P49841 (GSK3B_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Glycogen synthase kinase-3 beta
Short name=GSK-3 beta
EC=2.7.11.26

Alternative name(s):
Serine/threonine-protein kinase GSK3B
EC=2.7.11.1

Gene names

Name:

GSK3B

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	420 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

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. Phosphorylates SNAI1, leading to its BTRC-triggered ubiquitination and proteasomal degradation. Phosphorylates SFPQ at 'Thr-687' upon T-cell activation. Ref.6 Ref.7 Ref.10 Ref.12 Ref.16 Ref.18 Ref.19 Ref.21 Ref.24 Ref.30 Ref.32 Ref.39 Ref.43
Catalytic activity	ATP + [tau protein] = ADP + [tau protein] phosphate. 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. Ref.9 Ref.43
Subunit structure	Monomer. Interacts with ARRB2, DISC1 and ZBED3 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. Interacts with DAB2IP (via C2 domain); the interaction stimulates GSK3B kinase activation. Interacts (via C2 domain) with PPP2CA. Ref.11 Ref.12 Ref.14 Ref.17 Ref.19 Ref.20 Ref.21 Ref.22 Ref.23 Ref.27 Ref.31 Ref.43
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. Ref.19 Ref.32
Tissue specificity	Expressed in testis, thymus, prostate and ovary and weakly expressed in lung, brain and kidney. Co-localizes with EIF2AK2/PKR and TAU in the Alzheimer's disease (AD) brain.
Post-translational modification	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. Ref.8 Ref.17 Ref.32 Ref.43 Mono-ADP-ribosylation by PARP10 negatively regulates kinase activity.
Miscellaneous	Higher expression and activity of GSK3B are found in the skeletal muscle (vastus lateralis) of patients with type 2 diabetes (Ref.15). Several potent GSK3 (GSK3A and GSK3B) inhibitors have been identified and characterized in preclinical models for treatments of type 2 diabetes (Ref.35).
Sequence similarities	Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. GSK-3 subfamily. Contains 1 protein kinase domain.

Ontologies

Keywords
Biological process	Carbohydrate metabolism Differentiation Glycogen metabolism Neurogenesis Wnt signaling pathway
Cellular component	Cell membrane Cytoplasm Membrane Nucleus
Coding sequence diversity	Alternative splicing
Disease	Alzheimer disease Diabetes mellitus
Ligand	ATP-binding Nucleotide-binding
Molecular function	Developmental protein Kinase Serine/threonine-protein kinase Signal transduction inhibitor Transferase
PTM	ADP-ribosylation Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	ER overload response Inferred from direct assay PubMed 14744935. Source: MGI axon guidance Traceable author statement. Source: Reactome canonical Wnt receptor signaling pathway Inferred by curator PubMed 9601641. Source: UniProtKB canonical Wnt receptor signaling pathway involved in positive regulation of apoptotic process Inferred from electronic annotation. Source: Compara cell migration Inferred from electronic annotation. Source: Compara circadian rhythm Inferred from sequence or structural similarity. Source: UniProtKB epidermal growth factor receptor signaling pathway Traceable author statement. Source: Reactome epithelial to mesenchymal transition Inferred from mutant phenotype Ref.19. Source: UniProtKB establishment of cell polarity Inferred from electronic annotation. Source: Compara fat cell differentiation Inferred from electronic annotation. Source: Compara fibroblast growth factor receptor signaling pathway Traceable author statement. Source: Reactome glycogen metabolic process Inferred from direct assay PubMed 8638126. Source: BHF-UCL hippocampus development Inferred from mutant phenotype PubMed 19581563. Source: BHF-UCL hypermethylation of CpG island Inferred from electronic annotation. Source: Compara innate immune response Traceable author statement. Source: Reactome myoblast fusion Inferred from electronic annotation. Source: Compara negative regulation of MAP kinase activity Inferred from electronic annotation. Source: Compara negative regulation of NFAT protein import into nucleus Inferred from mutant phenotype Ref.10. Source: UniProtKB negative regulation of apoptotic process Inferred from direct assay PubMed 14744935. Source: MGI negative regulation of canonical Wnt receptor signaling pathway Traceable author statement Ref.35. Source: UniProtKB negative regulation of dendrite morphogenesis Inferred from electronic annotation. Source: Compara negative regulation of glycogen (starch) synthase activity Traceable author statement Ref.35. Source: UniProtKB negative regulation of glycogen biosynthetic process Traceable author statement Ref.35. Source: UniProtKB negative regulation of protein binding Inferred from direct assay PubMed 16890161. Source: BHF-UCL negative regulation of protein complex assembly Inferred from mutant phenotype PubMed 16188939. Source: BHF-UCL negative regulation of transcription, DNA-dependent Inferred from electronic annotation. Source: Compara negative regulation of type B pancreatic cell development Traceable author statement Ref.35. Source: UniProtKB neurotrophin TRK receptor signaling pathway Traceable author statement. Source: Reactome organ morphogenesis Inferred from electronic annotation. Source: Compara peptidyl-serine phosphorylation Inferred from direct assay PubMed 8638126. Source: BHF-UCL phosphatidylinositol-mediated signaling Traceable author statement. Source: Reactome positive regulation of Rac GTPase activity Inferred from mutant phenotype PubMed 18156211. Source: BHF-UCL positive regulation of cell-matrix adhesion Inferred from mutant phenotype PubMed 18156211. Source: BHF-UCL positive regulation of peptidyl-serine phosphorylation Inferred from electronic annotation. Source: Compara positive regulation of peptidyl-threonine phosphorylation Inferred from electronic annotation. Source: Compara positive regulation of protein binding Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of protein catabolic process Inferred by curator PubMed 16188939. Source: BHF-UCL positive regulation of protein complex assembly Inferred from direct assay PubMed 8638126. Source: BHF-UCL positive regulation of protein export from nucleus Inferred from direct assay PubMed 14744935. Source: MGI positive regulation of stem cell differentiation Inferred from electronic annotation. Source: Compara positive regulation of transcription from RNA polymerase II promoter Inferred from electronic annotation. Source: Compara protein export from nucleus Inferred from electronic annotation. Source: Compara protein localization to microtubule Inferred from electronic annotation. Source: Compara re-entry into mitotic cell cycle Inferred from electronic annotation. Source: Compara regulation of gene expression by genetic imprinting Inferred from electronic annotation. Source: Compara regulation of microtubule-based process Inferred from mutant phenotype Ref.32. Source: UniProtKB regulation of neuronal synaptic plasticity Inferred from electronic annotation. Source: Compara response to drug Inferred from electronic annotation. Source: Compara response to lithium ion Inferred from electronic annotation. Source: Compara superior temporal gyrus development Inferred from mutant phenotype PubMed 19581563. Source: BHF-UCL
Cellular_component	beta-catenin destruction complex Inferred from direct assay PubMed 16188939PubMed 9601641. Source: UniProtKB centrosome Inferred from direct assay PubMed 21399614. Source: UniProtKB cytosol Traceable author statement. Source: Reactome dendritic shaft Inferred from electronic annotation. Source: Compara dendritic spine Inferred from electronic annotation. Source: Compara growth cone Inferred from electronic annotation. Source: Compara membrane raft Inferred from electronic annotation. Source: Compara neuronal cell body Inferred from electronic annotation. Source: Compara nucleus Inferred from direct assay Ref.19. Source: UniProtKB perinuclear region of cytoplasm Inferred from electronic annotation. Source: Compara plasma membrane Inferred from direct assay Ref.32. Source: UniProtKB ribonucleoprotein complex Inferred from electronic annotation. Source: Compara
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW p53 binding Inferred from direct assay PubMed 14744935. Source: MGI protein serine/threonine kinase activity Inferred from direct assay Ref.24Ref.10. Source: UniProtKB tau-protein kinase activity Inferred from direct assay Ref.18. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
AKT1	P31749	2	EBI-373586,EBI-296087
AKT2	P31751	2	EBI-373586,EBI-296058
AXIN1	O15169	27	EBI-373586,EBI-710484
Axin1	O35625	4	EBI-373586,EBI-2365912	From a different organism.
Axin1	Q14DJ8	2	EBI-373586,EBI-4312125	From a different organism.
CTNNB1	P35222	5	EBI-373586,EBI-491549
DACT1	Q9NYF0	3	EBI-373586,EBI-3951744
DEAF1	O75398	2	EBI-373586,EBI-718185
Disc1	Q811T9	4	EBI-373586,EBI-2298259	From a different organism.
Mapk1	P63085	2	EBI-373586,EBI-397697	From a different organism.
NIN	Q8N4C6	2	EBI-373586,EBI-1164022
RELB	Q01201	4	EBI-373586,EBI-357837
SNAI1	O95863	4	EBI-373586,EBI-1045459
TRIM29	Q14134	2	EBI-373586,EBI-702370
YWHAZ	P63104	4	EBI-373586,EBI-347088
ZFPM1	Q8IX07	2	EBI-373586,EBI-3942619

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P49841-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: P49841-2)

The sequence of this isoform differs from the canonical sequence as follows:
     303-303: K → KDSSGTGHFTSGVR

Note: No experimental confirmation available.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 420

420

Glycogen synthase kinase-3 beta

PRO_0000085980

Regions

Domain

56 – 340

285

Protein kinase

Nucleotide binding

62 – 70

9

ATP By similarity

Sites

Active site

181

1

Proton acceptor

Binding site

85

1

ATP By similarity

Amino acid modifications

Modified residue

7

1

Phosphothreonine By similarity

Modified residue

9

1

Phosphoserine; by PKB/AKT1, RPS6KA3 and SGK3 Ref.8 Ref.17 Ref.32

Modified residue

215

1

Phosphoserine By similarity

Modified residue

216

1

Phosphotyrosine Ref.43

Modified residue

219

1

Phosphoserine By similarity

Modified residue

389

1

Phosphoserine By similarity

Modified residue

390

1

Phosphothreonine Ref.26

Modified residue

395

1

Phosphothreonine By similarity

Modified residue

402

1

Phosphothreonine Ref.25

Natural variations

Alternative sequence

303

1

K → KDSSGTGHFTSGVR in isoform 2.

VSP_004790

Experimental info

Mutagenesis

9

1

S → A: Loss of phosphorylation; No inhibition of activity and constitutively active. Ref.1

Mutagenesis

96

1

R → A: Prevents the phosphorylation of phosphate-primed glycogen synthase. Ref.16

Mutagenesis

128

1

L → A: Abolishes activity toward AXIN1. Ref.16

Sequence conflict

28

1

V → G in AAD48517. Ref.4

Sequence conflict

350

1

L → H in AAA66475. Ref.1

Secondary structure

1

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420

Helix Strand Turn

Details...

Beta strand

10 – 12

3

Beta strand

26 – 29

4

Beta strand

32 – 34

3

Beta strand

38 – 48

11

Beta strand

52 – 64

13

Beta strand

66 – 75

10

Turn

76 – 78

3

Beta strand

81 – 88

8

Beta strand

91 – 93

3

Helix

96 – 102

7

Beta strand

112 – 120

9

Turn

121 – 124

4

Beta strand

125 – 133

9

Beta strand

136 – 138

3

Helix

139 – 148

10

Helix

155 – 173

19

Turn

174 – 176

3

Helix

184 – 186

3

Beta strand

187 – 190

4

Turn

191 – 194

4

Beta strand

195 – 198

4

Beta strand

209 – 211

3

Helix

220 – 222

3

Helix

225 – 228

4

Helix

237 – 252

16

Helix

262 – 273

12

Helix

278 – 284

7

Helix

286 – 288

3

Beta strand

289 – 291

3

Helix

301 – 304

4

Helix

311 – 320

10

Helix

325 – 327

3

Helix

331 – 335

5

Helix

338 – 344

7

Beta strand

345 – 347

3

Helix

364 – 367

4

Helix

371 – 373

3

Helix

374 – 377

4

Turn

380 – 383

4

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified May 2, 2002. Version 2. Checksum: 4ACC24D00CDBB9C3	FASTA	420	46,744
	10 20 30 40 50 60 MSGRPRTTSF AESCKPVQQP SAFGSMKVSR DKDGSKVTTV VATPGQGPDR PQEVSYTDTK 70 80 90 100 110 120 VIGNGSFGVV YQAKLCDSGE LVAIKKVLQD KRFKNRELQI MRKLDHCNIV RLRYFFYSSG 130 140 150 160 170 180 EKKDEVYLNL VLDYVPETVY RVARHYSRAK QTLPVIYVKL YMYQLFRSLA YIHSFGICHR 190 200 210 220 230 240 DIKPQNLLLD PDTAVLKLCD FGSAKQLVRG EPNVSYICSR YYRAPELIFG ATDYTSSIDV 250 260 270 280 290 300 WSAGCVLAEL LLGQPIFPGD SGVDQLVEII KVLGTPTREQ IREMNPNYTE FKFPQIKAHP 310 320 330 340 350 360 WTKVFRPRTP PEAIALCSRL LEYTPTARLT PLEACAHSFF DELRDPNVKL PNGRDTPALF 370 380 390 400 410 420 NFTTQELSSN PPLATILIPP HARIQAAAST PTNATAASDA NTGDRGQTNN AASASASNST
	Isoform 2 [UniParc]. Checksum: 540F853E1603A080	FASTA	433	48,034
	10 20 30 40 50 60 MSGRPRTTSF AESCKPVQQP SAFGSMKVSR DKDGSKVTTV VATPGQGPDR PQEVSYTDTK 70 80 90 100 110 120 VIGNGSFGVV YQAKLCDSGE LVAIKKVLQD KRFKNRELQI MRKLDHCNIV RLRYFFYSSG 130 140 150 160 170 180 EKKDEVYLNL VLDYVPETVY RVARHYSRAK QTLPVIYVKL YMYQLFRSLA YIHSFGICHR 190 200 210 220 230 240 DIKPQNLLLD PDTAVLKLCD FGSAKQLVRG EPNVSYICSR YYRAPELIFG ATDYTSSIDV 250 260 270 280 290 300 WSAGCVLAEL LLGQPIFPGD SGVDQLVEII KVLGTPTREQ IREMNPNYTE FKFPQIKAHP 310 320 330 340 350 360 WTKDSSGTGH FTSGVRVFRP RTPPEAIALC SRLLEYTPTA RLTPLEACAH SFFDELRDPN 370 380 390 400 410 420 VKLPNGRDTP ALFNFTTQEL SSNPPLATIL IPPHARIQAA ASTPTNATAA SDANTGDRGQ 430 TNNAASASAS NST

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Mitogen inactivation of glycogen synthase kinase-3 beta in intact cells via serine 9 phosphorylation." Stambolic V., Woodgett J.R. Biochem. J. 303:701-704(1994) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), MUTAGENESIS OF SER-9.
[2]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[3]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). Tissue: Eye and Placenta.
[4]	"Molecular cloning and characterization of the human glycogen synthase kinase-3beta promoter." Lau K.F., Miller C.C.J., Anderton B.H., Shaw P.C. Genomics 60:121-128(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-28.
[5]	"Radiation hybrid mapping of genes in the lithium-sensitive wnt signaling pathway." Rhoads A.R., Karkera J.D., Detera-Wadleigh S.D. Mol. Psychiatry 4:437-442(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 185-202.
[6]	"Activation of protein kinase C decreases phosphorylation of c-Jun at sites that negatively regulate its DNA-binding activity." Boyle W.J., Smeal T., Defize L.H., Angel P., Woodgett J.R., Karin M., Hunter T. Cell 64:573-584(1991) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF JUN.
[7]	"Glycogen synthase kinase-3 is rapidly inactivated in response to insulin and phosphorylates eukaryotic initiation factor eIF-2B." Welsh G.I., Proud C.G. Biochem. J. 294:625-629(1993) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF EIF2BE/EIF2B5.
[8]	"Inactivation of glycogen synthase kinase-3 beta by phosphorylation: new kinase connections in insulin and growth-factor signalling." Sutherland C., Leighton I.A., Cohen P. Biochem. J. 296:15-19(1993) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT SER-9.
[9]	"Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B." Cross D.A., Alessi D.R., Cohen P., Andjelkovich M., Hemmings B.A. Nature 378:785-789(1995) [PubMed] [Europe PMC] [Abstract] Cited for: ENZYME REGULATION BY AKT1.
[10]	"Nuclear export of NF-ATc enhanced by glycogen synthase kinase-3." Beals C.R., Sheridan C.M., Turck C.W., Gardner P., Crabtree G.R. Science 275:1930-1934(1997) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF NFATC1/NFATC.
[11]	"Human dynamin-like protein interacts with the glycogen synthase kinase 3beta." Hong Y.-R., Chen C.-H., Cheng D.-S., Howng S.-L., Chow C.-C. Biochem. Biophys. Res. Commun. 249:697-703(1998) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH DNM1L. Tissue: Liver.
[12]	"Interaction of glycogen synthase kinase 3beta with the DF3/MUC1 carcinoma-associated antigen and beta-catenin." Li Y., Bharti A., Chen D., Gong J., Kufe D. Mol. Cell. Biol. 18:7216-7224(1998) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH MUC1, FUNCTION.
[13]	"Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase." Delcommenne M., Tan C., Gray V., Rue L., Woodgett J.R., Dedhar S. Proc. Natl. Acad. Sci. U.S.A. 95:11211-11216(1998) [PubMed] [Europe PMC] [Abstract] Cited for: CHARACTERIZATION.
[14]	"Cloning and characterization of a novel human ninein protein that interacts with the glycogen synthase kinase 3beta." Hong Y.-R., Chen C.-H., Chang J.-H., Wang S.-K., Sy W.-D., Chou C.-K., Howng S.-L. Biochim. Biophys. Acta 1492:513-516(2000) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH NIN.
[15]	"Potential role of glycogen synthase kinase-3 in skeletal muscle insulin resistance of type 2 diabetes." Nikoulina S.E., Ciaraldi T.P., Mudaliar S., Mohideen P., Carter L., Henry R.R. Diabetes 49:263-271(2000) [PubMed] [Europe PMC] [Abstract] Cited for: ASSOCIATION WITH DIABETES MELLITUS.
[16]	"A common phosphate binding site explains the unique substrate specificity of GSK3 and its inactivation by phosphorylation." Frame S., Cohen P., Biondi R.M. Mol. Cell 7:1321-1327(2001) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, MUTAGENESIS OF ARG-96 AND LEU-128.
[17]	"Human serum and glucocorticoid-inducible kinase-like kinase (SGKL) phosphorylates glycogen syntheses kinase 3 beta (GSK-3beta) at serine-9 through direct interaction." Dai F., Yu L., He H., Chen Y., Yu J., Yang Y., Xu Y., Ling W., Zhao S. Biochem. Biophys. Res. Commun. 293:1191-1196(2002) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT SER-9 BY SGK3, INTERACTION WITH SGK3.
[18]	"Primed phosphorylation of tau at Thr231 by glycogen synthase kinase 3beta (GSK3beta) plays a critical role in regulating tau's ability to bind and stabilize microtubules." Cho J.H., Johnson G.V. J. Neurochem. 88:349-358(2004) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF MAPT/TAU.
[19]	"Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition." Zhou B.P., Deng J., Xia W., Xu J., Li Y.M., Gunduz M., Hung M.C. Nat. Cell Biol. 6:931-940(2004) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH SNAI1, SUBCELLULAR LOCATION.
[20]	"Characterization of two non-testis-specific CABYR variants that bind to GSK3beta with a proline-rich extensin-like domain." Hsu H.-C., Lee Y.-L., Cheng T.-S., Howng S.-L., Chang L.-K., Lu P.-J., Hong Y.-R. Biochem. Biophys. Res. Commun. 329:1108-1117(2005) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH CABYR.
[21]	"Wnt-dependent regulation of the E-cadherin repressor snail." Yook J.I., Li X.Y., Ota I., Fearon E.R., Weiss S.J. J. Biol. Chem. 280:11740-11748(2005) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH SNAI1.
[22]	"Glycogen synthase kinase 3 and h-prune regulate cell migration by modulating focal adhesions." Kobayashi T., Hino S., Oue N., Asahara T., Zollo M., Yasui W., Kikuchi A. Mol. Cell. Biol. 26:898-911(2006) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH PRUNE.
[23]	"Protein phosphatase 1 regulates assembly and function of the beta-catenin degradation complex." Luo W., Peterson A., Garcia B.A., Coombs G., Kofahl B., Heinrich R., Shabanowitz J., Hunt D.F., Yost H.J., Virshup D.M. EMBO J. 26:1511-1521(2007) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH AXIN1.
[24]	"Importance of autophosphorylation at Ser186 in the A-loop of salt inducible kinase 1 for its sustained kinase activity." Hashimoto Y.K., Satoh T., Okamoto M., Takemori H. J. Cell. Biochem. 104:1724-1739(2008) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF SIK1.
[25]	"Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle." Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M. Mol. Cell 31:438-448(2008) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-402, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[26]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-390, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[27]	"Glycogen synthase kinase-3beta is activated by matrix metalloproteinase-2 mediated proteolysis in cardiomyoblasts." Kandasamy A.D., Schulz R. Cardiovasc. Res. 83:698-706(2009) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH MMP2.
[28]	"Large-scale proteomics analysis of the human kinome." Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., Mann M., Daub H. Mol. Cell. Proteomics 8:1751-1764(2009) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[29]	"Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions." Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K. Sci. Signal. 2:RA46-RA46(2009) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. Tissue: Leukemic T-cell.
[30]	"Phosphorylation-dependent regulation of PSF by GSK3 controls CD45 alternative splicing." Heyd F., Lynch K.W. Mol. Cell 40:126-137(2010) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[31]	"Role of DAB2IP in modulating epithelial-to-mesenchymal transition and prostate cancer metastasis." Xie D., Gore C., Liu J., Pong R.C., Mason R., Hao G., Long M., Kabbani W., Yu L., Zhang H., Chen H., Sun X., Boothman D.A., Min W., Hsieh J.T. Proc. Natl. Acad. Sci. U.S.A. 107:2485-2490(2010) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH DAB2IP AND PPP2CA.
[32]	"ErbB2 receptor controls microtubule capture by recruiting ACF7 to the plasma membrane of migrating cells." Zaoui K., Benseddik K., Daou P., Salaun D., Badache A. Proc. Natl. Acad. Sci. U.S.A. 107:18517-18522(2010) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-9.
[33]	"Glycogen synthase kinase-3: properties, functions, and regulation." Ali A., Hoeflich K.P., Woodgett J.R. Chem. Rev. 101:2527-2540(2001) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON FUNCTION AND ENZYME REGULATION.
[34]	"The role of GSK3 in glucose homeostasis and the development of insulin resistance." Lee J., Kim M.S. Diabetes Res. Clin. Pract. 77:S49-S57(2007) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON FUNCTION.
[35]	"Glycogen synthase kinase 3: more than a namesake." Rayasam G.V., Tulasi V.K., Sodhi R., Davis J.A., Ray A. Br. J. Pharmacol. 156:885-898(2009) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON FUNCTION AND ENZYME REGULATION.
[36]	"Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis." Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M. Sci. Signal. 3:RA3-RA3(2010) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. Tissue: Cervix carcinoma.
[37]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[38]	"Modulation of tau phosphorylation by the kinase PKR: implications in Alzheimer's disease." Bose A., Mouton-Liger F., Paquet C., Mazot P., Vigny M., Gray F., Hugon J. Brain Pathol. 21:189-200(2011) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION, TISSUE SPECIFICITY, PHOSPHORYLATION.
[39]	"Glycogen synthase kinase 3? (GSK3?) modulates antiviral activity of zinc-finger antiviral protein (ZAP)." Sun L., Lv F., Guo X., Gao G. J. Biol. Chem. 287:22882-22888(2012) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[40]	"ARTD10 substrate identification on protein microarrays: regulation of GSK3beta by mono-ADP-ribosylation." Feijs K.L., Kleine H., Braczynski A., Forst A.H., Herzog N., Verheugd P., Linzen U., Kremmer E., Luscher B. Cell Commun. Signal. 11:5-5(2013) [PubMed] [Europe PMC] [Abstract] Cited for: ADP-RIBOSYLATION BY PARP10.
[41]	"Crystal structure of glycogen synthase kinase 3 beta: structural basis for phosphate-primed substrate specificity and autoinhibition." Dajani R., Fraser E., Roe S.M., Young N., Good V., Dale T.C., Pearl L.H. Cell 105:721-732(2001) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 35-386.
[42]	"The structure of phosphorylated GSK-3beta complexed with a peptide, FRATtide, that inhibits beta-catenin phosphorylation." Bax B., Carter P.S., Lewis C., Guy A.R., Bridges A., Tanner R., Pettman G., Mannix C., Culbert A.A., Brown M.J.B., Smith D.G., Reith A.D. Structure 9:1143-1152(2001) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 27-393 OF PHOSPHORYLATED GSK3B.
[43]	"Structural basis for recruitment of glycogen synthase kinase 3beta to the axin-APC scaffold complex." Dajani R., Fraser E., Roe S.M., Yeo M., Good V.M., Thompson V., Dale T.C., Pearl L.H. EMBO J. 22:494-501(2003) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 35-384 IN COMPLEX WITH AXIN1, INTERACTION WITH AXIN1 AND FRAT1, FUNCTION, ENZYME REGULATION, PHOSPHORYLATION AT TYR-216.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

L33801 mRNA. Translation: AAA66475.1.
CH471052 Genomic DNA. Translation: EAW79533.1.
CH471052 Genomic DNA. Translation: EAW79536.1.
BC000251 mRNA. Translation: AAH00251.1.
BC012760 mRNA. Translation: AAH12760.1.
AF074333 Genomic DNA. Translation: AAD48517.1.
AF098789 Genomic DNA. Translation: AAC69340.1.

IPI

IPI00028570.
IPI00216190.

PIR

S53324.

RefSeq

NP_001139628.1. NM_001146156.1.
NP_002084.2. NM_002093.3.

UniGene

Hs.445733.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1GNG	X-ray	2.60	A/B	27-393	[»]
1H8F	X-ray	2.80	A/B	35-386	[»]
1I09	X-ray	2.70	A/B	1-420	[»]
1J1B	X-ray	1.80	A/B	1-420	[»]
1J1C	X-ray	2.10	A/B	1-420	[»]
1O9U	X-ray	2.40	A	35-384	[»]
1PYX	X-ray	2.40	A/B	1-420	[»]
1Q3D	X-ray	2.20	A/B	2-420	[»]
1Q3W	X-ray	2.30	A/B	2-420	[»]
1Q41	X-ray	2.10	A/B	2-420	[»]
1Q4L	X-ray	2.77	A/B	2-420	[»]
1Q5K	X-ray	1.94	A/B	7-420	[»]
1R0E	X-ray	2.25	A/B	35-420	[»]
1UV5	X-ray	2.80	A	35-384	[»]
2JDO	X-ray	1.80	C	3-12	[»]
2JDR	X-ray	2.30	C	3-12	[»]
2JLD	X-ray	2.35	A/B	1-420	[»]
2O5K	X-ray	3.20	A	29-393	[»]
2OW3	X-ray	2.80	A/B	35-386	[»]
2UW9	X-ray	2.10	C	3-12	[»]
2X39	X-ray	1.93	C	3-12	[»]
2XH5	X-ray	2.72	C	3-12	[»]
3CQU	X-ray	2.20	C	3-12	[»]
3CQW	X-ray	2.00	C	3-12	[»]
3DU8	X-ray	2.20	A/B	1-420	[»]
3E87	X-ray	2.30	C/D	3-12	[»]
3E88	X-ray	2.50	C/D	3-12	[»]
3E8D	X-ray	2.70	C/D	3-12	[»]
3F7Z	X-ray	2.40	A/B	35-383	[»]
3F88	X-ray	2.60	A/B	35-383	[»]
3GB2	X-ray	2.40	A	34-383	[»]
3I4B	X-ray	2.30	A/B	7-420	[»]
3L1S	X-ray	2.90	A/B	7-420	[»]
3M1S	X-ray	3.13	A/B	1-420	[»]
3PUP	X-ray	2.99	A/B	1-420	[»]
3Q3B	X-ray	2.70	A/B	2-420	[»]
3SAY	X-ray	2.23	A/B	1-420	[»]
3SD0	X-ray	2.70	A/B	35-384	[»]
3ZDI	X-ray	2.64	A	35-384	[»]
3ZRK	X-ray	2.37	A/B	23-393	[»]
3ZRL	X-ray	2.48	A/B	23-393	[»]
3ZRM	X-ray	2.49	A/B	23-393	[»]
4ACC	X-ray	2.21	A/B	1-420	[»]
4ACD	X-ray	2.60	A/B	1-420	[»]
4ACG	X-ray	2.60	A/B	1-420	[»]
4ACH	X-ray	2.60	A/B	1-420	[»]
4AFJ	X-ray	1.98	A/B	27-393	[»]
4B7T	X-ray	2.77	A	35-384	[»]
4DIT	X-ray	2.60	A	27-394	[»]
4EKK	X-ray	2.80	C/D	3-12	[»]
4J1R	X-ray	2.70	A/B/C/D	1-420	[»]
4J71	X-ray	2.31	A/B	1-420	[»]

DisProt

DP00385.

ProteinModelPortal

P49841.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-878N.

IntAct

P49841. 55 interactions.

MINT

MINT-105006.

STRING

9606.ENSP00000324806.

PTM databases

PhosphoSite

P49841.

Polymorphism databases

DMDM

20455502.

Proteomic databases

PaxDb

P49841.

PRIDE

P49841.

Protocols and materials databases

DNASU

2932.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000264235; ENSP00000264235; ENSG00000082701.
ENST00000316626; ENSP00000324806; ENSG00000082701.

GeneID

2932.

KEGG

hsa:2932.

UCSC

uc003edn.3. human.
uc003edo.3. human.

Organism-specific databases

CTD

2932.

GeneCards

GC03M119540.

HGNC

HGNC:4617. GSK3B.

HPA

CAB016263.
HPA028017.

MIM

605004. gene.

neXtProt

NX_P49841.

PharmGKB

PA29009.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0515.

HOGENOM

HOG000233017.

HOVERGEN

HBG014652.

KO

K03083.

OMA

PSLFNFT.

OrthoDB

EOG4WH8KZ.

Enzyme and pathway databases

BRENDA

2.7.11.26. 2681.

Pathway_Interaction_DB

aurora_a_pathway. Aurora A signaling.
bmppathway. BMP receptor signaling.
wnt_canonical_pathway. Canonical Wnt signaling pathway.
pi3kciaktpathway. Class I PI3K signaling events mediated by Akt.
hedgehog_glipathway. Hedgehog signaling events mediated by Gli proteins.
insulin_glucose_pathway. Insulin-mediated glucose transport.
lysophospholipid_pathway. LPA receptor mediated events.
ps1pathway. Presenilin action in Notch and Wnt signaling.
reelinpathway. Reelin signaling pathway.
ar_tf_pathway. Regulation of Androgen receptor activity.
nfat_3pathway. Role of Calcineurin-dependent NFAT signaling in lymphocytes.
kitpathway. Signaling events mediated by Stem cell factor receptor (c-Kit).
pi3kplctrkpathway. Trk receptor signaling mediated by PI3K and PLC-gamma.

Reactome

REACT_111045. Developmental Biology.
REACT_111102. Signal Transduction.
REACT_116125. Disease.
REACT_6900. Immune System.

SignaLink

P49841.

Gene expression databases

ArrayExpress

P49841.

Bgee

P49841.

CleanEx

HS_GSK3B.

Genevestigator

P49841.

GermOnline

ENSG00000082701. Homo sapiens.

Family and domain databases

InterPro

IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_cat_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR002290. Ser/Thr_dual-sp_kinase_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]

Pfam

PF00069. Pkinase. 1 hit.
[Graphical view]

SMART

SM00220. S_TKc. 1 hit.
[Graphical view]

SUPFAM

SSF56112. Kinase_like. 1 hit.

PROSITE

PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

P49841.

ChEMBL

CHEMBL262.

ChiTaRS

GSK3B. human.

DrugBank

DB01356. Lithium.

EvolutionaryTrace

P49841.

GenomeRNAi

2932.

NextBio

11619.

SOURCE

Search...

Entry information

Entry name

GSK3B_HUMAN

Accession

Primary (citable) accession number: P49841
Secondary accession number(s): D3DN89, Q9BWH3, Q9UL47

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1996
Last sequence update:	May 2, 2002
Last modified:	May 29, 2013
This is version 169 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.