Jak STAT Signalling Pathway

Dedicated At Thy Lotus Feet1

JAK STAT Signalling Pathway

Aum Sri Sai Ram2

Amit Kumar SahooI MSc BIOSCIENCES15151

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What Is Jak STAT?

The JAK-STAT(Janus kinasesignal transducer and activator of transcription) signalling pathway transmits information from chemical signals outside the cell, which causes DNA transcription and activity in the cell.

The JAK-STAT system is a major signalling alternative to the second messenger system.3

It acts through the cell membrane, and into gene promoters on the DNA in the cell nucleus.3

The JAK-STAT system consists of three main components:

(1) a receptor

(2) Janus kinase (JAK) and

(3) Signal Transducer and Activator of Transcription (STAT).

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Many JAK-STAT pathways are expressed in white blood cells, and are therefore involved in regulation of the immune system.

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MechanismJAKs, which have tyrosine kinase activity, bind to some cell surface cytokine receptors. The binding of the ligand to the receptor triggers activation of JAKs.

With increased kinase activity, they phosphorylate tyrosine residues on the receptor STATs possessing SH2 domains are recruited to the receptors, and are themselves tyrosine-phosphorylated by JAKs. Activated STAT dimers accumulate in the cell nucleus and activate transcription of their target genes.

STATs may also be tyrosine-phosphorylated directly by receptor tyrosine kinases, such as the epidermal growth factor receptor, as well as by non-receptor tyrosine kinases such as c-src.5

and create sites for interaction with proteins that contain phosphotyrosine-binding SH2 domains.

capable of binding these phosphotyrosine residues

These phosphotyrosines then act as binding sites for SH2 domains of other STATs, mediating their dimerization. Different STATs form hetero- or homodimers. 5

How Pathway Works.The receptor is activated by a signal from interferon, interleukin, growth factors, or other chemical messengers.

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This activates the kinase function of JAK, which autophosphorylates itself (phosphate groups act as "on" and "off" switches on proteins). The STAT protein then binds to the phosphorylated receptor, where STAT is phosphorylated by JAK. The phosphorylated STAT protein binds to another phosphorylated STAT protein (dimerizes) and translocates into the cell nucleus. In the nucleus, it binds to DNA and promotes transcription of genes responsive to STAT.6

Jason S. Rawlings et al. J Cell Sci 2004;117:1281-12832004 by The Company of Biologists Ltd

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Negative Regulation

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MechanismThe pathway is negatively regulated on multiple levels. Protein tyrosine phosphatases remove phosphates from cytokine receptors and activated STATs. Suppressors of cytokine signalling (SOCS) inhibit STAT phosphorylation.

Protein inhibitors of activated STAT (PIAS), which also act in the nucleus through several mechanisms.

For example, PIAS1 and PIAS3 inhibit transcriptional activation by STAT1 and STAT3 respectively by binding and blocking access to the DNA sequences they recognize.10

More recently identified

by binding and inhibiting JAKs or competing with STATs for phosphotyrosine binding sites on cytokine receptors. STATs are also negatively regulated by 10

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Interpreting experiments using STAT loss-of-function systems.Experiments with the different STAT knockout mice, and cellsderived from these animals, have been critical for understanding specific requirements of individual STATs in gene expression following cytokine receptor signalling.For example,STAT5a and STAT5b are essential for the expression of genes that promote hemopoietic survival whereas STAT1 is required for the expression of IFN-regulated genes that are involved in the protection against pathogens .

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The ExperimentAn initial example of this type of approach was performed by Schreiber and colleagues who interrogated gene expression profiles induced by IFN- signalling in the absence of STAT1.

Numerous genes were induced by IFN- in the absence of STAT1, leading to the conclusion that the IFN- R activates a STAT1-independent gene expression program.

However, inspection of the genes induced by IFN- signalling in STAT1-deficient cells shows many to be STAT3-regulated genes such as Socs3, Gadd45, and Cebpb.

In the absence of STAT1, STAT3 signalling is dominant.

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STAT3 phosphorylation is normally induced by IFN- in wild-type cells but 14

Conclusion form the ExperimentIt was concluded from experiments using STAT-deficient cells that receptor occupancy, or lack of occupancy by the dominant STAT that binds the receptor, causes a switch from one activated STAT to another.

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A converse example is the conversion of IL-6R signaling to a dominant STAT1 activation in STAT3- deficient cells (34). This switch causes the downstream induction of the IFN gene expression pathway just as IFN- would cause in wild-type cells.15

Another ExampleA related example is observed when IL-6 signalling is tested in the absence of SOCS3. SOCS3 is induced by STAT signalling from different cytokine receptors and functions as a feedback inhibitor of the IL-6R. However in the absence of SOCS3, STAT3 phosphorylation is greatly increased. At the same time however, STAT1 phosphorylation is also induced, leading to a dominant IFN-like gene expression signature.Although loss of gene expression may be observed in a given STAT knockout, a corresponding increase in the ectopic activation of another STAT pathway may confound the interpretation of results in both in vitro and in vivo systems.

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(and the G-CSFR, LIFR, and leptinR) by binding to phosphorylated Y757 on the gp130 cytoplasmic domain (see below).Thus SOCS3 regulates both the quantity and type of STAT signal generated from the IL-6R.

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Is there functional equivalence in signalling from receptors using the sameJAK-STAT combination in the same cell?In macrophages stimulated with either IL-10 or IL-6, the JAK1-STAT3 pathway is activated. Even though both the IL- 10R and IL-6R activate a seemingly identical process, the downstream readouts of signalling from these receptors are remarkably distinct.The major function of IL-10 is to negatively regulate inflammatory responses from activated macrophages and dendritic cells.Cytokine receptors that are unrelated to the IL-10R but activate STAT3 in a SOCS3-independent way activate the anti inflammatory response.

By contrast, receptors that are regulated by SOCS3 cannot activate the anti-inflammatory response, such as the IL-6R .However, the IL-6R robustly activates STAT3, even in wild-type cells where SOCS3 is active .

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IL-10-mediated activation of STAT3 targets one or more STAT3- regulated genes whose products are responsible for inhibiting inflammatory gene expression at the level of transcription.

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Two conclusions can be drawn from these studies that allude to an unknown aspect of JAK-STAT signaling: that receptors generate different pools of the same activated STAT but have overlapping yet distinct activities (Fig. 3).18

Facts About JAK STAT:-In mammals, there are seven STAT genes, and each one binds to a different DNA sequence. This affects basic cell functions, like cell growth, differentiation and death.In mammals, the JAK/STAT pathway is the principal signaling mechanism for a wide array of cytokines and growth factors. JAK activation stimulates cell proliferation, differentiation, cell migration and apoptosis. These cellular events are critical to hematopoiesis, immune development, mammary gland development and lactation, adipogenesis, sexually dimorphic growth and other processes. Mutations that constitutively activate or fail to regulate JAK signaling properly cause inflammatory disease, erythrocytosis, gigantism and an array of leukemias. The JAK-STAT pathway is evolutionarily conserved, from slime molds and worms to mammals (but not fungi or plants). Disrupted or dysregulated JAK-STAT functionality (which is usually by inherited or acquired genetic defects) can result in immune deficiency syndromes and cancers.19

. STAT binds to a DNA sequence called a promoter, which controls the expression of other DNA sequencesPredictably, mutations that reduce JAK/STAT pathway activity affect these processes (reviewed by Igaz et al., 2001; O'Shea et al., 2002). Conversely,Here we present a general overview of the JAK/STAT pathway and illustrate the primary mechanisms of activation and regulation of this essential signaling cascade.

Here we present a general overview of the JAK/STAT pathway and illustrate the primary mechanisms of activation and regulation of this essential signaling cascade.

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New Players on the FieldRecently Identified Cytokines and ReceptorsInterleukin (IL)-21 is a new member of the cytokine subfamily that binds the common chain, c, and is produced by activated T cells. (Asao et al. 2001 and Parrish-Novak et al. 2000). Thymic stromal lymphopoietin is another cytokine that binds the IL-7 chain, but apparently does not require c for signaling. (Pandey et al. 2000 and Park et al. 2000)Recently a new partner for p40 has been identified, p19. This new cytokine is denoted IL-23, and it binds IL-12R1 but not IL-12R2. (Oppmann et al., 2000)20

New cytokines and receptors are continuing to be identified, and it is likely that there are still a number yet to be characterized.

IL-12 is the product of two genes, which encode subunits designated p35 and p40, the latter having homology to cytokine receptors. The receptor WSX-1/TCCR has homology to IL-12R2, and its deficiency is associated with deficits in cell-mediated immune responses and IFN- production Chen et al. 2000b and Yoshida et al. 2001; this phenotype makes it a possible candidate for an IL-23R subunit.The IFN family or Type II family of cytokine receptors includes the receptors for IFN-/, IFN-, IFN-, and IL-10. New members of this family include limitin, IL-19, IL-20, IL-22/ IL-TIF, IL-24 (mda-7), and IL-26 (AK155) Blumberg et al. 2001, Takahashi et al. 2001 and Xie et al. 2000. The precise physiologic functions of these new cytokines are uncertain, but this will surely be of interest.

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References

21Thank YouSai Ram

The JAK-STAT Signaling Pathway: Inputand Output IntegrationThe JAK-STAT Signaling Pathway: InputPeter J. Murrayhttp://www.jimmunol.org/content/178/5/2623doi: 10.4049/jimmunol.178.5.2623

The JAK/STAT signaling pathwayJason S. Rawlings, Kristin M.Rosler and Douglas A. Harrison*University of Kentucky, Department of Biology, 101T.H. Morgan Bldg., Lexington, KY 40506, USA

Journal of Cell Science 117, 1281-1283Published by The Company of Biologists 2004doi:10.1242/jcs.00963