GSK-3
Glycogen synthase kinase 3 is a serine/threonine protein kinase that mediates the addition of phosphate molecules onto serine and threonine amino acid residues. First discovered in 1980 as a regulatory kinase for its namesake, Glycogen synthase, GSK-3 has since been identified as a kinase for over forty different proteins in a variety of different pathways. In mammals GSK-3 is encoded by two known genes, GSK-3 alpha (GSK3A) and GSK-3 beta (GSK3B).
GSK-3 has recently been the subject of much research because it has been implicated in a number of diseases, including Type II diabetes (Diabetes mellitus type 2), Alzheimer's Disease, inflammation, cancer, and bipolar disorder.

# Mechanism
GSK-3 functions by phosphorylating a serine or threonine residue on its target substrate. A positively charged pocket adjacent to the active site binds a "priming" phosphate group attached to a serine or threonine four residues C-terminal of the target phosphorylation site. The active site, at residues 181, 200, 97, and 85, binds the terminal phosphate of ATP and transfers it to the target location on the substrate (see figure 1).

# Function
Phosphorylation of a protein by GSK-3 usually inhibits the activity of its downstream target.  GSK-3 is active in a number of central intracellular signaling pathways, including cellular proliferation, migration, glucose regulation, and apoptosis.
GSK-3 was originally discovered in the context of its involvement in regulating glycogen synthase. After being primed by casein kinase 2 (CK2), glycogen synthase gets phosphorylated at a cluster of three C-terminal serine residues, reducing its activity. In addition to its role in regulating glycogen synthase, GSK-3 has been implicated in other aspects of glucose homeostasis, including the phosphorylation of insulin receptor IRS1  and of the gluconeogenic enzymes phosphoenolpyruvate carboxykinase and glucose 6 phosphatase. However, these interactions have not been confirmed, as these pathways can be inhibited without the up-regulation of GSK-3.
GSK-3 has also been shown to regulate immune and migratory processes. GSK-3 participates in a number of signaling pathways in the innate immune response, including pro-inflammatory cytokine and interleukin production. The inactivation of GSK3B by various protein kinases also affects the adaptive immune response by inducing cytokine production and proliferation in naive and memory CD4+ T cells. In cellular migration, an integral aspect of inflammatory responses, the inhibition of GSK-3 has been reported to play conflicting roles, as local inhibition at growth cones has been shown to promote motility while global inhibition of cellular GSK-3 has been shown to inhibit cell spreading and migration.
GSK-3 is also integrally tied to pathways of cell proliferation and apoptosis. GSK-3 has been shown to phosphorylate Beta-catenin, thus targeting it for degradation. GSK-3 is therefore a part of the canonical Beta-catenin/Wnt pathway, which signals the cell to divide and proliferate. GSK-3 also participates in a number of apoptotic signaling pathways by phosphorylating transcription factors that regulate apoptosis. GSK-3 can promote apoptosis by both activating pro-apoptotic factors such as p53  and inactivating survival-promoting factors through phosphorylation. The role of GSK-3 in regulating apoptosis is controversial, however, as some studies have shown that GSK-3 knockout mice are overly sensitized to apoptosis and die in the embryonic stage, while others have shown that overexpression of GSK-3 can induce apoptosis. Overall, GSK-3 appears to both promote and inhibit apoptosis, and this regulation varies depending on the specific molecular and cellular context.

# Regulation
Due to its importance across numerous cellular functions, GSK-3 activity is subject to tight regulation.
The speed and efficacy of GSK-3 phosphorylation is regulated by a number of factors. Phosphorylation of certain GSK-3 residues can increase or decrease its ability to bind substrate. Phosphorylation at tyrosine-216 in GSK-3 or tyrosine-279 in GSK-3 enhances the enzymatic activity of GSK-3, while phosphorylation of serine-9 in GSK-3 or serine-21 in GSK-3 significantly decreases active site availability (see Figure 1). Further, GSK-3 is unusual among kinases in that it usually requires a "priming kinase" to first phosphorylate a substrate. A phosphorylated serine or threonine residue located four amino acids C-terminal to the target site of phosphorylation allows the substrate to bind a pocket of positive charge formed by arginine and lysine residues.
Depending on the pathway in which it is being utilized, GSK-3 may be further regulated by cellular localization or the formation of protein complexes. The activity of GSK-3 is far greater in the nucleus and mitochondria than in the cytosol in cortical neurons, while the phosphorylation of Beta-catenin by GSK-3 is mediated by the binding of both proteins to Axin, a scaffold protein, allowing Beta-catenin to access the active site of GSK-3.

# Disease relevance
Due to its involvement in a great number of signaling pathways, GSK-3 has been associated with a host of high-profile diseases. GSK-3 inhibitors are currently being tested for therapeutic effects in Alzheimer's disease, type 2 diabetes mellitus (T2DM), some forms of cancer, and bipolar disorder.
It has now been shown that lithium, which is used as a treatment for bipolar disorder, acts as a mood stabilizer by selectively inhibiting GSK-3. The mechanism through which GSK-3 inhibition stabilizes mood is not known, though it is suspected that the inhibition of GSK-3's ability to promote inflammation contributes to the therapeutic effect. Inhibition of GSK-3 also destabilises Rev-ErbA alpha transcriptional repressor, which has a significant role in the circadian clock. Elements of the circadian clock may be connected with predisposition to bipolar mood disorder.
GSK-3 activity has been associated with both pathological features of Alzheimer's disease, namely the buildup of amyloid- (A) deposits and the formation of neurofibrillary tangles. GSK-3 is thought to directly promote A production and to be tied to the process of the hyperphosphorylation of tau proteins, which leads to the tangles. Due to these roles of GSK-3 in promoting Alzheimer's disease, GSK-3 inhibitors may have positive therapeutic effects on Alzheimer's patients and are currently in the early stages of testing.
In a similar fashion, targeted inhibition of GSK-3 may have therapeutic effects on certain kinds of cancer. Though GSK-3 has been shown to promote apoptosis in some cases, it has also been reported to be a key factor in tumorigenesis in some cancers. Supporting this claim, GSK-3 inhibitors have been shown to induce apoptosis in glioma and pancreatic cancer cells.
GSK-3 inhibitors have also shown promise in the treatment of T2DM. Though GSK-3 activity under diabetic conditions can differ radically across different tissue types, studies have shown that introducing competitive inhibitors of GSK-3 can increase glucose tolerance in diabetic mice. GSK-3 inhibitors may also have therapeutic effects on hemorrhagic transformation after acute ischemic stroke. The role that inhibition of GSK-3 might play across its other signaling roles is not yet entirely understood.
GSK-3 inhibition also mediates an increase in the transcription of the transcription factor Tbet (Tbx21) and an inhibition of the transcription of the inhibitory co-receptor programmed cell death-1 (PD-1) on T-cells.  GSK-3 inhibitors increased in vivo CD8(+) OT-I CTL function and the clearance of viral infections by murine gamma-herpesvirus 68 and lymphocytic choriomeningitis clone 13 as well as anti-PD-1 in immunotherapy.

# Inhibitors
Inhibitors of GSK-3 include:

## Metal cations
- Beryllium
- Copper
- Lithium (IC50=2mM)
- Mercury
- Tungsten (Indirect)

## ATP-competitive

### Marine organism-derived
- 6-BIO (IC50=1.5M)
- Dibromocantharelline (IC50=3M)
- Hymenialdesine (IC50=10nM)
- Indirubin (IC50=5-50nM)
- Meridianin

### Aminopyrimidines
IC50=0.6-7nM:
- CT98014
- CT98023
- CT99021
- TWS119

### Arylindolemaleimide
- SB-216763 (IC50=34nM)
- SB-41528 (IC50=77nM)

### Thiazoles
- AR-A014418 (IC50=104nM)
- AZD-1080

### Paullones
IC50=4-80nM:
- Alsterpaullone
- Cazpaullone
- Kenpaullone

### Aloisines
IC50=0.5-1.5M:

## Non-ATP competitive

### Marine organism-derived
- Manzamine A (IC50=1.5M)
- Palinurine (IC50=4.5M)
- Tricantine (IC50=7.5M)

### Thiadiazolidindiones
- TDZD-8 (IC50=2M)
- NP00111 (IC50=2M)
- NP031115 (IC50=4M)
- Tideglusib

### Halomethylketones
- HMK-32 (IC50=1.5M)

### Peptides
- L803-mts (IC50=40M)
Other: Ketamine