fraction of both ERK and GSK3 is constitutively found in a protease-protected mitochondrial compartment. How this fraction of ERK and GSK3 enters mitochondria is an open question.
PMID:20080742
su_mpk1_mpk1_re271( Survival ):
Glycogen synthase kinase 3 (GSK3) is a target of Akt. This protein kinase is constitutively active in unstimulated cells and phosphorylates many proteins (including glycogen synthase C-MYC and cyclin D) to keep them in inactive states or promote their degradation. Phosphorylation of GSK3 (both alpha and beta isoforms) by Akt turns off the catalytic activity of this enzyme resulting in the activation of pathways that are normally repressed by GSK3.
PMID:12040186
su_mpk1_mpk1_re279( Survival ):
MAX interacts with the transcription factor C-MYC enabling C-MYC to trans-activate at least a subset of its target genes.
GSK3 is constitutively active in unstimulated cells and phosphorylates many proteins (including glycogen synthase C-MYC and cyclin D) to keep them in inactive states or promote their degradation.
PMID:11274345 PMID:12040186
su_akt1_s_akt1_re82( Survival ):
PMID:17444818
ANNOTATION:PTEN is destabilized by phosphorylation on T366 followed by phosphorylation on S370 by GSK3beta.
su_akt1_s_akt1_re114:( Survival ) PMID:17052453
su_akt1_s_akt1_re160:( Survival ) PMID:19797085
su_wca1_s_wca2_re54:( Survival ) PMID:10671551

GSK3_beta_*@Mitochondria

References
su_mpk1_mpk1_re110( Survival ):
A small fraction of both ERK and GSK3 is constitutively found in a protease-protected mitochondrial compartment. How this fraction of ERK and GSK3 enters mitochondria is an open question.
PMID:20080742
su_mpk1_mpk1_re114( Survival ):
We postulate a model in which ERK activation inhibits GSK3 activity (by phosphorylation) its association to CYPD and CYPD phosphorylation (by GSK3) leading to PTP desensitisation.

GSK3_beta_*|pho@Mitochondria

References
su_mpk1_mpk1_re114( Survival ):
We postulate a model in which ERK activation inhibits GSK3 activity (by phosphorylation) its association to CYPD and CYPD phosphorylation (by GSK3) leading to PTP desensitisation.
PMID:20080742

GSK3_beta_*|pho@Cytoplasm

References
su_mpk1_mpk1_re271( Survival ):
Glycogen synthase kinase 3 (GSK3) is a target of Akt. This protein kinase is constitutively active in unstimulated cells and phosphorylates many proteins (including glycogen synthase C-MYC and cyclin D) to keep them in inactive states or promote their degradation. Phosphorylation of GSK3 (both alpha and beta isoforms) by Akt turns off the catalytic activity of this enzyme resulting in the activation of pathways that are normally repressed by GSK3.
PMID:12040186

GSK3_beta_*|pho@Cytoplasm

References
su_akt1_s_akt1_re114:( Survival ) PMID:17052453

GSK3_beta_*@Cytoplasm

Maps_Modules
HMC:EVADING_GROWTH_SUPPRESSORS
Survival / WNT_CANONICAL

GSK3_beta_*|pho|active@Cytosol

References
s_shh1_re99( Survival ):
PMID:19575820
PMID:17052453

Modifications:
In compartment: Cytoplasm

GSK3_beta_*@Cytoplasm
GSK3_beta_*@Cytoplasm
GSK3_beta_*@Cytoplasm
GSK3_beta_*|pho@Cytoplasm
GSK3_beta_*|pho@Cytoplasm

In compartment: Cytosol

GSK3_beta_*@Cytosol
GSK3_beta_*|S_pho@Cytosol
GSK3_beta_*|S9_pho@Cytosol
GSK3_beta_*|pho|active@Cytosol
GSK3_beta_*|Y_pho|active@Cytosol

In compartment: INNATE_IMMUNE_CELL_Cytosol

GSK3_beta_*@INNATE_IMMUNE_CELL_Cytosol
GSK3_beta_*|pho@INNATE_IMMUNE_CELL_Cytosol

In compartment: Mitochondria

GSK3_beta_*@Mitochondria
GSK3_beta_*|pho@Mitochondria

In compartment: Nucleus

GSK3_beta_*@Nucleus

Participates in complexes:
In compartment: Cytoplasm

ERK*|pho|pho:GSK3_beta_*|pho:RSK*|pho@Cytoplasm

In compartment: Nucleus

AXIN2:GSK3_beta_*@Nucleus

Participates in reactions:
As Reactant or Product:

As Catalyser: