Jak stat signalling pathway

Jak Stat

1. Dedicated At Thy Lotus Feet 1

2. JAK STAT Signalling Pathway Aum Sri Sai Ram 2 Amit Kumar Sahoo I MSc BIOSCIENCES 15151

3. What Is Jak STAT? The JAK-STAT(Janus kinase–signal 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

4. 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). 4

5. Mechanism JAKs, 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

6. How Pathway Works. The receptor is activated by a signal from interferon, interleukin, growth factors, or other chemical messengers. 6

7. Jason S. Rawlings et al. J Cell Sci 2004;117:1281-1283 ©2004 by The Company of Biologists Ltd 7

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9. Negative Regulatio n 9

10. Mechanism The 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

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13. Interpreting experiments using STAT loss-of-function systems. Experiments with the different STAT knockout mice, and cells derived 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 . 13

14. The Experiment An 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. 14

15. Conclusion form the Experiment It 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. 15

16. Another Example A 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. 16

17. Is there functional equivalence in signalling from receptors using the same JAK-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 . 17

18. 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

19. 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. M utations 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

20. New Players on the Field—Recently Identified Cytokines and Receptors Interleukin (IL)-21 is a new member of the cytokine subfamily that binds the common γ chain, γc , 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-7α chain, but apparently does not require γc 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-12Rβ1 but not IL-12Rβ2. ( Oppmann et al., 2000) 20

21. References 21 Thank You Sai Ram The JAK-STAT Signaling Pathway: Input and Output Integration The JAK-STAT Signaling Pathway: Input Peter J. Murray http://www.jimmunol.org/content/178/5/2623 doi : 10.4049/jimmunol.178.5.2623 The JAK/STAT signaling pathway Jason S. Rawlings, Kristin M. Rosler and Douglas A. Harrison* University of Kentucky, Department of Biology, 101 T.H. Morgan Bldg., Lexington, KY 40506, USA Journal of Cell Science 117, 1281-1283 Published by The Company of Biologists 2004 doi:10.1242/jcs.00963