Glycogen synthase kinase-3 alpha (GSK3A)
The protein contains 483 amino acids for an estimated molecular weight of 50981 Da.
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 (updated: May 8, 2019)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
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| Variant | Description |
|---|---|
| dbSNP:rs35978177 | |
| dbSNP:rs35454502 |
Biological Process
Aging
Cardiac left ventricle morphogenesis
Cell migration
Cellular protein metabolic process
Cellular response to insulin stimulus
Cellular response to interleukin-3
Cellular response to lithium ion
Cellular response to organic cyclic compound
Chemical synaptic transmission, postsynaptic
Dopamine receptor signaling pathway
Endoplasmic reticulum unfolded protein response
Epidermal growth factor receptor signaling pathway
Excitatory postsynaptic potential
Extrinsic apoptotic signaling pathway
Extrinsic apoptotic signaling pathway in absence of ligand
Fc-epsilon receptor signaling pathway
Fibroblast growth factor receptor signaling pathway
Glycogen metabolic process
Hypermethylation of CpG island
Innate immune response
Insulin receptor signaling pathway
IRE1-mediated unfolded protein response
Negative regulation of canonical Wnt signaling pathway
Negative regulation of cell growth involved in cardiac muscle cell development
Negative regulation of dendrite development
Negative regulation of glucose import
Negative regulation of glycogen (starch) synthase activity
Negative regulation of glycogen biosynthetic process
Negative regulation of glycogen synthase activity, transferring glucose-1-phosphate
Negative regulation of insulin receptor signaling pathway
Negative regulation of TOR signaling
Negative regulation of transferase activity
Negative regulation of type B pancreatic cell development
Negative regulation of UDP-glucose catabolic process
Nervous system development
Neurotrophin TRK receptor signaling pathway
Obsolete activation of signaling protein activity involved in unfolded protein response
Obsolete positive regulation of cAMP biosynthetic process
Peptidyl-serine phosphorylation
Peptidyl-threonine phosphorylation
Phosphatidylinositol-mediated signaling
Positive regulation of adenylate cyclase-activating adrenergic receptor signaling pathway
Positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway
Positive regulation of amyloid-beta formation
Positive regulation of autophagy
Positive regulation of gene expression
Positive regulation of glycogen (starch) synthase activity
Positive regulation of heart contraction
Positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway
Positive regulation of neuron apoptotic process
Positive regulation of peptidyl-serine phosphorylation
Positive regulation of peptidyl-threonine phosphorylation
Positive regulation of proteasomal ubiquitin-dependent protein catabolic process
Positive regulation of protein catabolic process
Positive regulation of protein targeting to mitochondrion
Positive regulation of protein ubiquitination
Positive regulation of transcription by RNA polymerase II
Proteasome-mediated ubiquitin-dependent protein catabolic process
Protein phosphorylation
Regulation of apoptotic process
Regulation of autophagy of mitochondrion
Regulation of gene expression by genetic imprinting
Regulation of neuron projection development
Regulation of systemic arterial blood pressure
Signal transduction
Wnt signaling pathway
The reference OMIM entry for this protein is 606784
Glycogen synthase kinase 3-alpha; gsk3a
DESCRIPTION
Glycogen synthase kinase 3-alpha (GSK3A; EC 2.7.1.37) is a multifunctional protein serine kinase homologous to Drosophila 'shaggy' (zeste-white3) that is implicated in the control of several regulatory proteins, including glycogen synthase (see GYS1, 138570) and transcription factors (e.g., JUN, 165160). It also plays a role in the WNT (164820) and PI3K (see PIK3CG, 601232) signaling pathways (see review by Ali et al. (2001)).CLONING
Woodgett (1990) cloned rat Gsk3a and Gsk3b (605004). The deduced 483-amino acid Gsk3a protein is 93% identical overall and 99% identical in the kinase catalytic domain to the human protein (GenBank GENBANK AAA62432). SDS-PAGE analysis showed expression of the 51-kD rat protein as predicted from the primary sequence. Northern blot analysis revealed wide expression of a 2.5-kb transcript in rat tissues. Western blot analysis, however, showed that expression is variable, suggesting differential modes of transcriptional and translational regulation.GENE FUNCTION
Hughes et al. (1993) showed that under resting conditions GSK3A and its homologs are highly phosphorylated at tyr279 in the phosphorylation loop. Constitutive phosphorylation of this tyrosine is important for kinase activity. Dephosphorylation of tyr279 after mitogen activation is accompanied by kinase inactivation. Fang et al. (2000) found that PKA (see 188830) as well as PI3K-activated PKB (AKT1; 164730) inactivate GSK3A by phosphorylation at ser21. Yost et al. (1998) characterized the GSK3 binding activities of FRAT1 (602503) and FRAT2 (605006), which inhibit the phosphorylation of CTNNB1 (116806) and positively regulate the WNT signaling pathway. Fang et al. (2002) demonstrated that lysophosphatidic acid primarily utilizes a PKC (see 176960)-dependent pathway to modulate GSK3 and that certain growth factors (e.g., PDGFB, 190040), which control GSK3 mainly through PIK3-PKB, are able to regulate GSK3 through an alternative, redundant phospholipase-C-gamma (see 600220)-PKC pathway. Alzheimer disease (AD; 104300) is associated with increased production and aggregation of amyloid-beta-40 and -42 peptides into plaques. Phiel et al. (2003) showed that GSK3A is required for maximal production of the beta-amyloid-40 and -42 peptides generated from the amyloid precursor protein (APP; 104760) by presenilin (PSEN1; 104311)-dependent gamma-secretase cleavage. In vitro, lithium, a GSK3A inhibitor, blocked the production of the beta-amyloid peptides by interfering with the gamma-secretase step. In mice expressing familial AD-associated mutations in APP and PSEN1, lithium reduced the levels of beta-amyloid peptides. Phiel et al. (2003) noted that GSK3A also phosphorylates the tau protein (MAPT; 157140), the principal component of neurofibrillary tangles in AD, and suggested that inhibition of GSK3A may offer a new therapeutic approach to AD. Maurer et al. (2006) found that Gsk3 phosphorylated mouse Mcl1 (159552) at a conserved GSK3 phosphorylation site, and this phosphorylation led to increased ubiquitylation and degradation of Mcl1. In mouse pre-B lymphocytic cells, Il3 (147740) withdrawal or Pi3 kinase inhibition induced phosphorylation of Mcl1, and Akt or inhibition of Gsk3 activity prevented Mcl1 phosphorylation. Mcl1 with a mutation of the phosphorylation site showed enhanced stability upon Il3 withdrawal and conferred increased resistance to apoptosis compared with wildtype Mcl1. Maurer et al. (2006) concluded th ... More on the omim web site
May 11, 2019: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated
June 20, 2017: Protein entry updated
Automatic update: comparative model was added.
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 606784 was added.