Human Gene GSK3B (ENST00000316626.6) from GENCODE V44
Description: Homo sapiens glycogen synthase kinase 3 beta (GSK3B), transcript variant 1, mRNA. (from RefSeq NM_002093) RefSeq Summary (NM_002093): The protein encoded by this gene is a serine-threonine kinase belonging to the glycogen synthase kinase subfamily. It is a negative regulator of glucose homeostasis and is involved in energy metabolism, inflammation, ER-stress, mitochondrial dysfunction, and apoptotic pathways. Defects in this gene have been associated with Parkinson disease and Alzheimer disease. [provided by RefSeq, Aug 2017]. Gencode Transcript: ENST00000316626.6 Gencode Gene: ENSG00000082701.17 Transcript (Including UTRs) Position: hg38 chr3:119,821,322-120,093,666 Size: 272,345 Total Exon Count: 12 Strand: - Coding Region Position: hg38 chr3:119,826,788-120,093,434 Size: 266,647 Coding Exon Count: 12
ID:GSK3B_HUMAN DESCRIPTION: RecName: Full=Glycogen synthase kinase-3 beta; Short=GSK-3 beta; EC=2.7.11.26; AltName: Full=Serine/threonine-protein kinase GSK3B; EC=2.7.11.1; 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. 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. CATALYTIC ACTIVITY: ATP + [tau protein] = ADP + [tau protein] phosphate. CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein. 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. SUBUNIT: Monomer (By similarity). Interacts with ARRB2 and DISC1 (By similarity). Interacts with CABYR, MMP2, MUC1, NIN and PRUNE Interacts with AXIN1; the interaction mediates hyperphosphorylation of CTNNB1 leading to its ubiquitination and destruction. Interacts with and phosphorylates SNAI1. Interacts with DNM1L (via a C-terminal domain). Found in a complex composed of MACF1, APC, AXIN1, CTNNB1 and GSK3B (By similarity). Interacts with SGK3. INTERACTION: P31749:AKT1; NbExp=2; IntAct=EBI-373586, EBI-296087; P31751:AKT2; NbExp=2; IntAct=EBI-373586, EBI-296058; O15169:AXIN1; NbExp=26; IntAct=EBI-373586, EBI-710484; O35625:Axin1 (xeno); NbExp=4; IntAct=EBI-373586, EBI-2365912; Q14DJ8:Axin1 (xeno); NbExp=2; IntAct=EBI-373586, EBI-4312125; P35222:CTNNB1; NbExp=3; IntAct=EBI-373586, EBI-491549; Q9NYF0:DACT1; NbExp=3; IntAct=EBI-373586, EBI-3951744; O75398:DEAF1; NbExp=2; IntAct=EBI-373586, EBI-718185; Q811T9:Disc1 (xeno); NbExp=4; IntAct=EBI-373586, EBI-2298259; P63085:Mapk1 (xeno); NbExp=2; IntAct=EBI-373586, EBI-397697; Q8N4C6:NIN; NbExp=2; IntAct=EBI-373586, EBI-1164022; Q01201:RELB; NbExp=4; IntAct=EBI-373586, EBI-357837; O95863:SNAI1; NbExp=4; IntAct=EBI-373586, EBI-1045459; Q14134:TRIM29; NbExp=2; IntAct=EBI-373586, EBI-702370; Q8IX07:ZFPM1; NbExp=2; IntAct=EBI-373586, EBI-3942619; 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 phosophorylated form to the cell membrane. TISSUE SPECIFICITY: Expressed in testis, thymus, prostate and ovary and weakly expressed in lung, brain and kidney. PTM: Phosphorylated by AKT1 and ILK1. Upon insulin-mediated signaling, the activated PKB/AKT1 protein kinase phosphorylates and desactivates GSK3B, resulting in the dephosphorylation and activation of GYS1. Activated by phosphorylation at Tyr-216. MISCELLANEOUS: Higher expression and activity of GSK3B are found in the skeletal muscle (vastus lateralis) of patients with type 2 diabetes (PubMed:10868943). Several potent GSK3 (GSK3A and GSK3B) inhibitors have been identified and characterized in preclinical models for treatments of type 2 diabetes (PubMed:19366350). SIMILARITY: Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. GSK-3 subfamily. SIMILARITY: Contains 1 protein kinase domain.
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on P49841
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Biological Process: GO:0001837 epithelial to mesenchymal transition GO:0001954 positive regulation of cell-matrix adhesion GO:0005975 carbohydrate metabolic process GO:0005977 glycogen metabolic process GO:0006468 protein phosphorylation GO:0006983 ER overload response GO:0007212 dopamine receptor signaling pathway GO:0007275 multicellular organism development GO:0007399 nervous system development GO:0007623 circadian rhythm GO:0009968 negative regulation of signal transduction GO:0010628 positive regulation of gene expression GO:0010822 positive regulation of mitochondrion organization GO:0016055 Wnt signaling pathway GO:0016310 phosphorylation GO:0018105 peptidyl-serine phosphorylation GO:0018107 peptidyl-threonine phosphorylation GO:0021766 hippocampus development GO:0030010 establishment of cell polarity GO:0030011 maintenance of cell polarity GO:0030154 cell differentiation GO:0030516 regulation of axon extension GO:0031175 neuron projection development GO:0031333 negative regulation of protein complex assembly GO:0031334 positive regulation of protein complex assembly GO:0032091 negative regulation of protein binding GO:0032092 positive regulation of protein binding GO:0032436 positive regulation of proteasomal ubiquitin-dependent protein catabolic process GO:0032515 negative regulation of phosphoprotein phosphatase activity GO:0032886 regulation of microtubule-based process GO:0035556 intracellular signal transduction GO:0036016 cellular response to interleukin-3 GO:0043066 negative regulation of apoptotic process GO:0043547 positive regulation of GTPase activity GO:0045719 negative regulation of glycogen biosynthetic process GO:0045732 positive regulation of protein catabolic process GO:0046777 protein autophosphorylation GO:0046827 positive regulation of protein export from nucleus GO:0048511 rhythmic process GO:0048814 regulation of dendrite morphogenesis GO:0050770 regulation of axonogenesis GO:0060070 canonical Wnt signaling pathway GO:0060079 excitatory postsynaptic potential GO:0070507 regulation of microtubule cytoskeleton organization GO:0070885 negative regulation of calcineurin-NFAT signaling cascade GO:0071109 superior temporal gyrus development GO:0090090 negative regulation of canonical Wnt signaling pathway GO:0097191 extrinsic apoptotic signaling pathway GO:0097192 extrinsic apoptotic signaling pathway in absence of ligand GO:1900034 regulation of cellular response to heat GO:1900181 negative regulation of protein localization to nucleus GO:1901030 positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway GO:1901215 negative regulation of neuron death GO:1901216 positive regulation of neuron death GO:1901984 negative regulation of protein acetylation GO:1904339 negative regulation of dopaminergic neuron differentiation GO:1904646 cellular response to beta-amyloid GO:1904781 positive regulation of protein localization to centrosome GO:1904885 beta-catenin destruction complex assembly GO:1904886 beta-catenin destruction complex disassembly GO:2000077 negative regulation of type B pancreatic cell development GO:2000466 negative regulation of glycogen (starch) synthase activity
BioCarta from NCI Cancer Genome Anatomy Project h_g1Pathway - Cell Cycle: G1/S Check Point h_gsk3Pathway - Inactivation of Gsk3 by AKT causes accumulation of b-catenin in Alveolar Macrophages h_igf1mtorpathway - Skeletal muscle hypertrophy is regulated via AKT/mTOR pathway h_p35alzheimersPathway - Deregulation of CDK5 in Alzheimers Disease h_shhPathway - Sonic Hedgehog (Shh) Pathway h_ptdinsPathway - Phosphoinositides and their downstream targets. h_alkPathway - ALK in cardiac myocytes h_hesPathway - Segmentation Clock h_ps1Pathway - Presenilin action in Notch and Wnt signaling h_nfatPathway - NFAT and Hypertrophy of the heart (Transcription in the broken heart) h_pitx2Pathway - Multi-step Regulation of Transcription by Pitx2 h_wntPathway - WNT Signaling Pathway h_eif2Pathway - Regulation of eIF2
Reactome (by CSHL, EBI, and GO)
Protein P49841 (Reactome details) participates in the following event(s):
R-HSA-9008476 RUNX2 binds GSK3B R-NUL-9008555 Runx2 binds GSK3B R-HSA-195251 Assembly of the destruction complex R-HSA-5323526 FRAT proteins bind GSK3beta R-HSA-9008480 GSK3B phosphorylates RUNX2 R-NUL-9008636 GSK3B phosphorylates Runx2 R-HSA-9008478 FBXW7 binds RUNX2 and GSK3B R-HSA-75820 Phosphorylation of Cyclin D1 at T286 by glycogen synthase kinase-3 beta R-HSA-5229343 AXIN is phosphorylated in the destruction complex R-HSA-195280 Dissociation of beta-catenin from Axin and association of beta catenin with phospho-(20 aa) APC in the detruction complex R-HSA-195275 Phosphorylation of APC component of the destruction complex R-HSA-2130279 Association of beta-catenin with the RBX1:SCF(beta-TrCP1) ubiquitin ligase complex R-HSA-1504186 DVL recruits GSK3beta:AXIN1 to the receptor complex R-HSA-201685 Beta-catenin is released from the destruction complex R-HSA-195304 Association of beta-catenin with the destruction complex R-HSA-198371 AKT phosphorylates GSK3 R-HSA-2399966 AKT1 E17K mutant phosphorylates GSK3 R-NUL-209146 Murine Axin1 is further phosphorylated by Human GSK3beta R-HSA-399951 Phosphorylation of CRMPs by GSK3beta R-HSA-3371435 Constitutive phosphorylation by GSK3 R-HSA-5610730 GSK3 phosphorylates p-GLI2 R-HSA-5610732 GSK3 phosphorylates p-GLI3 R-HSA-9008479 FBXW7 polyubiquitinates RUNX2 R-HSA-2130286 Multi-ubiquitination of phospho-beta-catenin by RBX1:SCF(beta-TrCP1) R-HSA-201691 Phosphorylation of LRP5/6 cytoplasmic domain by CSNKI R-NUL-1458902 frog CK1gamma phosphorylates LRP5/6 R-HSA-201677 Phosphorylation of LRP5/6 cytoplasmic domain by membrane-associated GSK3beta R-HSA-195287 Phosphorylation of phospho-(Ser45 ) at Thr 41 by GSK-3 R-HSA-195318 Phosphorylation of beta-catenin at Ser45 by CK1 alpha R-HSA-195300 Phosphorylation of phospho-(Ser45,Thr41,Ser37) at Ser33 by GSK-3 R-HSA-195283 Phosphorylation of phospho- (Ser45, Thr41) beta-catenin at Ser37 by GSK-3 R-HSA-8939902 Regulation of RUNX2 expression and activity R-HSA-195253 Degradation of beta-catenin by the destruction complex R-HSA-5467337 APC truncation mutants have impaired AXIN binding R-HSA-5467340 AXIN missense mutants destabilize the destruction complex R-HSA-5467348 Truncations of AMER1 destabilize the destruction complex R-HSA-4641262 Disassembly of the destruction complex and recruitment of AXIN to the membrane R-HSA-8878166 Transcriptional regulation by RUNX2 R-HSA-69229 Ubiquitin-dependent degradation of Cyclin D1 R-HSA-198323 AKT phosphorylates targets in the cytosol R-HSA-5674400 Constitutive Signaling by AKT1 E17K in Cancer R-HSA-195721 Signaling by WNT R-HSA-4839744 truncated APC mutants destabilize the destruction complex R-HSA-4839735 AXIN mutants destabilize the destruction complex, activating WNT signaling R-HSA-4839748 AMER1 mutants destabilize the destruction complex R-HSA-201681 TCF dependent signaling in response to WNT R-HSA-399956 CRMPs in Sema3A signaling R-HSA-3371453 Regulation of HSF1-mediated heat shock response R-HSA-5610783 Degradation of GLI2 by the proteasome R-HSA-5610785 GLI3 is processed to GLI3R by the proteasome R-HSA-212436 Generic Transcription Pathway R-HSA-75815 Ubiquitin-dependent degradation of Cyclin D R-HSA-5358751 S45 mutants of beta-catenin aren't phosphorylated R-HSA-5358752 T41 mutants of beta-catenin aren't phosphorylated R-HSA-5358749 S37 mutants of beta-catenin aren't phosphorylated R-HSA-5358747 S33 mutants of beta-catenin aren't phosphorylated R-HSA-196299 Beta-catenin phosphorylation cascade R-HSA-1257604 PIP3 activates AKT signaling R-HSA-2219528 PI3K/AKT Signaling in Cancer R-HSA-162582 Signal Transduction R-HSA-4791275 Signaling by WNT in cancer R-HSA-373755 Semaphorin interactions R-HSA-3371556 Cellular response to heat stress R-HSA-5610787 Hedgehog 'off' state R-HSA-5339716 Misspliced GSK3beta mutants stabilize beta-catenin R-HSA-73857 RNA Polymerase II Transcription R-HSA-69242 S Phase R-HSA-4839743 phosphorylation site mutants of CTNNB1 are not targeted to the proteasome by the destruction complex R-HSA-9006925 Intracellular signaling by second messengers R-HSA-5663202 Diseases of signal transduction R-HSA-422475 Axon guidance R-HSA-2262752 Cellular responses to stress R-HSA-5358351 Signaling by Hedgehog R-HSA-74160 Gene expression (Transcription) R-HSA-69278 Cell Cycle (Mitotic) R-HSA-1643685 Disease R-HSA-1266738 Developmental Biology R-HSA-8953897 Cellular responses to external stimuli R-HSA-1640170 Cell Cycle
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