JAK/STAT signalling pathway

Components of the JAK-STAT signaling pathway represent novel targets for pharmacological interventions [4]. Recently, a specific and orally active JAK3 antagonist was identified from screening of a chemical library for inhibitors of in vitro JAK3 kinase activity. The most effective compound, CP-690,550, was shown... 

A. Oseltamivir inhibits neuraminidase, an enzyme that cleaves neuraminic acid from oligosaccharides. Neuraminidase activity aids the movement of viral particles through neuraminic acid-rich respiratory secretions and is required for the release of progeny virions. Inhibition of viral DNA polymerase is the mechanism of action of nucleoside analogue antiviral drugs. Interferons do stimulate the JAK-STAT signaling pathway but do not stimulate proliferation of immune cells. Ribavirin inhibits GTP synthesis, and the antiretroviral protease inhibitors (e.g., ritonavir) inhibit HIV protease. 

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)...

Murray PJ. 2007. The JAK-STAT signaling pathway Input and output integration. J Immunol. 178 2623-2629. 

The mutated hormone would bind to the growth-hormone receptor but would not favor receptor dimerization. Thus, it would not stimulate the JAK-STAT signaling pathway. Such a mutated hormone might be useful as a competitive inhibitor for growth hormone. It would block the activity of native growth hormone. 

Rawlings JS, Rosier KM, Harrison DA (2004) The JAK/STAT signaling pathway. J Cell Sci 117 1281-1283. 

This prediction can be tested experimentally. The substance Leptomicin B inhibits the nuclear export of STAT-5. Figure 17.1-8(a) shows the time course of the protein CIS whose translation is initiated by the JAK-STAT signaling pathway. The areas under the curves differ roughly by the predicted factor of 2. Results for repeated experiments in Fig. 17.1-8(b) demonstrate that Leptomicin B has no effect on CIS translation without Epo stimulus. In the case of stimulation, the protein production is decreased by a factor of 2 if Leptomicin B is applied, which confirms the in silico prediction of the extended model and finally validates the model. 

Systems Biology of the JAK-STAT Signaling Pathway 1045 Jens Timmer, Markus Kollmann, and Ursula Klingmuller... 

Among the four Jak kinases, Jak-1, Jak-2, Jak-3, and Tyk-2, the yc users all signal via Jak-1 and Jak-3 [30, 31]. This could be explained by the ability of Jak-1 to associate with the chain conferring the specificity for each receptor, namely 1L-2R3 [32, 33], IL-4Ra [34], IL-7Ra [35], and IL-9Ra [36], and probably lL-21Ra [37], whereas Jak-3 associates primarily with yc [33, 35]. The importance of the yc was demonstrated by the discovery that mutations in yc cause X-linked severe combined immunodeficiency (SCID) [30, 38], also named the bubble boy disease. In this disease, both cellular and humoral immunity are defective. In fact, T and NK cells do not develop and even if B cells are present, they are nonfunctional [30, 38]. Interestingly, mutations in Jak-3 were found to cause an autosomal recessive form of SCID [39] and the essential role of Jak-3 in lymphoid development was established [40]. This clearly demonstrated the important role of the Jak-STAT signaling pathway. 

Migita K, Komoii A, Toiigoshi T, Maeda Y, Izumi Y, Jiuchi Y, Miyashita T, Nakamura M, Motokawa S, Ishibashi H. 0 690 50 inhibits oncostatin M-induced JAK/STAT signaling pathway in rheumatoid synoviocytes. Arthritis Res Ther. 2011 13 (3) R72. doi 10.1186/ar3333. 

Wang Xie X, Lu WG, Ye DF, Cheng HZ, Li X, Cheng Q. Ovarian carcinoma cells inhibit T cell proliferation of IL-2 receptor beta and gamma expression and their JAK-STAT signaling pathway. Life Sci. 2004 74 1739-49. 

JAK/STAT signaling pathway see Signal transducers and activators of transcription. 

STATs are components of the JAK/STAT signaling pathway, which was identified by study of the transcriptional activator response to certain cytokines and growth factors. JAK proteins (janus kinases, a family of tyrosine kinases) are bound to the membrane-proximal domain of cytokine receptors Cytokine... 

Dell Alhani P, Santangelo R, Torrisi L, Nicoletti VG, de Vellis J, Giuffrida Stella AM (2001) JAK/STAT signaling pathway mediates cytokine-induced iNOS expression in primary astroglial cell cultures. J Neurosci Res 65(5) 417-424. doi 10.1002/jnr.ll69 [pii]... 

---