JAK-STAT signaling pathway

[1] Disrupted JAK-STAT signalling may lead to a variety of diseases, such as skin conditions, cancers, and disorders affecting the immune system.

[4] In addition, STATs also contain: tyrosine activation, amino-terminal, linker, coiled-coil and DNA-binding domains.

[6] The activated JAKs then phosphorylate tyrosine residues on the receptor, creating binding sites for proteins possessing SH2 domains.

[4] Studies indicate that STAT2 requires a protein called interferon regulatory factor 9 (IRF9) to enter the nucleus.

[8] After STATs are made by protein biosynthesis, they have non-protein molecules attached to them, called post-translational modifications.

[12] STAT5 acetylation on lysines at positions 694 and 701 is important for effective STAT dimerization in prolactin signalling.

Firstly, a protein important for MAPK/ERK signalling, called Grb2, has an SH2 domain, and therefore it can bind to receptors phosphorylated by JAKs (in a similar way to PI3K).

[19] Phosphorylation then recruits an adaptor protein called Shc, which activates the MAPK/ERK pathway, and this facilitates gene regulation by STAT5.

[2][23] 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.

[24] In some flies with faulty JAK genes, too much blood cell division can occur, potentially resulting in leukaemia.

[25] JAK-STAT signalling has also been associated with excessive white blood cell division in humans and mice.

[24] The signalling pathway is also crucial for eye development in the fruit fly (Drosophila melanogaster).

[24] The entire removal of a JAK and a STAT in Drosophila causes death of Drosophila embryos, whilst mutations in the genes coding for JAKs and STATs can cause deformities in the body patterns of flies, particularly defects in forming body segments.

[24] One theory as to how interfering with JAK-STAT signalling might cause these defects is that STATs may directly bind to DNA and promote the transcription of genes involved in forming body segments, and therefore by mutating JAKs or STATs, flies experience segmentation defects.

[26] STAT binding sites have been identified on one of these genes, called even-skipped (eve), to support this theory.

Here, SHP-1 binds directly to a tyrosine residue (at position 429) on EpoR and removes phosphate groups from the receptor-associated JAK2.

[42] Additionally, adding methyl groups to the SHP-1 gene (which reduces the amount of SHP-1 produced) has been linked to lymphoma (a type of blood cancer) .

[38] Negative regulation by SHP-2 has been reported in a number of experiments - one example has been when exploring JAK1/STAT1 signalling, where SHP-2 is able to remove phosphate groups from proteins in the pathway, such as STAT1.

[46] In a similar manner, SHP-2 has also been shown to reduce signalling involving STAT3 and STAT5 proteins, by removing phosphate groups.

[54] SOCS can also function by binding to proteins involved in JAK-STAT signalling and blocking their activity.

For example, alterations in JAK-STAT signalling can result in cancer and diseases affecting the immune system, such as severe combined immunodeficiency disorder (SCID).

[56] 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 cytokine receptors, and overexpression of STAT3 have both been associated with psoriasis (an autoimmune disease associated with red, flaky skin).

[63] Also, since many cytokines function through the STAT3 transcription factor, STAT3 plays a significant role in maintaining skin immunity.

[66] 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.

[6] Specifically, mutations in exons 12, 13, 14 and 15 of the JAK2 gene are proposed to be a risk factor in developing lymphoma or leukemia.

[66] Also, a JAK-STAT signalling pathway mediated by erythropoietin (EPO), which usually allows the development of red blood cells, may be altered in patients with leukemia.

[68] Since excessive JAK-STAT signalling is responsible for some cancers and immune disorders, JAK inhibitors have been proposed as drugs for therapy.

Once a ligand binds to the receptor, JAKs add phosphates to the receptor. Two STAT proteins then bind to the phosphates, and then the STATs are phosphorylated by JAKs to form a dimer. The dimer enters the nucleus, binds to DNA, and causes transcription of target genes.
Key steps of the JAK-STAT pathway. JAK-STAT signalling is made of three major proteins: cell-surface receptors, Janus kinases (JAKs), and signal transducer and activator of transcription proteins (STATs). Once a ligand (red triangle) binds to the receptor, JAKs add phosphates (red circles) to the receptor. Two STAT proteins then bind to the phosphates, and then the STATs are phosphorylated by JAKs to form a dimer. The dimer enters the nucleus, binds to DNA, and causes transcription of target genes. The JAK-STAT system consists of three main components: (1) a receptor (green), which penetrates the cell membrane; (2) Janus kinase (JAK) (yellow), which is bound to the receptor, and; (3) Signal Transducer and Activator of Transcription (STAT) (blue), which carries the signal into the nucleus and DNA. The red dots are phosphates. After the cytokine binds to the receptor, JAK adds a phosphate to (phosphorylates) the receptor. This attracts the STAT proteins, which are also phosphorylated and bind to each other, forming a pair (dimer). The dimer moves into the nucleus, binds to the DNA, and causes transcription of genes. Enzymes that add phosphate groups are called protein kinases. [ 5 ]
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 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
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 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
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.
Cytokine release via activation of JAK/STAT signalling pathway following SARS-Cov-2 infection resulting in ARDS related to COVID-19 . [ 68 ]