3.1.2 Canonical JAK/STAT pathway
Cytokines like IFNs, colony stimulating factors, growth factors, and
related molecules which have the similarity structure lack their own
enzymatic activity. These cytokines’ function relay seriously on series
of JAK kinases in the intracellular cell signaling known as type I/II
cytokines. Once they bind to their receptors on the cell membrane, the
cytosolic domain of the receptors would initiate active JAK kinases,
then creating docking sites for STAT. The JAK kinases include 4
memebers-JAK1, JAK2, JAK3 and TYK2(Waldmann & Chen, 2017). Each
cytokine receptor intracellular domain connects with at least two JAK
kinases. While the JAKs have an ability to deposit a phosphate on
themselves or on other JAKs. After the JAK is phosphorated, they soon
transfer their phosphates to STATs which are signal transducers and
activators of transcription. Phosphorylated STATs become to dimers, move
to the nucleus, then bind to the target gene promotors, thus activate
the gene transcription(Banerjee, Biehl, Gadina, Hasni & Schwartz, 2017;
Liongue, Sertori & Ward, 2016).
STATs contain an important class of molecules which transmit signals
from type I/II cytokine receptors to nucleus. There are 7 STATs in
mammals (STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6).
Different cytokines have the capacity to preferentially recruit
different STATs. The STATs protein is very important to the immune
system. At the very beginning STATs were linked with antiviral immunity,
a key feature of STAT1 and 2(Shuai, Stark, Kerr & Darnell, 1993). STAT4
and STAT1 both can drive activated Th cells into a Th1 phenotype which
is characterized by the secretion of IFN-𝛾(Zhu, Yamane & Paul, 2010).
STAT6 drives differentiation into an anti-helminth Th2 phenotype
characterized by the secretion of IL-4, IL-5, and IL-13. STAT3, being
activated by IL-6 and related cytokines, has diverse functions in many
cells. In T cells, it drives differentiation into an
antibacterial/antifungal Th17 phenotype characterized by the secretion
of IL-17 and IL-22. Like STAT3, STAT5A and STAT5B are also activated by
many cytokines including important hematopoietic factors like
erythropoietin (EPO) and CSFs. In lymphocytes, STAT5 drives
differentiation of innate lymphoid cells, promotes regulatory cell
phenotype (Treg) and Foxp3 expression, and inhibits Th17 and follicular
helper T cell differentiation(Gadina et al., 2018).
FIGURE 2 Activation of JAK kinases and its biological
significance.
*Tyk2 seems to be important for signaling by gp130 and other cytokines
but
the cell, cell-state, and species-specific requirements for gp130
cytokines are incompletely understood;