The mammalian STAT family comprises Stat1, Stat2, Stat3, Stat4, Stat5a, Stat5b and Stat6. The two Stat5 genes share > 90% homology but are encoded by separate genes. STAT proteins share an overall general structure that is organized into functional modular domains.

Janus (JAK)/Signal Transducers and Activators of Transcription (STAT) Pathway

The and immune responses.

Cytokines activate receptor-associated JAKs, which phosphorylate the receptor cytoplasmic domain on tyrosine residues, leading to recruitment of STATs. The JAKs then tyrosine phosphorylate STATs, promoting their activation. Once activated, STATs dimerize, translocate to the nucleus, and bind to regulatory elements to induce transcription of target genes. Over 60 cytokines and growth factors use the JAK/STAT pathway. There are four JAKs (JAK1, JAK2, JAK3 and TYK2), and a total of seven STATs (STAT 1, 2, 3, 4, 5a, 5b and 6). Various combinations of JAK/STAT usage result in differential gene expression, particularly depending on the STAT transcription factor(s) that is activated. Cytokines, through activation of the JAK/STAT pathway, are of paramount importance in regulating the development, differentiation and function of T-cells and myeloid cells. Specifically, Th1 cell differentiation is induced by IL-12 through activation of JAK2/TYK2 and STAT4, Th2 differentiation is induced by IL-4 activation of JAK1/3 and STAT6, Th17 cell differentiation requires IL-6 and IL-23, which signal through JAK1/2 and STAT3, while Treg cell differentiation needs TGF-β and IL-2, which signal through JAK1/3 and STAT5. STATs also regulate innate immune cells. JAK1/2 and STAT1 activation mediate the effects of IFN-γ on macrophage function, JAK1/2 and STAT3 are involved in IL-6 family signaling, and GM-CSF signals through JAK2 and STAT5 to affect myeloid development. JAKs and STATs are essential mediators of almost all biological signaling events initiated by cytokines. As such, unrestrained activation of the JAK/STAT pathway is detrimental and has been associated with numerous immune-mediated and autoimmune diseases, including Multiple Sclerosis. Indeed, a number of STAT target genes, including IL-23R, IL-17A, IL-17F, IL-21, IL-22, IL-6, IFN-γ, RORγt, T-bet, CXCR3 and MHC II, are overexpressed in both Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis, and have been implicated in contributing to disease pathogenesis. Activating mutations in STAT proteins are rare, thus STAT hyperactivation is usually due to an over-abundance of cytokines, and/or dysregulation of endogenous negative regulators of JAKs, most notably, Suppressors Of Cytokine Signaling (SOCS) proteins. The SOCS family is composed of eight members; CIS and SOCS1-7, and serve to restrict the duration of activation of cytokine-induced signaling by inhibiting JAK kinase activity after it has been turned on. SOCS proteins contain an N-terminal variable region, a classical SH2 domain, and a C-terminal SOCS box. SOCS proteins are not constitutively expressed, rather, are induced by cytokines, creating a negative feedback loop to prevent excessive activation of cytokine-induced JAK/STAT signaling. SOCS proteins bind to activated JAKs and to certain cytokine receptors via their SH2 domains, thereby suppressing further signaling events. In addition, the SOCS box interacts with components of the ubiquitin ligase machinery and mediates proteosomal degradation of associated proteins, most commonly, JAKs. SOCS1 and SOCS3 are unique amongst the SOCS proteins in terms of containing a 12 amino acid kinaseinhibitory region (KIR), which acts as a pseudosubstrate for JAKs, conferring inhibition of JAK kinase activity. SOCS1 and SOCS3 in particular have critical functions in repressing innate and adaptive immunity, in part by inhibiting STAT activation induced by IFN-γ, IL-6, IL-12, IL-23 and GM-CSF, which are all implicated in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis pathogenesis.


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