The JAK-STAT pathway

The intracellular events triggered upon binding of type I or II IFNs to their respective receptors are quite similar. The sequence of events, known as the JAK-STAT pathway, has been elucidated only in the last few years. It has quickly become apparent that this pathway plays a prominent role in mediating signal transduction, not only for IFN but also for many cytokines. 

Cytokine receptors can be divided into two groups those whose intracellular domains exhibit intrinsic protein tyrosine kinase (PTK) activity, and those whose intracellular domains are 

Not surprisingly, different ligands activate different members of the STAT family (Table 4.6). Some, e.g. STAT 1 and 3, are activated by many ligands, while others respond to far fewer ligands, e.g. STAT 2 appears to be activated only by type I IFNs. 

STAT phosphorylation ensures its binding to the receptor, with subsequent disengagement from the receptor in dimeric form. STAT dimerization is believed to involve intermolecular associations between the SH2 domain of one STAT and phosphotyrosine of its partner. Dimerization appears to be an essential prerequisite for DNA binding. Dimers may consist of two identical STATs, but STAT 1-STAT 2 and STAT 1-STAT 3 heterodimers are also frequently formed in response to certain cytokines. The STAT dimers then translocate to the 

Disassociation (and dimerization) of activated STATs, and translocation to nucleus 

STATs are differentially distributed in various cells/tissues. STATs 1,2 and 3 seem to be present in most cell types, all be it at varying concentrations. Tissue distribution of STATs 4 and 5 is more limited. 

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Cytokine receptors are a group of structurally related receptors, which couple to the JAK-STAT pathway. Cytokine receptors function as homodimers or heterooligomers. They are divided into two main subclasses, class I, which contains receptors for a variety of hematopoietic growth factors and interleukins and class II, which contains receptors for interferons and interleukins 10, 20/24 and 22. 

JAK-STAT Pathway. Figure 1 Activating and inhibitory mechanisms of the JAK-STAT pathway. 

The cytokine leptin is secreted by adipocytes (fat cells) in proportion to the size of the adipose dq>ot and circulates via the bloodstream to the brain, where it ultimately affects feeding behavior, endocrine systems including reproductive function and, at least in rodents, energy expenditure. The major effect of Lqrtin is on the hy-pothalamous, where it suppresses appetite and hence food intake. Leptin exerts its effects via binding to the leptin receptor in the brain (specifically in the hypothalamus), which activates the JAK-STAT Pathway. 

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... 

Vila-Coro AJ, Rodriguez-Frade JM, Martin De Ana A, Moreno-Ortiz MC, Martinez AC, Mellado M. The chemokine SDF-lalpha triggers CXCR4 receptor dimerization and activates the JAK/STAT pathway. FASEB J 1999 13(13) 1699-1710. 

Figure 8.2 Simplified overview of the signal transduction process mediated by the JAK-STAT pathway. Refer to text for specific details...

A number of proteins that inhibit the JAK-STAT function have also been identified. These include members of the so-called SOCS/Jab/Cis family and the PIAS family of regulatory proteins. Several appear to function by inhibiting the activation of various STATs, although the mechanisms by which this is achieved remain to be elucidated in detail. The JAK-STAT pathway likely does not function in isolation within the cell. JAKs are believed to activate elements of additional signalling pathways, and STATs are also likely activated by factors other than JAKs. As such, there may be considerable crosstalk between various JAK- and/or STAT-dependent signalling pathways. 

The molecular basis by which interferons promote their characteristic effects, in particular antiviral activity, is understood at least in part. Interferon stimulation of the JAK-STAT pathway induces synthesis of at least 30 different gene products, many of which cooperate to inhibit viral replication. These antiviral gene products are generally enzymes, the most important of which are 2 -5 oligoadenylate synthetase (2,5-A synthetase) and the eIF-2a protein kinase. 

O Shea, J.J., Gadina, M., and Schreiber, R.D. 2002. Cytokine signalling in 2002 new surprises in the JAK/STAT pathway. Cell 109, S121-S131. 

Young Could it be that the CRY interaction with PIAS3 has to do with regulation of the Jak/Stat pathway Have you looked at light-dependent regulation of the pathway ... 

The Jak-Stat pathway for the interferons a, P and y has been well investigated. The interferon y pathway uses Statl protein, which binds as a homodimer to the correspon-... 

Several factors determine the specificity and diversification of signal transduction in the Jak-Stat pathway (see DameU et al., 1994) ... 

In total, TGPP-Smad signal conduction has distinct similarities to signal conduction in the Jak-Stat pathway (see 11.1.3). In both pathways, cytosolic transcription factors are activated by phosphorylation and are translocated in oligomeric complexes to the nucleus and the DNA. Common to both pathways is the short distance from the extracellular signal to the transcription level. 

Another approach to the management of IM resistance is to combine agents that are individually active against CML but have differing mechanisms of action that may allow either additive or synergistic effects in a non-cross-resistant marmer. This approach has been extensively studied in the literature and will not be reviewed in detail here. An excellent discussion of combination therapy is foimd in the reviews by Hochhaus and La Rosee (52,85). Some combination approaches have utilized famesyl transferase inhibition such as lonafamib in combination with IM, inhibitors of the mammalian target of rapamycin (mTOR) in combination with IM and combining mycophenolic acid, an inhibitor of the JAK-STAT pathway. 

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). 

Harada M, Qin Y Takano H, et al. G-CSF prevents cardiac remodeling after myocardial infarction by activating the Jak-Stat pathway in cardiomyocytes. Nat Med 2005 I 1(3)305-3 I I. 

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