Glycogen synthase kinase 3 (
GSK-3) is a serine/threonine protein kinase, that mediates the addition of phosphate molecules on certain serine and threonine amino acids in particular cellular substrates. The phosphorylation of these other proteins by GSK-3 usually inhibits the target protein (as in the case of
glycogen synthaseGlycogen synthase is a glycosyltransferase enzyme that catalyses the reaction of UDP-glucose and n to yield UDP and n+1.In other words, this enzyme...
and
NFATNuclear factor of activated T-cells is a general name applied to a family of transcription factors shown to be important in immune response. One or more members of the NFAT family is expressed in most cells of the immune system...
; the target protein is also called the "substrate"). In
mammalMammals are a class of vertebrate animals whose females are characterized by the possession of mammary glands while both males and females are characterized by sweat glands, hair, three middle ear bones used in hearing, and a neocortex region in the brain.Mammals are divided into three main...
s GSK-3 is encoded by two known genes GSK-3
AlphaGlycogen synthase kinase-3 alpha is an enzyme that in humans is encoded by the GSK3A gene.Glycogen synthase kinase 3-alpha is a multifunctional protein serine kinase, homologous to Drosophila 'shaggy' and implicated in the control of several regulatory proteins including glycogen synthase and...
and
BetaGlycogen synthase kinase 3 beta, also known as GSK3B, is an enzyme which in humans is encoded by the GSK3B gene.- Function :Glycogen synthase kinase-3 is a proline-directed serine-threonine kinase that was initially identified as a phosphorylating and inactivating glycogen synthase. Two isoforms,...
.
As mentioned, GSK-3 is known for phosphorylating and thus inactivating
glycogen synthaseGlycogen synthase is a glycosyltransferase enzyme that catalyses the reaction of UDP-glucose and n to yield UDP and n+1.In other words, this enzyme...
.
Glycogen synthase kinase 3 (
GSK-3) is a serine/threonine protein kinase, that mediates the addition of phosphate molecules on certain serine and threonine amino acids in particular cellular substrates. The phosphorylation of these other proteins by GSK-3 usually inhibits the target protein (as in the case of
glycogen synthaseGlycogen synthase is a glycosyltransferase enzyme that catalyses the reaction of UDP-glucose and n to yield UDP and n+1.In other words, this enzyme...
and
NFATNuclear factor of activated T-cells is a general name applied to a family of transcription factors shown to be important in immune response. One or more members of the NFAT family is expressed in most cells of the immune system...
; the target protein is also called the "substrate"). In
mammalMammals are a class of vertebrate animals whose females are characterized by the possession of mammary glands while both males and females are characterized by sweat glands, hair, three middle ear bones used in hearing, and a neocortex region in the brain.Mammals are divided into three main...
s GSK-3 is encoded by two known genes GSK-3
AlphaGlycogen synthase kinase-3 alpha is an enzyme that in humans is encoded by the GSK3A gene.Glycogen synthase kinase 3-alpha is a multifunctional protein serine kinase, homologous to Drosophila 'shaggy' and implicated in the control of several regulatory proteins including glycogen synthase and...
and
BetaGlycogen synthase kinase 3 beta, also known as GSK3B, is an enzyme which in humans is encoded by the GSK3B gene.- Function :Glycogen synthase kinase-3 is a proline-directed serine-threonine kinase that was initially identified as a phosphorylating and inactivating glycogen synthase. Two isoforms,...
.
Function
As mentioned, GSK-3 is known for phosphorylating and thus inactivating
glycogen synthaseGlycogen synthase is a glycosyltransferase enzyme that catalyses the reaction of UDP-glucose and n to yield UDP and n+1.In other words, this enzyme...
. It has also been implicated in the control of cellular response to damaged
DNADeoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms and some viruses. The main role of DNA molecules is the long-term storage of information...
. GSK-3's
homologIn evolutionary biology, homology refers to any similarity between characteristics of organisms that is due to their shared ancestry. The word homologous derives from the ancient Greek ομολογειν, 'to agree'. There are examples in different branches of biology...
in the fruit fly
Drosophila melanogasterDrosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is commonly known as the common fruit fly or vinegar fly. Starting from Charles W...
is known as Shaggy (Zeste White 3). In
Drosophila and the frog
Xenopus laevis GSK-3 works in the Wnt signalling pathway to phosphorylate
β-cateninCatenins are proteins found in complexes with cadherin cell adhesion molecules of animal cells. The first two catenins that were identified became known as alpha-catenin and beta-catenin. Alpha-catenin can bind to beta-catenin and can also bind actin. Beta-catenin binds the cytoplasmic domain of...
. Phosphorylation leads to
ubiquitinUbiquitin is a small, highly-conserved regulatory protein that is ubiquitously expressed in eukaryotes. Ubiquitination refers to the post-translational modification of a protein by the covalent attachment of one or more ubiquitin monomers.The most prominent function of ubiquitin is labeling...
ation and degradation by cellular proteases, preventing it from entering the nucleus and activating transcription factors. When a protein called Disheveled is activated by Wnt signalling, GSK-3 is inactivated, allowing β-catenin to accumulate and effect transcription of Wnt target genes. GSK-3 also phosphorylates Ci in the Hedgehog (Hh) pathway, targeting it for proteolysis to an inactive form.
In addition to
glycogen synthaseGlycogen synthase is a glycosyltransferase enzyme that catalyses the reaction of UDP-glucose and n to yield UDP and n+1.In other words, this enzyme...
, GSK-3 has many other substrates. However, GSK-3 is unusual among the kinases in that it usually requires a "priming kinase" to first phosphorylate a substrate, and then, only when the priming kinase has done its job can GSK-3 additionally phosphorylate the substrate.
The consequence of GSK-3 phosphorylation is usually inhibition of the substrate. For example, when GSK-3 phosphorylates another of its substrates, the
NFATNuclear factor of activated T-cells is a general name applied to a family of transcription factors shown to be important in immune response. One or more members of the NFAT family is expressed in most cells of the immune system...
family of transcription factors, these transcription factors can not translocate to the nucleus and are therefore inhibited.
In addition to its important role in the Wnt signalling pathway, which is required for establishing tissue patterning during development, GSK-3 is also critical for the protein synthesis that is induced in settings such as skeletal muscle hypertrophy. Its roles as an NFAT kinase also places it as a key regulator of both differentiation and cellular proliferation.
GSK-3 inhibition
GSK-3 can be inhibited by
AKTAKT protein family, which members are also called protein kinases B plays an important role in mammalian cellular signaling.- Family members :In humans, there are three genes in the "Akt family": Akt1, Akt2, and Akt3...
phosphorylation, which is part of
insulinInsulin is a hormone that has extensive effects on metabolism and other body functions, such as vascular compliance. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle, and stopping use of fat as an energy...
signal transductionIn biology, signal transduction refers to any process by which a cell converts one kind of signal or stimulus into another. Most processes of signal transduction involve ordered sequences of biochemical reactions inside the cell, which are carried out by enzymes and activated by second messengers,...
. Therefore, Akt is an activator of many of the signaling pathways blocked by GSK-3. For example, in the setting of induced Akt signaling, it can be shown that NFAT is dephosphorylated.
Experimentally, it has been shown that certain concentrations of
lithium chlorideLithium chloride is a chemical compound with the formula LiCl. The salt is a typical ionic compound, although the small size of the Li+ ion gives rise to properties not seen for other alkali metal chlorides, such as extraordinary solubility in polar solvents and its hygroscopic...
(LiCl) and/or 6-bromoindirubin-3'-oxime (BIO) will inhibit
GSK3BGlycogen synthase kinase 3 beta, also known as GSK3B, is an enzyme which in humans is encoded by the GSK3B gene.- Function :Glycogen synthase kinase-3 is a proline-directed serine-threonine kinase that was initially identified as a phosphorylating and inactivating glycogen synthase. Two isoforms,...
. in the Wnt signaling pathway. This inhibition of GSK-3 is currently believed to underlie the therapeutic usefulness of
lithium saltsLithium pharmacology refers to use of the lithium ion, Li
+, as a drug. A number of chemical salts of lithium are used medically as a mood stabilizing drug, primarily in the treatment of bipolar disorder, where they have a role in the treatment of depression and particularly of mania,...
for the treatment of mood disorders.
Furthermore, cytokine-dependent GSK-3 phosphorylation in hemopoietic cells may regulate growth, and the
PKC family of kinasesProtein kinase C also known as PKC is a family of enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins. PKC enzymes in turn are activated by signals such as increases in...
may play a key role in GSK-3 phosphorylation.