GSK-3
Encyclopedia
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 synthase
Glycogen synthase
Glycogen synthase is an enzyme involved in converting glucose to glycogen. It takes short polymers of glucose and converts them into long polymers....

 and NFAT
NFAT
Nuclear 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 mammal
Mammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...

s GSK-3 is encoded by two known genes GSK-3 alpha
GSK3A
Glycogen 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 beta
GSK3B
Glycogen synthase kinase 3 beta, also known as GSK3B, is an enzyme that 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 synthase
Glycogen synthase
Glycogen synthase is an enzyme involved in converting glucose to glycogen. It takes short polymers of glucose and converts them into long polymers....

. It has also been implicated in the control of cellular response to damaged DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...

. GSK-3's homolog
Homology (biology)
Homology forms the basis of organization for comparative biology. In 1843, Richard Owen defined homology as "the same organ in different animals under every variety of form and function". Organs as different as a bat's wing, a seal's flipper, a cat's paw and a human hand have a common underlying...

 in the fruit fly Drosophila melanogaster
Drosophila melanogaster
Drosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally 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-catenin
Beta-catenin
Beta-catenin is a protein that in humans is encoded by the CTNNB1 gene. In Drosophila, the homologous protein is called armadillo...

. Phosphorylation leads to ubiquitin
Ubiquitin
Ubiquitin is a small regulatory protein that has been found in almost all tissues of eukaryotic organisms. Among other functions, it directs protein recycling.Ubiquitin can be attached to proteins and label them for destruction...

ation and degradation by cellular proteases, preventing it from entering the nucleus and activating transcription factors. When a protein called Dishevelled
Dishevelled
Dishevelled is a family of proteins involved in canonical and non-canonical Wnt signalling pathways. Dsh is a cytoplasmic phosphoprotein that acts directly downstream of frizzled receptors...

 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 synthase
Glycogen synthase
Glycogen synthase is an enzyme involved in converting glucose to glycogen. It takes short polymers of glucose and converts them into long polymers....

, 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 NFAT
NFAT
Nuclear 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 cannot 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 AKT
AKT
Akt, also known as Protein Kinase B , is a serine/threonine protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, cell proliferation, apoptosis, transcription and cell migration.-Family members:...

 phosphorylation, which is part of insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. 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....

 signal transduction
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...

. 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.

In experiments, it has been shown that certain concentrations of lithium chloride
Lithium chloride
Lithium 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 GSK3B
GSK3B
Glycogen synthase kinase 3 beta, also known as GSK3B, is an enzyme that 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 salts
Lithium pharmacology
Lithium 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, both acutely...

 for the treatment of mood disorders.

Furthermore, cytokine-dependent GSK-3 phosphorylation in hemopoietic cells may regulate growth, and the PKC family of kinases
Protein kinase C
Protein 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.
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