InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: GSK3B

Summary

InnateDB Protein

IDBP-51667.7

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

GSK3B

Protein Name

glycogen synthase kinase 3 beta

Synonyms

Species

Homo sapiens

Ensembl Protein

ENSP00000324806

InnateDB Gene

IDBG-51663 (GSK3B)

Protein Structure

UniProt Annotation

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. {ECO:0000269PubMed:11430833, ECO:0000269PubMed:12554650, ECO:0000269PubMed:14690523, ECO:0000269PubMed:15448698, ECO:0000269PubMed:15647282, ECO:0000269PubMed:16484495, ECO:0000269PubMed:18348280, ECO:0000269PubMed:1846781, ECO:0000269PubMed:19946213, ECO:0000269PubMed:20932480, ECO:0000269PubMed:20937854, ECO:0000269PubMed:22514281, ECO:0000269PubMed:8397507, ECO:0000269PubMed:9072970, ECO:0000269PubMed:9819408}.

Subcellular Localization

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.

Disease Associations

Tissue Specificity

Expressed in testis, thymus, prostate and ovary and weakly expressed in lung, brain and kidney. Colocalizes with EIF2AK2/PKR and TAU in the Alzheimer disease (AD) brain. {ECO:0000269PubMed:21029237}.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 482 experimentally validated interaction(s) in this database.
They are also associated with 32 interaction(s) predicted by orthology.

Experimentally validated
Total	482 [view]
Protein-Protein	477 [view]
Protein-DNA	2 [view]
Protein-RNA	1 [view]
DNA-DNA	2 [view]
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	32 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0001085	RNA polymerase II transcription factor binding
GO:0002039	p53 binding
GO:0004672	protein kinase activity
GO:0004674	protein serine/threonine kinase activity
GO:0004713	protein tyrosine kinase activity
GO:0005178	integrin binding
GO:0005515	protein binding
GO:0005524	ATP binding
GO:0008013	beta-catenin binding
GO:0016301	kinase activity
GO:0016772	transferase activity, transferring phosphorus-containing groups
GO:0019901	protein kinase binding
GO:0031625	ubiquitin protein ligase binding
GO:0034236	protein kinase A catalytic subunit binding
GO:0035255	ionotropic glutamate receptor binding
GO:0048156	tau protein binding
GO:0050321	tau-protein kinase activity
GO:0051059	NF-kappaB binding

Biological Process

GO:0000320	re-entry into mitotic cell cycle
GO:0001837	epithelial to mesenchymal transition
GO:0001954	positive regulation of cell-matrix adhesion
GO:0005977	glycogen metabolic process
GO:0006349	regulation of gene expression by genetic imprinting
GO:0006468	protein phosphorylation
GO:0006611	protein export from nucleus
GO:0006983	ER overload response
GO:0007163	establishment or maintenance of cell polarity
GO:0007173	epidermal growth factor receptor signaling pathway
GO:0007409	axonogenesis
GO:0007411	axon guidance
GO:0007520	myoblast fusion
GO:0007623	circadian rhythm
GO:0008543	fibroblast growth factor receptor signaling pathway
GO:0009887	organ morphogenesis
GO:0010226	response to lithium ion
GO:0010614	negative regulation of cardiac muscle hypertrophy
GO:0010800	positive regulation of peptidyl-threonine phosphorylation
GO:0010977	negative regulation of neuron projection development
GO:0014043	negative regulation of neuron maturation
GO:0014902	myotube differentiation
GO:0016055	Wnt signaling pathway
GO:0016310	phosphorylation
GO:0016477	cell migration
GO:0018105	peptidyl-serine phosphorylation
GO:0021766	hippocampus development
GO:0030010	establishment of cell polarity
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:0032855	positive regulation of Rac GTPase activity
GO:0032886	regulation of microtubule-based process
GO:0033138	positive regulation of peptidyl-serine phosphorylation
GO:0035372	protein localization to microtubule
GO:0035556	intracellular signal transduction
GO:0036016	cellular response to interleukin-3
GO:0038095	Fc-epsilon receptor signaling pathway
GO:0042493	response to drug
GO:0043065	positive regulation of apoptotic process
GO:0043066	negative regulation of apoptotic process
GO:0043407	negative regulation of MAP kinase activity
GO:0044027	hypermethylation of CpG island
GO:0044337	canonical Wnt signaling pathway involved in positive regulation of apoptotic process
GO:0045087	innate immune response (InnateDB)
GO:0045444	fat cell differentiation
GO:0045719	negative regulation of glycogen biosynthetic process
GO:0045732	positive regulation of protein catabolic process
GO:0045944	positive regulation of transcription from RNA polymerase II promoter
GO:0046827	positive regulation of protein export from nucleus
GO:0048011	neurotrophin TRK receptor signaling pathway
GO:0048015	phosphatidylinositol-mediated signaling
GO:0048168	regulation of neuronal synaptic plasticity
GO:0050774	negative regulation of dendrite morphogenesis
GO:0051534	negative regulation of NFAT protein import into nucleus
GO:0060070	canonical Wnt signaling pathway
GO:0071109	superior temporal gyrus development
GO:0071260	cellular response to mechanical stimulus
GO:0090090	negative regulation of canonical Wnt signaling pathway
GO:0097192	extrinsic apoptotic signaling pathway in absence of ligand
GO:1901030	positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway
GO:2000077	negative regulation of type B pancreatic cell development
GO:2000466	negative regulation of glycogen (starch) synthase activity
GO:2000738	positive regulation of stem cell differentiation

Cellular Component

GO:0005634	nucleus
GO:0005737	cytoplasm
GO:0005813	centrosome
GO:0005829	cytosol
GO:0005886	plasma membrane
GO:0016020	membrane
GO:0030426	growth cone
GO:0030529	ribonucleoprotein complex
GO:0030877	beta-catenin destruction complex
GO:0043025	neuronal cell body
GO:0043197	dendritic spine
GO:0043198	dendritic shaft
GO:0043227	membrane-bounded organelle
GO:0043234	protein complex
GO:0044297	cell body
GO:0045121	membrane raft
GO:0048471	perinuclear region of cytoplasm

Protein Structure and Domains

PDB ID

InterPro

IPR000719 Protein kinase domain
IPR001245 Serine-threonine/tyrosine-protein kinase catalytic domain
IPR002290 Serine/threonine/dual specificity protein kinase, catalytic domain
IPR011009 Protein kinase-like domain
IPR020635 Tyrosine-protein kinase, catalytic domain

PFAM

PF00069
PF07714

PRINTS

PR00109

PIRSF

SMART

SM00220
SM00219

TIGRFAMs

Post-translational Modifications

Modification

Cross-References

SwissProt