The JAK-STAT signaling pathway is a chain of interactions between proteins in a cell, and is involved in processes such as immunity, cell division, cell death, and tumor formation. The pathway communicates information from chemical signals outside of a cell to the cell nucleus, resulting in the activation of genes through the process of transcription. There are three key parts of JAK-STAT signalling: Janus kinases (JAKs), signal transducer and activator of transcription proteins (STATs), and receptors (which bind the chemical signals). Disrupted JAK-STAT signalling may lead to a variety of diseases, such as skin conditions, cancers, and disorders affecting the immune system. The kinase domain is vital for JAK activity, since it allows JAKs to phosphorylate (add phosphate groups to) proteins.

There are seven STAT proteins: STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B and STAT6. STATs also have transcriptional activation domains (TAD), which are less conserved and are located at the C-terminus. In addition, STATs also contain: tyrosine activation, amino-terminal, linker, coiled-coil and DNA-binding domains.]]

The binding of various ligands, usually cytokines, such as interferons and interleukins, to cell-surface receptors, causes the receptors to dimerize, which brings the receptor-associated JAKs into close proximity. The JAKs then phosphorylate each other on tyrosine residues located in regions called activation loops, through a process called transphosphorylation, which increases the activity of their kinase domains. These activated STATs form hetero- or homodimers, where the SH2 domain of each STAT binds the phosphorylated tyrosine of the opposite STAT, and the dimer then translocates to the cell nucleus to induce transcription of target genes. The STAT dimer is then free in the nucleus.

Specific STATs appear to bind to specific importin proteins. For example, STAT3 proteins can enter the nucleus by binding to importin α3 and importin α6. On the other hand, STAT1 and STAT2 bind to importin α5. There is debate as to whether STAT1 is methylated on an arginine residue (at position 31), and what the function of this methylation could be.

  • Acetylation. STAT1, STAT2, STAT3, STAT5 and STAT6 have been shown to be acetylated. STAT1 may have an acetyl group attached to lysines at positions 410 and 413, and as a result, STAT1 can promote the transcription of apoptotic genes - triggering cell death. Adding acetyl groups to STAT6 is suggested to be essential for gene transcription in some forms of IL-4 signalling, but not all the amino acids which are acetylated on STAT6 are known. It is also required for the transcription of some target genes of the cytokines IL-6 and IFN- γ.

Recruitment of co-activators

Like many other transcription factors, STATs are capable of recruiting co-activators such as CBP and p300, and these co-activators increase the rate of transcription of target genes. these HATs add acetyl groups to lysine residues on proteins associated with DNA called histones. Adding acetyl groups removes the positive charge on lysine residues, and as a result there are weaker interactions between histones and DNA, making DNA more accessible to STATs and enabling an increase in the transcription of target genes.

Integration with other signalling pathways

400 px|thumb|alt=An example of the integration between JAK-STAT, MAPK/ERK and PI3K/AKT/mTOR signalling pathways. JAKs phosphorylate cytokine receptors which can bind a protein called Grb2, which activates MAPK signalling. MAPK can also phosphorylate STATs. Phosphorylated cytokine receptors can also be bound by PI3K proteins, which activates the PI3K pathway.| An example of the integration between JAK-STAT, MAPK/ERK and PI3K/AKT/mTOR signalling pathways. JAKs phosphorylate cytokine receptors which can bind a protein called Grb2. Grb2 then activates [[Son of Sevenless|SOS proteins which stimulate MAPK signalling. MAPK can also phosphorylate STATs. Phosphorylated cytokine receptors can also be bound by PI3K, which allows activation of AKT. ERK, STATs and Akt can then interact with other proteins. The receptor is not shown as a dimer, and only one side of the receptors are shown phosphorylated for simplification]]

JAK-STAT signalling is able to interconnect with other cell-signalling pathways, such as the PI3K/AKT/mTOR pathway. When JAKs are activated and phosphorylate tyrosine residues on receptors, proteins with SH2 domains (such as STATs) are able bind to the phosphotyrosines, and the proteins can carry out their function. Like STATs, the PI3K protein also has an SH2 domain, and therefore it is also able to bind to these phosphorylated receptors.

One example of JAK-STAT signalling integrating with other pathways is Interleukin-2 (IL-2) receptor signaling in T cells. IL-2 receptors have γ (gamma) chains, which are associated with JAK3, which then phosphorylates key tyrosines on the tail of the receptor. Phosphorylation then recruits an adaptor protein called Shc, which activates the MAPK/ERK pathway, and this facilitates gene regulation by STAT5.

Role in cytokine receptor signalling

Given that many JAKs are associated with cytokine receptors, the JAK-STAT signalling pathway plays a major role in cytokine receptor signalling. Since cytokines are substances produced by immune cells that can alter the activity of neighbouring cells, the effects of JAK-STAT signalling are often more highly seen in cells of the immune system. For example, JAK3 activation in response to IL-2 is vital for lymphocyte development and function. Also, one study indicates that JAK1 is needed to carry out signalling for receptors of the cytokines IFNγ, IL-2, IL-4 and IL-10.

The JAK-STAT pathway in cytokine receptor signalling can activate STATs, which can bind to DNA and allow the transcription of genes involved in immune cell division, survival, activation and recruitment. For example, STAT1 can enable the transcription of genes which inhibit cell division and stimulate inflammation. In response to cytokines, such as IL-4, JAK-STAT signalling is also able to stimulate STAT6, which can promote B-cell proliferation, immune cell survival, and the production of an antibody called IgE. In some flies with faulty JAK genes, too much blood cell division can occur, potentially resulting in leukaemia. JAK-STAT signalling has also been associated with excessive white blood cell division in humans and mice. STAT binding sites have been identified on one of these genes, called even-skipped (eve), to support this theory. Of all the segment stripes affected by JAK or STAT mutations, the fifth stripe is affected the most, the exact molecular reasons behind this are still unknown. protein tyrosine phosphatases (PTPs) and suppressors of cytokine signalling (SOCS). Computational models of JAK-STAT signaling based on the laws of chemical kinetics have elucidated the importance of these different regulatory mechanisms on JAK-STAT signaling dynamics.

Protein inhibitors of activated STATs (PIAS)

400px|thumb|alt=Three ways PIAS proteins can inhibit JAK-STAT signalling. Adding a SUMO group to STATs can block their phosphorylation, which prevents STATs entering the nucleus. Histone deacetylase recruitment can remove acetyl groups on histones, lowering gene expression. PIAS can also prevent STATs binding to DNA.|Three ways PIAS proteins can inhibit JAK-STAT signaling. (A) Adding a [[SUMO protein|SUMO group to STATs can block their phosphorylation, which prevents STATs entering the nucleus. (B) HDAC (histone deacetylase) recruitment can remove acetyl modifications on histones, lowering gene expression. (C) PIAS can also prevent STATs binding to DNA]]

PIAS are a four-member protein family made of: PIAS1, PIAS3, PIASx, and PIASγ. The proteins add a marker, called SUMO (small ubiquitin-like modifier), onto other proteins – such as JAKs and STATs, modifying their function. Other studies have demonstrated that adding a SUMO group to STATs may block phosphorylation of tyrosines on STATs, preventing their dimerization and inhibiting JAK-STAT signalling. PIASγ has also been shown to prevent STAT1 from functioning. PIAS proteins may also function by preventing STATs from binding to DNA (and therefore preventing gene activation), and by recruiting proteins called histone deacetylases (HDACs), which lower the level of gene expression.

  • SHP-1. SHP-1 is mainly expressed in blood cells. It contains two SH2 domains and a catalytic domain (the region of a protein that carries out the main function of the protein) - the catalytic domain contains the amino acid sequence VHCSAGIGRTG (a sequence typical of PTPs). As with all PTPs, a number of amino acid structures are essential for their function: conserved cysteine, arginine and glutamine amino acids, and a loop made of tryptophan, proline and aspartate amino acids (WPD loop). The ability of SHP-1 to negatively regulate the JAK-STAT pathway has also been seen in experiments using mice lacking SHP-1. These mice experience characteristics of autoimmune diseases and show high levels of cell proliferation, which are typical characteristics of an abnormally high level of JAK-STAT signalling.

However, SHP-1 may also promote JAK-STAT signalling. A study in 1997 found that SHP-1 potentially allows higher amounts of STAT activation, as opposed to reducing STAT activity. A detailed molecular understanding for how SHP-1 can both activate and inhibit the signalling pathway is still unknown. Humans have two SHP-2 proteins, each made up of 593 and 597 amino acids. In a similar manner, SHP-2 has also been shown to reduce signalling involving STAT3 and STAT5 proteins, by removing phosphate groups.

Like SHP-1, SHP-2 is also believed to promote JAK-STAT signalling in some instances, as well as inhibit signalling. For example, one study indicates that SHP-2 may promote STAT5 activity instead of reducing it. Also, other studies propose that SHP-2 may increase JAK2 activity, and promote JAK2/STAT5 signalling. It is still unknown how SHP2 can both inhibit and promote JAK-STAT signalling in the JAK2/STAT5 pathway; one theory is that SHP-2 may promote activation of JAK2, but inhibit STAT5 by removing phosphate groups from it. whereas in mice, CD45 is capable of acting on all JAKs. One study indicates that CD45 can reduce the amount of time that JAK-STAT signalling is active. The SOCS box can interact with a number of proteins to form a protein complex, and this complex can then cause the breakdown of JAKs and the receptors themselves, therefore inhibiting JAK-STAT signalling. The proteins, such as JAKs and the receptors, are then transported to a compartment in the cell called the proteasome, which carries out protein breakdown. The exact details of how other SOCS function is less understood.

300px|thumb|alt=Psoriasis on a pair of hands. The disease can be caused by faulty JAK-STAT signalling. |Psoriasis on the hands can be caused by faulty JAK-STAT signalling.

JAK3 can be used for the signalling of IL-2, IL-4, IL-15 and IL-21 (as well as other cytokines); therefore patients with mutations in the JAK3 gene often experience issues affecting many aspects of the immune system. For example, non-functional JAK3 causes SCID, which results in patients having no NK cells, B cells or T cells, and this would make SCID individuals susceptible to infection.

It has been suggested that patients with mutations in STAT1 and STAT2 are often more likely to develop infections from bacteria and viruses. Also, STAT4 mutations have been associated with rheumatoid arthritis, and STAT6 mutations are linked to asthma.

Patients with a faulty JAK-STAT signalling pathway may also experience skin disorders. For example, non-functional cytokine receptors, and overexpression of STAT3 have both been associated with psoriasis (an autoimmune disease associated with red, flaky skin). Also, since many cytokines function through the STAT3 transcription factor, STAT3 plays a significant role in maintaining skin immunity. For example, too much STAT3 activity has been associated with increasing the likelihood of melanoma (skin cancer) returning after treatment and abnormally high levels of STAT5 activity have been linked to a greater probability of patient death from prostate cancer. High STAT3 activity plays a major role in this process, as it can allow the transcription of genes such as BCL2 and c-Myc, which are involved in cell division.

Covid-19

thumb|300x300px|[[Cytokine release syndrome|Cytokine release via activation of JAK/STAT signalling pathway following SARS-Cov-2 infection resulting in ARDS related to COVID-19.]]

The Janus kinase (JAK)/signal transducer and the activator of the transcription (STAT) pathway were at the centre of attention for driving hyperinflammation in COVID-19, i.e., the SARS-CoV-2 infection triggers hyperinflammation through the JAK/STAT pathway, resulting in the recruitment of dendritic cells, macrophages, and natural killer (NK) cells, as well as differentiation of B cells and T cells progressing towards cytokine storm.