Protein: Glycogen synthase kinase-3 beta (GSK-3 beta) (EC 2.7.11.26) (Serine/threonine-protein kinase GSK3B) (EC 2.7.11.1) (Q9WV60)
Organism: Mus musculus (Mouse)
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 (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 (By similarity). Phosphorylates JUN at sites proximal to its DNA-binding domain, thereby reducing its affinity for DNA (By similarity). 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 (By similarity). Phosphorylates MAPT/TAU on 'Thr-548', decreasing significantly MAPT/TAU ability to bind and stabilize microtubules (By similarity). MAPT/TAU is the principal component of neurofibrillary tangles in Alzheimer disease (By similarity). 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). 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 (By similarity). Is necessary for the establishment of neuronal polarity and axon outgrowth. Phosphorylates MARK2, leading to inhibition of its activity (By similarity). Phosphorylates SIK1 at 'Thr-182', leading to sustainment of its activity (By similarity). Phosphorylates ZC3HAV1 which enhances its antiviral activity (By similarity). Phosphorylates SNAI1, leading to its BTRC-triggered ubiquitination and proteasomal degradation (By similarity). Phosphorylates SFPQ at 'Thr-687' upon T-cell activation (By similarity). Phosphorylates NR1D1 st 'Ser-55' and 'Ser-59' and stabilizes it by protecting it from proteasomal degradation (By similarity). Regulates the circadian clock via phosphorylation of the major clock components including BMAL1, CLOCK and PER2. Phosphorylates CLOCK AT 'Ser-427' and targets it for proteasomal degradation (By similarity). Phosphorylates BMAL1 at 'Ser-17' and 'Ser-21' and primes it for ubiquitination and proteasomal degradation. Phosphorylates FBXL2 at 'Thr-404' and primes it for ubiquitination by the SCF(FBXO3) complex and proteasomal degradation. Phosphorylates OGT at 'Ser-3' or 'Ser-4' which positively regulates its activity (By similarity). Phosphorylates MYCN in neuroblastoma cells which may promote its degradation (By similarity). Regulates the circadian rhythmicity of hippocampal long-term potentiation and BMAL1 and PER2 expression. 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. Negatively regulates extrinsic apoptotic signaling pathway via death domain receptors (By similarity). Promotes the formation of an anti-apoptotic complex, made of DDX3X, BRIC2 and GSK3B, at death receptors, including TNFRSF10B (By similarity). 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, stabilizing E2F1 and promoting its activity (By similarity).
Subcellular location: Cytoplasm {ECO:0000250|UniProtKB:P49841}. Nucleus {ECO:0000250|UniProtKB:P49841}. 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}.
InterPro domains:
- IPR011009: Protein kinase-like domain superfamily (homologous_superfamily) [55-377]
- IPR050591: Glycogen Synthase Kinase-3 (family) [29-384]
- IPR008271: Serine/threonine-protein kinase, active site (active_site) [177-189]
- IPR039192: Glycogen synthase kinase 3, catalytic domain (domain) [51-343]
- IPR017441: Protein kinase, ATP binding site (binding_site) [62-86]
- IPR000719: Protein kinase domain (domain) [56-340]
Sequence:
MSGRPRTTSFAESCKPVQQPSAFGSMKVSRDKDGSKVTTVVATPGQGPDRPQEVSYTDTKVIGNGSFGVVYQAKLCDSGELVAIKKVLQDKRFKNRELQIMRKLDHCNIVRLRYFFYSSGEKKDEVYLNLVLDYVPETVYRVARHYSRAKQTLPVIYVKLYMYQLFRSLAYIHSFGICHRDIKPQNLLLDPDTAVLKLCDFGSAKQLVRGEPNVSYICSRYYRAPELIFGATDYTSSIDVWSAGCVLAELLLGQPIFPGDSGVDQLVEIIKVLGTPTREQIREMNPNYTEFKFPQIKAHPWTKVFRPRTPPEAIALCSRLLEYTPTARLTPLEACAHSFFDELRDPNVKLPNGRDTPALFNFTTQELSSNPPLATILIPPHARIQAAASPPANATAASDTNAGDRGQTNNAASASASNST
Predicted GO terms:
Molecular Function (MF): GO:0003674 (molecular function), GO:0005488 (binding), GO:0003824 (catalytic activity), GO:0016740 (transferase activity), GO:0140096 (catalytic activity, acting on a protein), GO:0005515 (protein binding), GO:0004672 (protein kinase activity), GO:0005102 (signaling receptor binding), GO:0016772 (transferase activity, transferring phosphorus-containing groups), GO:0016773 (phosphotransferase activity, alcohol group as acceptor), GO:0004674 (protein serine/threonine kinase activity), GO:0016301 (kinase activity)
Biological Process (BP): GO:0008150 (biological process), GO:0051179 (localization), GO:0048518 (positive regulation of biological process), GO:0050789 (regulation of biological process), GO:0023052 (signaling), GO:0032501 (multicellular organismal process), GO:0065007 (biological regulation), GO:0050896 (response to stimulus), GO:0032502 (developmental process), GO:0009987 (cellular process), GO:0008152 (metabolic process), GO:0048519 (negative regulation of biological process), GO:0051641 (cellular localization), GO:0048856 (anatomical structure development), GO:0023057 (negative regulation of signaling), GO:0009653 (anatomical structure morphogenesis), GO:0048870 (cell motility), GO:0042221 (response to chemical), GO:0051240 (positive regulation of multicellular organismal process), GO:0006807 (nitrogen compound metabolic process), GO:0071840 (cellular component organization or biogenesis), GO:0051241 (negative regulation of multicellular organismal process), GO:0051239 (regulation of multicellular organismal process), GO:0051050 (positive regulation of transport), GO:0009892 (negative regulation of metabolic process), GO:0065008 (regulation of biological quality), GO:0050793 (regulation of developmental process), GO:0009719 (response to endogenous stimulus), GO:0008219 (cell death), GO:0050794 (regulation of cellular process), GO:0048583 (regulation of response to stimulus), GO:0051716 (cellular response to stimulus), GO:0023051 (regulation of signaling), GO:0051093 (negative regulation of developmental process), GO:0048523 (negative regulation of cellular process), GO:0007165 (signal transduction), GO:0023056 (positive regulation of signaling), GO:0007275 (multicellular organism development), GO:0048584 (positive regulation of response to stimulus), GO:0019222 (regulation of metabolic process), GO:0032879 (regulation of localization), GO:0051234 (establishment of localization), GO:0071704 (organic substance metabolic process), GO:0009056 (catabolic process), GO:0003008 (system process), GO:0044237 (cellular metabolic process), GO:0009893 (positive regulation of metabolic process), GO:0065009 (regulation of molecular function), GO:0045926 (negative regulation of growth), GO:0048585 (negative regulation of response to stimulus), GO:0007154 (cell communication), GO:0044238 (primary metabolic process), GO:0040008 (regulation of growth), GO:0048522 (positive regulation of cellular process), GO:0009968 (negative regulation of signal transduction), GO:0012501 (programmed cell death), GO:0044248 (cellular catabolic process), GO:0048731 (system development), GO:0046621 (negative regulation of organ growth), GO:0048513 (animal organ development), GO:0009966 (regulation of signal transduction), GO:0060255 (regulation of macromolecule metabolic process), GO:0071495 (cellular response to endogenous stimulus), GO:0046620 (regulation of organ growth), GO:0008217 (regulation of blood pressure), GO:0043502 (regulation of muscle adaptation), GO:0003013 (circulatory system process), GO:0009725 (response to hormone), GO:0006793 (phosphorus metabolic process), GO:0009894 (regulation of catabolic process), GO:0010035 (response to inorganic substance), GO:0009887 (animal organ morphogenesis), GO:0046907 (intracellular transport), GO:0010605 (negative regulation of macromolecule metabolic process), GO:0097190 (apoptotic signaling pathway), GO:0030308 (negative regulation of cell growth), GO:0051171 (regulation of nitrogen compound metabolic process), GO:0045595 (regulation of cell differentiation), GO:0016043 (cellular component organization), GO:0007166 (cell surface receptor signaling pathway), GO:0051128 (regulation of cellular component organization), GO:1901575 (organic substance catabolic process), GO:0014741 (negative regulation of muscle hypertrophy), GO:0044260 (cellular macromolecule metabolic process), GO:0048638 (regulation of developmental growth), GO:1902074 (response to salt), GO:0016477 (cell migration), GO:0009967 (positive regulation of signal transduction), GO:0050790 (regulation of catalytic activity), GO:0010648 (negative regulation of cell communication), GO:0044093 (positive regulation of molecular function), GO:0051049 (regulation of transport), GO:1901564 (organonitrogen compound metabolic process), GO:0010604 (positive regulation of macromolecule metabolic process), GO:0019538 (protein metabolic process), GO:0001558 (regulation of cell growth), GO:0051649 (establishment of localization in cell), GO:1901700 (response to oxygen-containing compound), GO:0051130 (positive regulation of cellular component organization), GO:0003205 (cardiac chamber development), GO:0038034 (signal transduction in absence of ligand), GO:0043170 (macromolecule metabolic process), GO:0010033 (response to organic substance), GO:0009891 (positive regulation of biosynthetic process), GO:2000026 (regulation of multicellular organismal development), GO:1901698 (response to nitrogen compound), GO:0010646 (regulation of cell communication), GO:0031325 (positive regulation of cellular metabolic process), GO:0070887 (cellular response to chemical stimulus), GO:0045596 (negative regulation of cell differentiation), GO:0048640 (negative regulation of developmental growth), GO:1903524 (positive regulation of blood circulation), GO:0006810 (transport), GO:0009889 (regulation of biosynthetic process), GO:0003206 (cardiac chamber morphogenesis), GO:0010647 (positive regulation of cell communication), GO:0031323 (regulation of cellular metabolic process), GO:0080090 (regulation of primary metabolic process), GO:0009896 (positive regulation of catabolic process), GO:1901652 (response to peptide), GO:0045823 (positive regulation of heart contraction), GO:0061117 (negative regulation of heart growth), GO:0010556 (regulation of macromolecule biosynthetic process), GO:0008015 (blood circulation), GO:0051246 (regulation of protein metabolic process), GO:0030163 (protein catabolic process), GO:1902075 (cellular response to salt), GO:0008277 (regulation of G protein-coupled receptor signaling pathway), GO:0048545 (response to steroid hormone), GO:0051148 (negative regulation of muscle cell differentiation), GO:0003231 (cardiac ventricle development), GO:0090257 (regulation of muscle system process), GO:1901028 (regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway), GO:1903522 (regulation of blood circulation), GO:0010468 (regulation of gene expression), GO:0003208 (cardiac ventricle morphogenesis), GO:0009057 (macromolecule catabolic process), GO:0055021 (regulation of cardiac muscle tissue growth), GO:0043412 (macromolecule modification), GO:0060420 (regulation of heart growth), GO:0003007 (heart morphogenesis), GO:0010508 (positive regulation of autophagy), GO:0072359 (circulatory system development), GO:0061050 (regulation of cell growth involved in cardiac muscle cell development), GO:0051252 (regulation of RNA metabolic process), GO:0010614 (negative regulation of cardiac muscle hypertrophy), GO:0043085 (positive regulation of catalytic activity), GO:1901701 (cellular response to oxygen-containing compound), GO:0010629 (negative regulation of gene expression), GO:0061024 (membrane organization), GO:0007507 (heart development), GO:0006839 (mitochondrial transport), GO:0010038 (response to metal ion), GO:0071417 (cellular response to organonitrogen compound), GO:0034097 (response to cytokine), GO:0097192 (extrinsic apoptotic signaling pathway in absence of ligand), GO:0007167 (enzyme-linked receptor protein signaling pathway), GO:1901565 (organonitrogen compound catabolic process), GO:0010562 (positive regulation of phosphorus metabolic process), GO:0006508 (proteolysis), GO:0071310 (cellular response to organic substance), GO:1905710 (positive regulation of membrane permeability), GO:0045745 (positive regulation of G protein-coupled receptor signaling pathway), GO:0010506 (regulation of autophagy), GO:1901699 (cellular response to nitrogen compound), GO:0006325 (chromatin organization), GO:0010628 (positive regulation of gene expression), GO:0006796 (phosphate-containing compound metabolic process), GO:1902532 (negative regulation of intracellular signal transduction), GO:0051147 (regulation of muscle cell differentiation), GO:0036211 (protein modification process), GO:0043434 (response to peptide hormone), GO:0010557 (positive regulation of macromolecule biosynthetic process), GO:0055022 (negative regulation of cardiac muscle tissue growth), GO:0045935 (positive regulation of nucleobase-containing compound metabolic process), GO:0046902 (regulation of mitochondrial membrane permeability), GO:0051254 (positive regulation of RNA metabolic process), GO:0032870 (cellular response to hormone stimulus), GO:0010243 (response to organonitrogen compound), GO:0071241 (cellular response to inorganic substance), GO:0044265 (cellular macromolecule catabolic process), GO:0003073 (regulation of systemic arterial blood pressure), GO:0033993 (response to lipid), GO:0006915 (apoptotic process), GO:0031326 (regulation of cellular biosynthetic process), GO:0010611 (regulation of cardiac muscle hypertrophy), GO:0051247 (positive regulation of protein metabolic process), GO:0019219 (regulation of nucleobase-containing compound metabolic process), GO:0033043 (regulation of organelle organization), GO:0031331 (positive regulation of cellular catabolic process), GO:0097191 (extrinsic apoptotic signaling pathway), GO:0010226 (response to lithium ion), GO:0014070 (response to organic cyclic compound), GO:0051338 (regulation of transferase activity), GO:0031329 (regulation of cellular catabolic process), GO:0006996 (organelle organization), GO:0010638 (positive regulation of organelle organization), GO:0031328 (positive regulation of cellular biosynthetic process), GO:1902531 (regulation of intracellular signal transduction), GO:0051174 (regulation of phosphorus metabolic process)
Cellular Component (CC): GO:0005575 (cellular component), GO:0032991 (protein-containing complex), GO:0110165 (cellular anatomical entity), GO:0005622 (intracellular anatomical structure), GO:0043226 (organelle), GO:0042995 (cell projection), GO:0016020 (membrane), GO:0005829 (cytosol), GO:0030054 (cell junction), GO:0140535 (intracellular protein-containing complex), GO:0099080 (supramolecular complex), GO:0098794 (postsynapse), GO:1902494 (catalytic complex), GO:0036477 (somatodendritic compartment), GO:0005737 (cytoplasm), GO:0120025 (plasma membrane bounded cell projection), GO:0043229 (intracellular organelle), GO:0045202 (synapse), GO:0043228 (non-membrane-bounded organelle), GO:0005739 (mitochondrion), GO:0043197 (dendritic spine), GO:0098857 (membrane microdomain), GO:0097447 (dendritic tree), GO:0043227 (membrane-bounded organelle), GO:0099081 (supramolecular polymer), GO:0045121 (membrane raft), GO:0098685 (Schaffer collateral - CA1 synapse), GO:0043231 (intracellular membrane-bounded organelle), GO:0043232 (intracellular non-membrane-bounded organelle), GO:0098978 (glutamatergic synapse), GO:0030425 (dendrite), GO:0043005 (neuron projection), GO:0099512 (supramolecular fiber), GO:0099513 (polymeric cytoskeletal fiber), GO:0005634 (nucleus), GO:0005856 (cytoskeleton), GO:0030424 (axon), GO:0044309 (neuron spine), GO:0005874 (microtubule), GO:0015630 (microtubule cytoskeleton)