The name of the JAK comes from a Roman two-faced god that implies two domains, including a catalytic domain and a kinase-like domain. Then, JAKs were discovered in 1992 by three separate labs and the JAK-STAT pathway was coined.
STATs were firstly found in 1988 as proteins that bind to interferon (IFN)-stimulated response elements of DNA sequences to stimulate the transcription of type I IFNs. Eventually, novel and approved therapeutic strategies are discussed in order to target the JAK-STAT pathway and its regulators in several immune disorders. In this review, we aim to introduce the JAK-STAT pathway and its regulator proteins and elucidate the role of them in the differentiation of T helper(Th) cell subsets. Eventually, dimerized STATs enter to the nucleus and regulate transcription of myriad target genes. Activation of the receptors that are associated with JAKs is critical to initiate the JAK transphosphorylation and subsequent recruitment of one or more STATs to be phosphorylated. erythropoietin and growth hormone while other receptor subunits are expressed as heteromultimers, such as interferons (IFN) and Interleukins (IL). Subunits of some receptor are expressed as homodimers, e.g. Multimerization of receptors occurs when ligands bind to their receptors. JAKs are kinds of tyrosine kinases that are bound to the cytoplasmic regions of type I and II cytokine receptors. These cytokines are inevitable for initiating and orchestrating of innate and adaptive immunities. A main subgroup of cytokines, ranging from over 60 factors, binds to receptors termed type I and type II cytokine receptors. Cytokines are one of the major players of myeloid and lymphoid lineages which their receptors utilize this pathway. The JAK-STAT pathway is essential for a wide range of cytokines and growth factors, leading to critical cellular events, such as hematopoiesis, lactation and development of the immune system and mammary glands.
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The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway plays a major role in transferring of signals from cell-membrane receptors to the nucleus.
The result of this process may be proliferation, differentiation (polarization), activation/inhibition and survival/apoptosis. Each receptor like a sentinel senses stimuli and starts to transfer corps of signals to the castle of the nucleus in order to provoke vital responses. There is a reciprocal interaction between external actions and internal reactions that enables a cell to live. Therefore, further investigation is needed. Studies are ongoing for identifying the other regulators of the JAK-STAT pathway and designing innovative therapeutic strategies. Finally, we introduce novel targeted strategies as promising therapeutic approaches in the treatment of immune disorders. In this review, we represent how the JAK-STAT pathway is generally regulated and then in Th cell subsets in more detail. Dysregulation of the JAK-STAT pathway in T helper cells may result in various immune disorders.
This pathway is regulated by an array of regulator proteins, including Suppressors of Cytokine Signaling (SOCS), Protein Inhibitors of Activated STATs (PIAS) and Protein Tyrosine Phosphatases (PTPs) determining the initiation, duration and termination of the signaling cascades. The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway plays critical roles in orchestrating of immune system, especially cytokine receptors and they can modulate the polarization of T helper cells.
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