JAK-STAT Signalling and Cytokines: The What, How, and Why

JAK-STAT stands for Janus kinase's and signals transducer and activator of transcription proteins. JAKs are small proteins that contain the JAK homology (JH) domain. This domain is found in all JAKs; it allows two JH domains to come together and form an interaction site. JH domains are responsible for JAK-STAT signalling, as JAKs have tyrosine kinase activity. What does this mean? JAKs can phosphorylate tyrosines on the proteins they bind to, including cytokine receptors.

JAK-STAT signalling is initiated when a ligand, e.g., cytokine, binds to the cognate transmembrane receptor. This result in two or more JAKs being brought into close proximity, triggering JAKs to phosphorylate both the receptor and JAKs themselves. This creates two binding sites for STAT proteins: JH domains on JAKs and phosphorylated tyrosines of receptors that have become bound by JAKs. The STAT protein then binds these sites through their Src homology 2 domain (SH2). When a tyrosine residue found between SH2 domain and the C-terminal transactivationon STATs are phosphorylated a homodimer (two identical copies) forms. These newly formed homodimers are stabilised by reciprocal phosphotyrosine and SH2 domain interactions.

This dimer has nuclear localization signals, meaning it can be transported into the cell nucleus from the cytoplasm. Once in the nucleus, STAT proteins bind DNA at specific enhancer sequences and activate or repress transcription. STAT proteins are important in JAK-STAT signalling as they control which genes are turned on or off.

What are JAK proteins?

All JAKs are tryosine kinases. There are 4 different JAKs: JAK1, JAK2, JAK3, and JAK4. All JAKs have four domains: a N‐terminal FERM domain, an SH2 domain, and two kinase domains.​ The first of these kinase domains is a pseudokinase domain because it is catalysis inactive. The second kinase domain of JAK is responsible for phosphorylation of the receptor and subsequently STAT transcription factors.

What are STAT proteins?

STAT proteins have 2 functions transducing signals from cytokines and promoting transcription of specific genes. The STATs are present in the cytoplasm as inactive dimers but are rapidly activated by cytokine signaling and transported into the nucleus. A STAT protein consists of an N‐terminal portion, a coiled-coil domain, a DNA binding domain, a linker region, an SH2 domain, and a C terminus transactivation domain. There is a single conserved tyrosine residue between the SH2 domain and the transactivation domain, which is where the STAT proteins are phosphorylated by JAKs and is required for their activation.

There are 7 STAT proteins in mammals; STAT1-4, 5a, 5b, and 6. STAT1 is expressed at high levels in the heart, thymus and spleen. STAT2,3 and 6 are expressed in the majority of tissues. STAT4 is mainly located in the testis, thymus, and spleen. STAT 5a and 5b are deferentially expressed in muscle tissue, the brain, and the mammary gland and secretory organs (seminal vesicle and salivary gland).

What are the functions of the JAK-STAT pathway?

JAK-STAT signalling is responsible for many aspects of immunity and inflammation, including:

- the activation of T cells, B cells, and macrophages

- the production of cytokines

- the differentiation and activation of immune cells

JAK-STAT signalling plays an important role in the innate immune system. One example of this is macrophages, white blood cells that detect infections by binding pathogen-associated molecules and initiate inflammation by secreting cytokines. JAK-STAT proteins regulate many aspects of macrophage function, including differentiation from monocytes; maturation; activation; phagocytosis (engulfing and destroying pathogens); and production of cytokines.

In addition, JAK-STAT has been shown to be involved in diseases such as cancer, rheumatoid arthritis, and psoriasis. Disruptions in this pathway can lead to diseases such as cancer, psoriasis, rheumatoid arthritis, and Crohn's disease. Therefore, understanding how JAK-STAT signalling works is crucial for developing new treatments for these diseases.

JAK3 inactivating mutations have been documented in people with severe combined immunodeficiency disease (SCID), which is characterized by T and NK cell loss, aberrant B cell function, and lymphoid tissue hypoplasia.

How do JAK-STAT inhibitirs work?

JAK inhibitors block JAKs from phosphorylating their substrates, such as receptors and JH domains on JAKs themselves. This prevents STAT proteins from dimerizing and binding DNA to activate or repress the transcription of genes involved in immune responses. Inhibition of JAK-STAT signalling has been shown to reduce inflammation by blocking the production of proinflammatory cytokines (e.g., TNF alpha). It also decreases other signalling pathways that are activated when Jak-STAT is not working properly, including NF kappa B (nuclear factor kappa beta).

According to studies, JAK-STAT signalling has been linked to the development of cancer as a tumour driver of tumor growth/metastasis or as a modulator of immune surveillance. JAK inhibitors are a promising new class of drugs that target these pathways and could be used as treatments for different types of cancers, including lung cancer, breast cancer, melanoma (skin cancer), and ovarian carcinomas. JAK inhibitors have also been proposed as potential therapies for autoimmune diseases such as rheumatoid arthritis or systemic lupus erythematosus because JAKs are involved in regulating inflammation by producing cytokines like TNF alpha which contributes significantly to inflammatory responses seen during these conditions.

What are cytokines

Cytokines are a secreted glycoprotein that act as messengers between cells of the immune system or between cells and their environment. They are secreted by many different types of cells, e.g, white blood cells, in response to injury or infection; some examples include interleukins (IL), interferons (IF), granulocyte colony-stimulating factor (GCSF), platelet-derived growth factor (PDGF). They can activate other cells to fight the infection or heal the damage. JAK-STAT signalling is responsible for the production of cytokines, which are essential in regulating many aspects of immunity.

Cytokine receptors type 1 and type 2

Type I cytokine receptors are single transmembrane proteins that do not contain JH domains. Their external domains consist of cytokine receptor homology region (CHR). This CHR is formed from firbronectin type 3 domains orientated at nearly 90 right angles to each other. Class 1 receptors bind to a wide range of interleukin, hematopoietins and growth factors.

Type II cytokines receptors are hetrodimers consisting of a ligand-binding chain and a transmembrane chain. Class 2 receptors only bind to interferons and IL-10 family cytokines.

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22nd Feb 2022 Laura O'Donoghue

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