JAK - STAT Pathway
Index
1.Introduction:
The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway is regarded as one of the central communication nodes in the cell function. More than 50 cytokines are produced by the JAK/STAT pathway and it also initiates downstream processes. Mutation in JAK/STAT causes a lot of diseases. JAKs are noncovalently associated with cytokine receptors, mediate tyrosine phosphorylation of receptors, and recruit one or more STAT proteins. Although STATs can be activated by partially overlapping cytokines, different STATs have non redundant biological effects. Thus, inhibiting the JAK/STAT pathway is promising for treating various diseases.
2.Discovery of JAK/STAT Pathway:
The JAK/STAT signaling pathway was first discovered when studying how IFNs lead to the activation of a transcription factor.
In 1990, the transcriptional activator interferon-stimulated gene factor 3 (ISGF3), a transcription factor that responds to IFN-α, was discovered to be composed of multiple interacting polypep-tide chains (48, 84, 91, and 113 kDa).
The discovery of JAKs happened in 1989–1994. In 1989, Wilks et al. identified that a tyrosine kinase has a recognizable kinase domain and a pseudokinase domain.
Thus, in the late 1980s to early 1990s, the components and outlines of the JAK/STAT signaling pathway were completed.
Research on more proteins and functions of the JAK/STAT pathway has continued to the present, making the JAK/STAT landscape more abundant.
3.Components of JAK/STAT Pathway:
The JAK/STAT signaling pathway is evolutionarily conserved. It is composed of ligand-receptor complexes, JAKs, and STATs. There are 4 members in the JAK family: JAK1, JAK2, JAK3, and TYK2. The STAT family comprises seven members: STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6.
3.1.The JAK family:
JAK family consists of non-receptor tyrosine protein kinases. When cytokines bind to their receptors, JAK tyrosine kinases are activated and transmit regulatory signals. The JAK family has four main members, JAK1, JAK2, JAK3, and TYK2.
JAK3 - Only expressed in the bone marrow and lymphatic system, as well as endothelial cells and vascular smooth muscle cells, Other members - Expressed in almost all tissues.
JAKs have seven homology domains (the JAK homology domain, JH).
Starting from the carboxyl terminus, JH1 is the first JH, known as the kinase domain, and is composed of approximately 250 amino acid residues.
JH1 encodes a kinase protein that constitutes the kinase structure domain that phosphorylates a substrate.
JH2 is a PK domain. Its main function is to regulate the activity of the kinase domain.
JH3 with one-half of JH4 constitutes the Src-homology 2(SH2) domain.
The combination of one-half of JH4, JH5, JH6, and JH7 constitutes the FERM domain. and
The SH2 and FERM domains mainly regulate the binding of JAK and cytokine-receptor membrane- proximal box 1/2 regions.
3.2.The STAT family:
STAT family is composed of STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6. STAT family members consist of 750–900 amino acids.
From the N-terminus to the C-terminus, there are the N-terminal domain and coil, helix domain, DNA- binding domain, connection domain, SH2 domain, and transcription-activation domain. Six domains regulate different functions of STAT.
(1) The N-terminal domain promotes the formation of STAT dimers, which enables their subsequent binding with transcription factors. Studies have also shown that the N-terminus can also promote the interaction of STAT and transcription coactivators, the PIAS family, and receptors and regulate nuclear translocation.
(2) The coiled-coil domain is composed of a potentially dynamic four-helix bundle. This domain is related to regulatory proteins and participates in the control of nuclear import and export processes. It can interact with p48/IRF9, Nmi, c-Jun, StlP, etc.
(3) The linking domain, as the name implies, structurally connects the DNA-binding domain to the SH2 domain. It is involved in the transcriptional regulation of STAT1.
(4) The DNA-binding domain can recognize and bind to the DNA sequence in the regulatory region of the target gene. It also participates in the regulation of nuclear import and export.
(5) The SH2 domain of STAT is very different from other SH2 domains, but this domain is very conserved in the STAT family.68 The primary function of SH2 is to recognize phosphotyrosine motifs of cytokine receptors. Moreover, the SH2 domain cooperates with activated JAK to drive the SH2 domain of STAT to interact with the tail of another STAT monomer after phosphorylation to form a homodimer or heterodimer.
(6) The transcriptional activation domain is critical for DNA transcription elements and the recruitment of co-activators through a conserved serine phos- phorylation site and regulating the transcription.
STAT4, STAT5, and STAT6 can be used as targets for ubiquitin-dependent destruction, while STAT1, STAT2, and STAT3 are more stable, indicating that the transcriptional active region also regulates protein stability.
4.Activation of JAK/STAT Pathway:
The classic JAK/STAT signaling is as follows the cell ligand interacts with its receptor to cause receptor dimerization.
Never-theless, gp130,134 EpoR,135,136 TNF-R1,137 IL-17R,138, IL-10R,139 and GH receptor140 etc., can pre-form inactive receptor dimers before binding to the ligands, which may facilitate rapid receptor complex assembly and signal transduction.
The connection between the ligand and the receptor induces transphosphoryla-tion of JAK.
Activated JAK causes tyrosine phosphorylation of the bound receptor, forming a docking site for STATs.
At this docking site, JAK phosphorylates STAT, and then STAT dissociates from the receptor and forms homodimers or heterodimers through SH2- domain–phosphotyrosine interactions.
These dimers translocate to target gene promoters, regulating the transcription of the target genes.
STAT usually regulates transcription through the following mechanisms: (1) STAT binds to its DNA target site to drive transcription activation. (2) STAT protein may form a transcription complex with non-STAT transcription factors to trigger the transcription mediated by STAT; (3) STAT associates with non-STAT DNA-binding elements to promote STAT- dependent transcription; (4) STAT and non-STAT transcription factors can synergistically activate transcription by binding to clusters of independent DNA-binding sites.
5.Regulation of JAK/STAT Pathway:
Regulation of JAK/STAT signaling pathway was mediated by cascade pathways by downstream and upstream process of DNA, that regulates in two different ways positive as well as negative way of regulation.
5.1.Positive regulation of JAK/STAT signaling
In addition to the main components of the JAK/STAT signaling pathway, many related proteins play indispensable roles in STAT- dependent transcription and JAK–STAT interactions with other signaling pathways.
Upon costimulation of glucocorticoids and prolactin, activated STAT5 and glucocorticoid receptor (GR) form a complex.
GR acts as a transcriptional coactivator of STAT5 to promote STAT5-dependent transcription.
Moreover, CBP and p300 act as auxiliary activators of STAT1α to regulate the response of JAK/STAT, but this regulation can be realized by integration of common transcripts of the JAK/STAT and other signaling path- ways.
Another cytoplasmic protein, Nmi, may promote the activation of STAT1 and STAT5 through the recruitment of STAT1 and STAT5 by CBP.
In vitro GST pull-down assay results showed that STATs except STAT2 could interact with Nmi.66 Some adaptor proteins can also promote the JAK/STAT signaling pathway.
The SH2 protein subfamily composed of lymphocyte adaptor protein (Lnk), SH2-B, and APS has potential adaptor functions. SH2-2B can promote the activation of JAK2 induced by GH, while APS is a negative regulator of the JAK/STAT signaling pathway.
The signal transducing adapter molecule is a transduction adapter molecule containing an SH3 domain and one ITAM domain. It can interact with JAK2 and JAK3 through its ITAM domain to enhance IL-2 and GM-CSF-mediated C-myc transcription.
5.2Negative regulation of JAK/STAT signaling
Many negative regulators are involved in the regulation of JAK/ STAT signal transduction. They maintain the balance and steady state of the JAK/STAT pathway. There are three main types of negative regulation of the JAK/STAT signaling pathway: protein inhibitor of activated STAT (PIAS), SOCS/CIS family members, and PTPs (protein tyrosine phosphatases).
6.Human Disease:
The JAK/STAT pathway is a highly conserved pathway of signal transduction. It regulates multiple cellular mechanisms associated with varieties of disease development. Dysregulation of the JAK/STAT pathway is associated with various diseases. For example, JAK2V617F mutation frequently occurs in myeloproliferative neo-plasms (MPN).
7.Conclusion:
The JAK/STAT pathway is central to extracellular cytokine-activated receptor-mediated signal transduction, which is involved in cellular proliferation and differentiation, organ development, and immune homeostasis. In this review, we discussed the composition and function of the JAK/STAT pathway and discussed the role of JAK/STAT in various diseases. Dysregulation of the JAK/STAT signaling pathway is recognized as a major contributor to various diseases, especially malignant tumors, and autoimmune diseases.
