JAK:STAT pathway

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. 

Immune Defense JAK-STAT Pathway PIAS proteins Map Kinase Cascades Toll-like Receptors Growth Factors... 

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... 

On binding to its receptor, the IFN molecule is sandwiched between the two chains of the receptor, thus forming a ternary complex that activates the canonical Jak/Stat pathway through activation of the transduction elements located in the intracyto-plasmic tail of each receptor subunit (Fig. 1). 

Darnell JE Jr, Kerr IM, Stark GR Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 1994 264 l4l5. 

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. 

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

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. 

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