JAK/STAT signaling

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... 

C) Stimulation of the tyrosine kinase activity of the JAK-STAT signal transduction pathway, resulting in enhanced proliferation of immune cells... 

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. 

The Jak-Stat signal transduction is an example of a signaling pathway in which a signal is coupled, in the form of a tyrosine phosphorylation, directly to activation of a transcription factor. In contrast to other signaling pathways that also regulate trans-... 

Auwerx, J. Staels, B. (1998) Leptin.Lancet 351, 737-742. Brief overview of the leptin system and JAK-STAT signal transductions. 

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. 

Radtke S, Haan S, Jorissen A, Hermanns HM, et al. 2005. The JAK1 SH2 domain does not fulfill a classical SH2 function in JAK/STAT signaling but plays a role for receptor interaction and up-regulation of receptor surface expression. J Biol Chem. 280 25760-25768. 

Shuai K, Liu B. 2003. Regulation of JAK-STAT signaling in the immune system. Nat Rev Immunol. 3 900-911. 

Pernis AB, Rothman PB. 2002. JAK-STAT signaling in asthma. J Clin Inv. 109 1279-1283. Platts-Mills TA. 2001. The role of immunoglobulin E in allergy and asthma. Am J Respir Crit Care Med. 164 S1-S5. 

The RAS-RAF-MAPK signaling pathway can cross-react with the JAK-STAT pathway in eosinophils (Fig. 1). It has been shown that MAPK interacts with the a subunit of IFN- //i receptor and the activation of early-response genes by IFNs requires tyrosine phosphorylation of STAT. Therefore, MAPK can regulate IFN-o and IFN-/1 activation of early-response genes by modifying the JAK-STAT signaling cascade (D5). 

Booz, G.W., Day, J.N.E., and Baker, K.M. 2002. Interplay between the cardiac renin angiotensin system and JAK-STAT signaling Role in cardiac hypertrophy, ischemia/reperfusion dysfunction, and heart failure. J. Mol. Cell. Cardiol. 34 1443-1453. 

Green tea Camellia sinensis (tea) (Theaceae) [leaf] Leptin (JAK/STAT signalling)... 

Yoshimura, A. (1998). The CIS family negative regulators of JAK-STAT signaling. Cytokine Growth Factor Rev. 9, 197-204. 

Kim OS, Park EJ, Joe E-H, Jou I (2002) JAK-STAT signaling mediates gtmgliosides-induced inflammatory responses in brain microglial cells. J Biol Chem 277 40594-40601 Kong G-Y, Peng Z-C, Costanzo C, Kristensson K, Bentivoglio M (2000) Inducible nitric oxide synthase expression elicited in the mouse brain by inflammatory mediators circulating in the... 

Activation of STATs is transient, like that of other transcriptional regulators. When cytokine signalling is terminated, the concentrations of active STATs in the nucleus decline, because STATs are either inactivated by dephosphorylation or removed by proteolysis, or both. Accordingly, the half-life of STAT 1 can be prolonged by preventing dephosphorylation, through inhibition of phosphotyrosine phosphatases. Finally, there are inhibitors of JAK/STAT signalling that are induced by STATs. 

Papin, J.A. and Palsson, B.O. (2004a). The JAK-STAT signaling network in the human B-cell an extreme signaling pathway analysis. Biophys. J. 87, 37-46. 

Yamada S, Shiono S, Joo A, Yoshimura A. Control mechanism of JAK/STAT signal transduction pathway. FEBS Lett. 

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. 

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