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Names & Taxonomy

Uniprot ID:: P49841
Entry Name:: GSK3B_HUMAN
Status:: reviewed
Protein Names:: Glycogen synthase kinase-3 beta (GSK-3 beta) (EC 2.7.11.26) (Serine/threonine-protein kinase GSK3B) (EC 2.7.11.1)
Gene Names:: GSK3B
Gene Names Primary:: GSK3B
Organism:: Homo sapiens (Human)

Structure

Length:: 420
Sequence:: MSGRPRTTSFAESCKPVQQPSAFGSMKVSRDKDGSKVTTVVATPGQGPDRPQEVSYTDTKVIGNGSFGVVYQAKLCDSGELVAIKKVLQDKRFKNRELQIMRKLDHCNIVRLRYFFYSSGEKKDEVYLNLVLDYVPETVYRVARHYSRAKQTLPVIYVKLYMYQLFRSLAYIHSFGICHRDIKPQNLLLDPDTAVLKLCDFGSAKQLVRGEPNVSYICSRYYRAPELIFGATDYTSSIDVWSAGCVLAELLLGQPIFPGDSGVDQLVEIIKVLGTPTREQIREMNPNYTEFKFPQIKAHPWTKVFRPRTPPEAIALCSRLLEYTPTARLTPLEACAHSFFDELRDPNVKLPNGRDTPALFNFTTQELSSNPPLATILIPPHARIQAAASTPTNATAASDANTGDRGQTNNAASASASNST
Proteomes:: UP000005640

Subcellular location

Subcellular Location:: Cytoplasm. Nucleus. Cell membrane. 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.

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. 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).
Catalytic Activity:: ATP + = ADP + phosphate.; ATP + a protein = ADP + a phosphoprotein.
Enzyme Regulation:: ENZYME 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 lithium.
Active Site:: ACT_SITE 181 181 Proton acceptor.
Cross Reference Drug Bank:: DB01356
Gene Ontology Go:: axon
beta-catenin destruction complex
centrosome
cytoplasm
cytosol
dendritic shaft
dendritic spine
growth cone
intracellular ribonucleoprotein complex
membrane raft
mitochondrion
neuronal cell body
neuronal postsynaptic density
nucleus
perinuclear region of cytoplasm
plasma membrane
Wnt signalosome
ATP binding
beta-catenin binding
kinase activity
NF-kappaB binding
p53 binding
protein kinase A catalytic subunit binding
protein kinase activity
protein kinase binding
protein serine/threonine kinase activity
RNA polymerase II transcription factor binding
tau-protein kinase activity
ubiquitin protein ligase binding
aging
axon guidance
canonical Wnt signaling pathway
canonical Wnt signaling pathway involved in positive regulation of apoptotic process
cell migration
cellular response to dopamine
cellular response to erythropoietin
cellular response to heat
cellular response to hepatocyte growth factor stimulus
cellular response to hydrogen peroxide
cellular response to interleukin-3
cellular response to iron(II) ion
cellular response to lithium ion
cellular response to mechanical stimulus
chemical synaptic transmission, postsynaptic
circadian rhythm
dopamine receptor signaling pathway
epidermal growth factor receptor signaling pathway
epithelial to mesenchymal transition
ER overload response
establishment of cell polarity
extrinsic apoptotic signaling pathway in absence of ligand
fat cell differentiation
Fc-epsilon receptor signaling pathway
fibroblast growth factor receptor signaling pathway
glycogen metabolic process
hippocampus development
hypermethylation of CpG island
innate immune response
intracellular signal transduction
intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress
myoblast fusion
negative regulation of apoptotic process
negative regulation of canonical Wnt signaling pathway
negative regulation of cardiac muscle hypertrophy
negative regulation of dendrite morphogenesis
negative regulation of dopaminergic neuron differentiation
negative regulation of glycogen (starch) synthase activity
negative regulation of glycogen biosynthetic process
negative regulation of MAP kinase activity
negative regulation of neuron maturation
negative regulation of neuron migration
negative regulation of NFAT protein import into nucleus
negative regulation of nitric-oxide synthase activity
negative regulation of protein binding
negative regulation of protein complex assembly
negative regulation of protein localization to nucleus
negative regulation of smooth muscle cell apoptotic process
negative regulation of type B pancreatic cell development
neurotrophin TRK receptor signaling pathway
organ morphogenesis
peptidyl-serine phosphorylation
peptidyl-threonine phosphorylation
phosphatidylinositol-mediated signaling
positive regulation of axon extension
positive regulation of canonical Wnt signaling pathway
positive regulation of cell-matrix adhesion
positive regulation of DNA biosynthetic process
positive regulation of excitatory postsynaptic potential
positive regulation of GTPase activity
positive regulation of mitochondrial membrane potential
positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway
positive regulation of neuron apoptotic process
positive regulation of neuron death
positive regulation of peptidyl-serine phosphorylation
positive regulation of peptidyl-threonine phosphorylation
positive regulation of proteasomal ubiquitin-dependent protein catabolic process
positive regulation of protein binding
positive regulation of protein catabolic process
positive regulation of protein complex assembly
positive regulation of protein export from nucleus
positive regulation of smooth muscle cell proliferation
positive regulation of stem cell differentiation
positive regulation of transcription from RNA polymerase II promoter
protein autophosphorylation
protein export from nucleus
protein localization to microtubule
protein phosphorylation
re-entry into mitotic cell cycle
regulation of cellular response to heat
regulation of gene expression by genetic imprinting
regulation of microtubule-based process
regulation of neuronal synaptic plasticity
response to activity
response to angiotensin
response to drug
response to epinephrine
response to estradiol
response to insulin
response to insulin-like growth factor stimulus
response to L-glutamate
response to ultrasound
superior temporal gyrus development
Gene Ontology Biological Process:: aging
axon guidance
canonical Wnt signaling pathway
canonical Wnt signaling pathway involved in positive regulation of apoptotic process
cell migration
cellular response to dopamine
cellular response to erythropoietin
cellular response to heat
cellular response to hepatocyte growth factor stimulus
cellular response to hydrogen peroxide
cellular response to interleukin-3
cellular response to iron(II) ion
cellular response to lithium ion
cellular response to mechanical stimulus
chemical synaptic transmission, postsynaptic
circadian rhythm
dopamine receptor signaling pathway
epidermal growth factor receptor signaling pathway
epithelial to mesenchymal transition
ER overload response
establishment of cell polarity
extrinsic apoptotic signaling pathway in absence of ligand
fat cell differentiation
Fc-epsilon receptor signaling pathway
fibroblast growth factor receptor signaling pathway
glycogen metabolic process
hippocampus development
hypermethylation of CpG island
innate immune response
intracellular signal transduction
intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress
myoblast fusion
negative regulation of apoptotic process
negative regulation of canonical Wnt signaling pathway
negative regulation of cardiac muscle hypertrophy
negative regulation of dendrite morphogenesis
negative regulation of dopaminergic neuron differentiation
negative regulation of glycogen (starch) synthase activity
negative regulation of glycogen biosynthetic process
negative regulation of MAP kinase activity
negative regulation of neuron maturation
negative regulation of neuron migration
negative regulation of NFAT protein import into nucleus
negative regulation of nitric-oxide synthase activity
negative regulation of protein binding
negative regulation of protein complex assembly
negative regulation of protein localization to nucleus
negative regulation of smooth muscle cell apoptotic process
negative regulation of type B pancreatic cell development
neurotrophin TRK receptor signaling pathway
organ morphogenesis
peptidyl-serine phosphorylation
peptidyl-threonine phosphorylation
phosphatidylinositol-mediated signaling
positive regulation of axon extension
positive regulation of canonical Wnt signaling pathway
positive regulation of cell-matrix adhesion
positive regulation of DNA biosynthetic process
positive regulation of excitatory postsynaptic potential
positive regulation of GTPase activity
positive regulation of mitochondrial membrane potential
positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway
positive regulation of neuron apoptotic process
positive regulation of neuron death
positive regulation of peptidyl-serine phosphorylation
positive regulation of peptidyl-threonine phosphorylation
positive regulation of proteasomal ubiquitin-dependent protein catabolic process
positive regulation of protein binding
positive regulation of protein catabolic process
positive regulation of protein complex assembly
positive regulation of protein export from nucleus
positive regulation of smooth muscle cell proliferation
positive regulation of stem cell differentiation
positive regulation of transcription from RNA polymerase II promoter
protein autophosphorylation
protein export from nucleus
protein localization to microtubule
protein phosphorylation
re-entry into mitotic cell cycle
regulation of cellular response to heat
regulation of gene expression by genetic imprinting
regulation of microtubule-based process
regulation of neuronal synaptic plasticity
response to activity
response to angiotensin
response to drug
response to epinephrine
response to estradiol
response to insulin
response to insulin-like growth factor stimulus
response to L-glutamate
response to ultrasound
superior temporal gyrus development
Gene Ontology Molecular Function:: ATP binding
beta-catenin binding
kinase activity
NF-kappaB binding
p53 binding
protein kinase A catalytic subunit binding
protein kinase activity
protein kinase binding
protein serine/threonine kinase activity
RNA polymerase II transcription factor binding
tau-protein kinase activity
ubiquitin protein ligase binding
Gene Ontology Cellular Component:: axon
beta-catenin destruction complex
centrosome
cytoplasm
cytosol
dendritic shaft
dendritic spine
growth cone
intracellular ribonucleoprotein complex
membrane raft
mitochondrion
neuronal cell body
neuronal postsynaptic density
nucleus
perinuclear region of cytoplasm
plasma membrane
Wnt signalosome
Keywords:: 3D-structure
ADP-ribosylation
ATP-binding
Alternative splicing
Alzheimer disease
Biological rhythms
Carbohydrate metabolism
Cell membrane
Complete proteome
Cytoplasm
Developmental protein
Diabetes mellitus
Differentiation
Glycogen metabolism
Kinase
Membrane
Neurogenesis
Nucleotide-binding
Nucleus
Phosphoprotein
Reference proteome
Serine/threonine-protein kinase
Signal transduction inhibitor
Transferase
Wnt signaling pathway
Interacts With:: P31749; P31751; O15169; O35625; Q14DJ8; Q96G01; O75952-3; O75952-5; P35222; Q5VWQ8; Q5VWQ8-2; Q9NYF0; O75398; Q811T9; P13807; O75581; Q5S007; P63085; P10636; P10636-8; Q8N4C6; P17612; Q01201; Q15797; O95863; P37840; Q6J9G0; P04637; Q14134; O95071; P63104; Q8IX07

Names & Taxonomy

Structure

Subcellular location

Function

Publication