GSK-3

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 and NFAT; the target protein is also called the "substrate"). In mammals GSK-3 is encoded by two known genes GSK-3 alpha and beta.

Function
As mentioned, GSK-3 is known for phosphorylating and thus inactivating glycogen synthase. It has also been implicated in the control of cellular response to damaged DNA. GSK-3's homolog in the fruit fly Drosophila melanogaster 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. Phosphorylation leads to ubiquitination and degradation by cellular proteases, preventing it from entering the nucleus and activating transcription factors. When a protein called Dishevelled 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, 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 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 phosphorylation, which is part of insulin signal transduction. 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 (LiCl) and/or 6-bromoindirubin-3'-oxime (BIO) will inhibit GSK3B. in the Wnt signaling pathway. This inhibition of GSK-3 is currently believed to underlie the therapeutic usefulness of lithium salts for the treatment of mood disorders.

Furthermore, cytokine-dependent GSK-3 phosphorylation in hemopoietic cells may regulate growth, and the PKC family of kinases may play a key role in GSK-3 phosphorylation.