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;