P49840 · GSK3A_HUMAN
- ProteinGlycogen synthase kinase-3 alpha
- GeneGSK3A
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids483 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
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), CTNNB1/beta-catenin, APC and AXIN1 (PubMed:11749387, PubMed:17478001, PubMed:19366350).
Requires primed phosphorylation of the majority of its substrates (PubMed:11749387, PubMed:17478001, PubMed:19366350).
Contributes to insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity and hence glycogen synthesis (PubMed:11749387, PubMed:17478001, PubMed:19366350).
Regulates glycogen metabolism in liver, but not in muscle (By similarity).
May also mediate the development of insulin resistance by regulating activation of transcription factors (PubMed:10868943, PubMed:17478001).
In Wnt signaling, regulates the level and transcriptional activity of nuclear CTNNB1/beta-catenin (PubMed:17229088).
Facilitates amyloid precursor protein (APP) processing and the generation of APP-derived amyloid plaques found in Alzheimer disease (PubMed:12761548).
May be involved in the regulation of replication in pancreatic beta-cells (By similarity).
Is necessary for the establishment of neuronal polarity and axon outgrowth (By similarity).
Through phosphorylation of the anti-apoptotic protein MCL1, may control cell apoptosis in response to growth factors deprivation (By similarity).
Acts as a regulator of autophagy by mediating phosphorylation of KAT5/TIP60 under starvation conditions which activates KAT5/TIP60 acetyltransferase activity and promotes acetylation of key autophagy regulators, such as ULK1 and RUBCNL/Pacer (PubMed:30704899).
Negatively regulates extrinsic apoptotic signaling pathway via death domain receptors. Promotes the formation of an anti-apoptotic complex, made of DDX3X, BRIC2 and GSK3B, at death receptors, including TNFRSF10B. The anti-apoptotic function is most effective with weak apoptotic signals and can be overcome by stronger stimulation (By similarity).
Phosphorylates mTORC2 complex component RICTOR at 'Thr-1695' which facilitates FBXW7-mediated ubiquitination and subsequent degradation of RICTOR (PubMed:25897075).
Requires primed phosphorylation of the majority of its substrates (PubMed:11749387, PubMed:17478001, PubMed:19366350).
Contributes to insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity and hence glycogen synthesis (PubMed:11749387, PubMed:17478001, PubMed:19366350).
Regulates glycogen metabolism in liver, but not in muscle (By similarity).
May also mediate the development of insulin resistance by regulating activation of transcription factors (PubMed:10868943, PubMed:17478001).
In Wnt signaling, regulates the level and transcriptional activity of nuclear CTNNB1/beta-catenin (PubMed:17229088).
Facilitates amyloid precursor protein (APP) processing and the generation of APP-derived amyloid plaques found in Alzheimer disease (PubMed:12761548).
May be involved in the regulation of replication in pancreatic beta-cells (By similarity).
Is necessary for the establishment of neuronal polarity and axon outgrowth (By similarity).
Through phosphorylation of the anti-apoptotic protein MCL1, may control cell apoptosis in response to growth factors deprivation (By similarity).
Acts as a regulator of autophagy by mediating phosphorylation of KAT5/TIP60 under starvation conditions which activates KAT5/TIP60 acetyltransferase activity and promotes acetylation of key autophagy regulators, such as ULK1 and RUBCNL/Pacer (PubMed:30704899).
Negatively regulates extrinsic apoptotic signaling pathway via death domain receptors. Promotes the formation of an anti-apoptotic complex, made of DDX3X, BRIC2 and GSK3B, at death receptors, including TNFRSF10B. The anti-apoptotic function is most effective with weak apoptotic signals and can be overcome by stronger stimulation (By similarity).
Phosphorylates mTORC2 complex component RICTOR at 'Thr-1695' which facilitates FBXW7-mediated ubiquitination and subsequent degradation of RICTOR (PubMed:25897075).
Miscellaneous
Higher expression and activity of GSK3A 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).
Several potent GSK3 (GSK3A and GSK3B) inhibitors have been identified and characterized in preclinical models for treatments of type 2 diabetes (PubMed:19366350).
Catalytic activity
- ATP + L-seryl-[tau protein] = ADP + H+ + O-phospho-L-seryl-[tau protein]
Activity regulation
Activated by phosphorylation at Tyr-279. In response to insulin, inhibited by phosphorylation at Ser-21 by PKB/AKT1; phosphorylation at this site causes a conformational change, preventing access of substrates to the active site. Inhibited by lithium.
Features
Showing features for binding site, active site.
GO annotations
Keywords
- Molecular function
- Biological process
- Ligand
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameGlycogen synthase kinase-3 alpha
- EC number
- Short namesGSK-3 alpha
- Alternative names
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionP49840
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
Disease & Variants
Features
Showing features for natural variant.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Natural variant | VAR_051625 | 109 | in dbSNP:rs35978177 | |||
Sequence: Q → E | ||||||
Natural variant | VAR_040539 | 461 | in dbSNP:rs35454502 | |||
Sequence: L → F |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 394 variants from UniProt as well as other sources including ClinVar and dbSNP.
Keywords
- Disease
Organism-specific databases
Miscellaneous
Chemistry
Genetic variation databases
PTM/Processing
Features
Showing features for initiator methionine, modified residue, modified residue (large scale data), chain.
Type | ID | Position(s) | Source | Description | |||
---|---|---|---|---|---|---|---|
Initiator methionine | 1 | UniProt | Removed | ||||
Sequence: M | |||||||
Modified residue | 2 | UniProt | N-acetylserine | ||||
Sequence: S | |||||||
Modified residue | 2 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 2 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Chain | PRO_0000085978 | 2-483 | UniProt | Glycogen synthase kinase-3 alpha | |||
Sequence: SGGGPSGGGPGGSGRARTSSFAEPGGGGGGGGGGPGGSASGPGGTGGGKASVGAMGGGVGASSSGGGPGGSGGGGSGGPGAGTSFPPPGVKLGRDSGKVTTVVATLGQGPERSQEVAYTDIKVIGNGSFGVVYQARLAETRELVAIKKVLQDKRFKNRELQIMRKLDHCNIVRLRYFFYSSGEKKDELYLNLVLEYVPETVYRVARHFTKAKLTIPILYVKVYMYQLFRSLAYIHSQGVCHRDIKPQNLLVDPDTAVLKLCDFGSAKQLVRGEPNVSYICSRYYRAPELIFGATDYTSSIDVWSAGCVLAELLLGQPIFPGDSGVDQLVEIIKVLGTPTREQIREMNPNYTEFKFPQIKAHPWTKVFKSRTPPEAIALCSSLLEYTPSSRLSPLEACAHSFFDELRCLGTQLPNNRPLPPLFNFSAGELSIQPSLNAILIPPHLRSPAGTTTLTPSSQALTETPTSSDWQSTDATPTLTNSS | |||||||
Modified residue (large scale data) | 7 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 14 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 19 | PRIDE | Phosphothreonine | ||||
Sequence: T | |||||||
Modified residue | 21 | UniProt | Phosphoserine; by PKB/AKT1 | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 21 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 39 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 41 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 72 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 72 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 77 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 77 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 97 | UniProt | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 278 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 279 | UniProt | Phosphotyrosine | ||||
Sequence: Y | |||||||
Modified residue (large scale data) | 279 | PRIDE | Phosphotyrosine | ||||
Sequence: Y | |||||||
Modified residue (large scale data) | 282 | PRIDE | Phosphoserine | ||||
Sequence: S |
Post-translational modification
Phosphorylated by AKT1 at Ser-21: upon insulin-mediated signaling, the activated PKB/AKT1 protein kinase phosphorylates and deactivates GSK3A, resulting in the dephosphorylation and activation of GYS1. Activated by phosphorylation at Tyr-279.
(Microbial infection) Dephosphorylated at Tyr-279 by M.tuberculosis PtpA, which leads to prevention of apoptosis during early stages of microbial infection.
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Interaction
Subunit
Monomer. Interacts with ARRB2 (By similarity).
Interacts with AXIN1 and CTNNB1/beta-catenin (PubMed:17229088).
Interacts with CTNND2 (PubMed:19706605).
Interacts with LMBR1L (PubMed:31073040).
Interacts with DDX3X (PubMed:18846110).
Interacts with TNFRSF10B (PubMed:18846110).
Interacts with RICTOR; the interaction results in phosphorylation of RICTOR at 'Thr-1695' by GSK3A which facilitates FBXW7-mediated ubiquitination and subsequent degradation of RICTOR (PubMed:25897075).
Interacts with AXIN1 and CTNNB1/beta-catenin (PubMed:17229088).
Interacts with CTNND2 (PubMed:19706605).
Interacts with LMBR1L (PubMed:31073040).
Interacts with DDX3X (PubMed:18846110).
Interacts with TNFRSF10B (PubMed:18846110).
Interacts with RICTOR; the interaction results in phosphorylation of RICTOR at 'Thr-1695' by GSK3A which facilitates FBXW7-mediated ubiquitination and subsequent degradation of RICTOR (PubMed:25897075).
(Microbial infection) Interacts with M.tuberculosis PtpA.
Binary interactions
Type | Entry 1 | Entry 2 | Number of experiments | Intact | |
---|---|---|---|---|---|
BINARY | P49840 | APP PRO_0000000093 P05067 | 3 | EBI-1044067, EBI-2431589 | |
BINARY | P49840 | AXIN1 O15169 | 6 | EBI-1044067, EBI-710484 | |
BINARY | P49840 | AXIN2 Q9Y2T1 | 4 | EBI-1044067, EBI-4400025 | |
BINARY | P49840 | DEAF1 O75398 | 3 | EBI-1044067, EBI-718185 | |
BINARY | P49840 | FBXO42 Q6P3S6 | 3 | EBI-1044067, EBI-2506081 | |
BINARY | P49840 | FRAT1 Q92837 | 5 | EBI-1044067, EBI-3934879 | |
BINARY | P49840 | GSKIP Q9P0R6 | 5 | EBI-1044067, EBI-1052580 | |
BINARY | P49840 | HSP90AB1 P08238 | 3 | EBI-1044067, EBI-352572 | |
BINARY | P49840 | HTT P42858 | 6 | EBI-1044067, EBI-466029 | |
BINARY | P49840 | LRP6 O75581 | 3 | EBI-1044067, EBI-910915 | |
BINARY | P49840 | MAPT P10636-8 | 2 | EBI-1044067, EBI-366233 | |
BINARY | P49840 | NBR1 Q14596 | 7 | EBI-1044067, EBI-742698 | |
BINARY | P49840 | YWHAE P62258 | 3 | EBI-1044067, EBI-356498 | |
BINARY | P49840 | ZDHHC17 Q8IUH5 | 3 | EBI-1044067, EBI-524753 |
Protein-protein interaction databases
Chemistry
Miscellaneous
Structure
Family & Domains
Features
Showing features for region, domain.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Region | 1-96 | Disordered | ||||
Sequence: MSGGGPSGGGPGGSGRARTSSFAEPGGGGGGGGGGPGGSASGPGGTGGGKASVGAMGGGVGASSSGGGPGGSGGGGSGGPGAGTSFPPPGVKLGRD | ||||||
Domain | 119-403 | Protein kinase | ||||
Sequence: YTDIKVIGNGSFGVVYQARLAETRELVAIKKVLQDKRFKNRELQIMRKLDHCNIVRLRYFFYSSGEKKDELYLNLVLEYVPETVYRVARHFTKAKLTIPILYVKVYMYQLFRSLAYIHSQGVCHRDIKPQNLLVDPDTAVLKLCDFGSAKQLVRGEPNVSYICSRYYRAPELIFGATDYTSSIDVWSAGCVLAELLLGQPIFPGDSGVDQLVEIIKVLGTPTREQIREMNPNYTEFKFPQIKAHPWTKVFKSRTPPEAIALCSSLLEYTPSSRLSPLEACAHSFF | ||||||
Region | 449-483 | Disordered | ||||
Sequence: AGTTTLTPSSQALTETPTSSDWQSTDATPTLTNSS |
Sequence similarities
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Length483
- Mass (Da)50,981
- Last updated2000-12-01 v2
- ChecksumF18C012C03B7D786
Computationally mapped potential isoform sequences
There are 35 potential isoforms mapped to this entry
Entry | Entry name | Gene name | Length | ||
---|---|---|---|---|---|
A8MT37 | A8MT37_HUMAN | GSK3A | 401 | ||
A0A7I2YQ76 | A0A7I2YQ76_HUMAN | GSK3A | 77 | ||
A0A7I2YQA1 | A0A7I2YQA1_HUMAN | GSK3A | 101 | ||
A0A7I2YQA9 | A0A7I2YQA9_HUMAN | GSK3A | 96 | ||
A0A7I2YQM8 | A0A7I2YQM8_HUMAN | GSK3A | 92 | ||
A0A7I2YQJ1 | A0A7I2YQJ1_HUMAN | GSK3A | 84 | ||
A0A7I2YQU7 | A0A7I2YQU7_HUMAN | GSK3A | 24 | ||
A0A7I2YQV9 | A0A7I2YQV9_HUMAN | GSK3A | 100 | ||
A0A7I2V2H8 | A0A7I2V2H8_HUMAN | GSK3A | 97 | ||
A0A7I2V2J2 | A0A7I2V2J2_HUMAN | GSK3A | 83 | ||
A0A7I2V2P8 | A0A7I2V2P8_HUMAN | GSK3A | 36 | ||
A0A7I2V2P9 | A0A7I2V2P9_HUMAN | GSK3A | 64 | ||
A0A7I2V2P0 | A0A7I2V2P0_HUMAN | GSK3A | 92 | ||
A0A7I2V2Q4 | A0A7I2V2Q4_HUMAN | GSK3A | 81 | ||
A0A7I2V341 | A0A7I2V341_HUMAN | GSK3A | 38 | ||
A0A7I2V345 | A0A7I2V345_HUMAN | GSK3A | 50 | ||
A0A7I2V379 | A0A7I2V379_HUMAN | GSK3A | 56 | ||
A0A7I2V3H9 | A0A7I2V3H9_HUMAN | GSK3A | 108 | ||
A0A7I2V3M8 | A0A7I2V3M8_HUMAN | GSK3A | 37 | ||
A0A7I2V442 | A0A7I2V442_HUMAN | GSK3A | 43 | ||
A0A7I2V418 | A0A7I2V418_HUMAN | GSK3A | 65 | ||
A0A7I2V3W5 | A0A7I2V3W5_HUMAN | GSK3A | 76 | ||
A0A7I2V485 | A0A7I2V485_HUMAN | GSK3A | 100 | ||
A0A7I2V4D4 | A0A7I2V4D4_HUMAN | GSK3A | 82 | ||
A0A7I2V553 | A0A7I2V553_HUMAN | GSK3A | 55 | ||
A0A7I2V4Q6 | A0A7I2V4Q6_HUMAN | GSK3A | 106 | ||
A0A7I2V511 | A0A7I2V511_HUMAN | GSK3A | 81 | ||
A0A7I2V4Y3 | A0A7I2V4Y3_HUMAN | GSK3A | 59 | ||
A0A7I2V4Z1 | A0A7I2V4Z1_HUMAN | GSK3A | 69 | ||
A0A7I2V5B3 | A0A7I2V5B3_HUMAN | GSK3A | 48 | ||
A0A7I2V5D7 | A0A7I2V5D7_HUMAN | GSK3A | 48 | ||
A0A7I2V5P6 | A0A7I2V5P6_HUMAN | GSK3A | 75 | ||
A0A7I2V5Q2 | A0A7I2V5Q2_HUMAN | GSK3A | 123 | ||
A0A7I2V5S8 | A0A7I2V5S8_HUMAN | GSK3A | 58 | ||
A0A7I2V627 | A0A7I2V627_HUMAN | GSK3A | 102 |
Features
Showing features for sequence conflict.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Sequence conflict | 449 | in Ref. 1; AAA62432 | ||||
Sequence: A → S |
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
L40027 EMBL· GenBank· DDBJ | AAA62432.1 EMBL· GenBank· DDBJ | mRNA | ||
D63424 EMBL· GenBank· DDBJ | BAA23608.1 EMBL· GenBank· DDBJ | mRNA | ||
AC006486 EMBL· GenBank· DDBJ | AAD11986.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
BC027984 EMBL· GenBank· DDBJ | AAH27984.1 EMBL· GenBank· DDBJ | mRNA | ||
BC051865 EMBL· GenBank· DDBJ | AAH51865.1 EMBL· GenBank· DDBJ | mRNA |