Janus kinase STAT pathway

Natarajan et al. showed that treatment of activated T cells with curcumin inhibited IL-12-induced tyrosine phosphorylation of Janus kinase 2, tyrosine kinase 2, and STAT3 and STAT4 transcription factors. The inhibition of the Janus kinase-STAT pathway by curcumin resulted in a decrease in IL-12-induced T-cell proliferation and Thl differentiation. 

Natarajan, C. and Bright, J.J., Curcumin inhibits experimental allergic encephalomyelitis by blocking IL-12 signaling through Janus kinase-STAT pathway in T lymphocytes, J. Immunol, 168(12), 6506-6513,2002. 

JAK-STAT pathway a signaling pathway utilized by cells to respond to cytokines and growth factor stimuli. This pathway transduces the signals carried by cytokines to the cell nucleus, where activated STAT proteins modify gene expression. JAKs—Janus Kinases STATs—Signal Transducers and Activators of Transcription. 

Li WQ, Dehnade F, Zafarullah M (2001) Oncostatin M-induced matrix metalloproteinase and tissue inhibitor of metalloproteinase-3 genes expression in chondrocytes requires Janus kinase/STAT signaling pathway. J Immunol 166 3491-3498... 

Cytokine receptors that couple to the JAK-STAT Pathway decode the signaling though hematopoietic cytokines (erythropoietin, thrombopoietin, colony-stimulating factors), prolactin, growth hormone, the a-, (3- and y- interferons, and a number of immunomodulatory interleukins [3], They form homodimetic or heterodimeric receptor complexes, which after ligandbinding recruit and activate isotypes of Janus kinases (JAKs). Activated JAKs in turn... 

Fig. 11.4. Model of signal transduction via the IL-2 receptor. Binding of IL-2 to the IL-2 receptor initiates activation of the Janus kinases Jakl and Jak3. These phosphorylate tyrosine residues in the P-chain of the IL-2 receptor and in the transcription factor StatS. SH2 domains or PTB domains of adaptor proteins can bind to the Tyr phosphate residues of the P-chain and, as shown in the figure for the Shc/Grb2/Sos complex, can transmit a signal in the direction of the Ras pathway. The phosphorylated transcription factor StatS is translocated into the nucleus and activates the transcription of corresponding gene sections. Another signaling pathway starting from the activated IL-2 receptor involves the Lck and Syk tyrosine kinases (see Chapter 8). The pathway leads to induction of genes for transcription factors such as c-Myc and c-Fos.

Fig. 3.2 The JAK/STAT signaling pathway after cytokine binds to its receptors, the associated Janus kinase (JAK) is induced. This results in the phosphorylation of the receptor s cytoplasmic domain. STAT is recruited after the phosphorylation of the receptor s cytoplasmic domain, which after phosphorylation dimerizes and migrates into the nucleus. In the nucleus, STAT binds to its niche in the DNA and induces gene expression see Color Insert)...

The Janus Family Tyrosine Kinases-STAT Signaling Pathway... 

Fig. 6.5 Activation of the Jak/STAT pathway by angiotensin II. Binding of angiotensin II to the ATi receptor stimulates, via a G protein, the phosphorylation of janus family kinases (JAK). Jak2 participates in the phosphorylation and activation of signal transducers and activators of transcription (STAT) family members, which translocate to the nucleus and upregulate growth-linked genes.

The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway play a critical role in the signalling of a wide array of cytokines and growth factors, leading to various cellular functions, including proliferation, growth, haematopoiesis and immune response. 

IL-2 often synergizes with other cytokines (notably IL-12) to induce IFNy production by NK cells and to increase cytotoxicity by NK and LAK cells. The expression of the receptor for this cytokine on NK cells is, however, continuous in character, but only a very small percentage of these cells have receptors of great affinity. The study of differential use of Janus kinase-signal transducer activator of transcription signaling pathways in the stimulation of human NK cells by IL-2, IL-12, and IFNa has demonstrated a differential phosphorylation and consequent differential activation of both separate and overlapping STAT proteins by IL-2, IL-12, and IFNa. This may provide a molecular basis for the similarities and differences in the actions of these cytokines on NK cells. ... 

CSF and IL-3, IL-5 binds with high affinity (452-454). Both subunits are necessary for signal transduction (455). The pathway for signal trai duction includes activation of two Janus kinases (JAKl and JAK2) and the signal transduction/activator STATS (456, 457). 

For signaling pathways, recent years have seen an increasing number of studies of specific pathways where mathematical modeling is applied to infer systems properties from the models. These applications include the mitogen-activated protein (MAP)-kinase pathways [14-16], apoptotic pathways [17-19], the Wnt/j6-Catenin [20], and the Janus kinase-signal transduction and activator of transcription (JAK-STAT) pathway [21], A regulatory network that has been studied intensively is the cell cycle [7, 22, 23]. 

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