JAK STAT Pathway.pptx

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1. Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) signaling pathway Saif Imtiyaz M Pharm, Pharmacology Jamia Hamdard

2. Introduction 03-06 Mechanism of JAK-STAT pathway 07 Regulation 08-11 Response of JAK STAT transduction pathway 12- 16 References 17 Presentation Outlines

3. In human body, numerous processes are required for coordinating individual cells to support the body as a whole. At the cellular level, Sensing of environments and cell communication for coordination relies on signal transduction. SIGNAL TRANSDUCTION is a process occurring within cells that convert one kind of signal/stimulus into another type. It also known as cell signaling in which the transmission of molecular signals from a cell's exterior to its interior. It is also defined as the ability of a cell to change behavior in response to a receptor-ligand interaction(signal). Introduction

4. Cells express a family of receptors for cytokines such as γ-interferon and hormones such as growth hormone and prolactin. These receptors have no intrinsic enzymatic activity; rather, binding of the cytokine causes dimerization of the receptor and recruits a separate, intracellular tyrosine kinase termed a JAK (Janus kinase) which binds to the cytoplasmic tails of the receptor. The JAK-STAT system consists of three main components: a receptor Janus kinase (JAK) and Signal Transducer and Activator of Transcription (STAT)

5. JAK- Family of cytoplasmic non-receptor tyrosine kinases which get activated after the binding of a cytokine to the cell-surface cytokine receptor. STAT- Family of transcription factors that become activated when one of the tyrosine residues is phosphorylated by JAK. JAKs trans-phosphorylate and lead to the phosphorylation of the STATs (signal transducer and activator of transcription). The phosphorylated STATs translocate to the nucleus and regulate transcription. The entire pathway is termed the JAK-STAT pathway. 

6. The JAK-STAT (Janus kinase-signal transducer and activator of transcription) signaling pathway is a chain of interactions between proteins in a cell, and is involved in processes such as immunity, cell division, cell death and tumor formation. JAK activation stimulates cell proliferation, differentiation, cell migration and apoptosis. These cellular events are critical to hematopoiesis, immune development, mammary gland development and lactation and other processes.

7. Mechanism of JAK-STAT In the first step the ligands bind to its receptor and dimerizes the receptor. This causes the activation of JAK. JAK phosphorylates tyrosine residue on itself (auto-phosphorylation). The freely moving STAT molecules in the cytoplasm goes and attaches to the phosphorylated tyrosine residue. JAK also phosphorylates the STAT protein and dimerizes it. Activated STAT dimers accumulate in the cell nucleus and activate transcription of their target genes.

8. Negative Regulation Protein Tyrosine Phosphatases dephosphorylates the tyrosine kinase receptor and STAT. SOCS (Suppressors of Cytokine Signaling) inhibit STAT phosphorylation by binding and inhibiting JAK or competing with STAT for phosphorylated tyrosine. PIAS (Protein Inhibitor of Activated STAT) are in the nucleus and correspond with different STATs to inhibit Transcription.

9. Protein inhibitors of activated STATs (PIAS) There are three ways PIAS proteins can inhibit JAK-STAT signaling. A. Adding a SUMO(small ubiquitin-like modifier) group to STATs can block their phosphorylation, which prevents STATs entering the nucleus. B. HDAC (histone deacetylase) recruitment can remove acetyl modifications on histones, lowering gene expression. C. PIAS can also prevent STATs binding to DNA.

10. Protein tyrosine phosphatases (PTPs) Since adding phosphate groups on tyrosine is such an important part of how the JAK-STAT signaling pathway functions, removing these phosphate groups can inhibit signaling. PTPs are tyrosine phosphatases, so are able to remove these phosphates and prevent signaling. PTPs can also remove phosphates from phosphorylated STATs

11. Suppressors of cytokine signalling (SOCS) It has an SH2 domain and a 40-amino-acid region called the SOCS box. The SOCS box can interact with a number of proteins to form a protein complex, and this complex can then cause the breakdown of JAKs and the receptors themselves, therefore inhibiting JAK-STAT signaling. The protein complex does this by allowing a marker called ubiquitin to be added to JAK or receptors, which signals for a protein to be broken down.

12. Response of JAK STAT transduction pathway Responses include proliferation, differentiation, migration, apoptosis, and cell survival. Essential for numerous developmental and homeostatic processes, including hematopoiesis, immune cell development, stem cell maintenance, organism growth and mammary gland development. Human JAK mutations cause numerous diseases, including SCID(Severe combined immunodeficiency), hyper IgE syndrome, certain leukemias and other disorders. Small molecular weight cell membrane-permeable drugs that target this pathways have been developed for leukemia therapy. (JAK Inhibitors)

13. Activation of JAK/STAT pathway mediated by GH (growth hormone). JAK/STAT pathway components are inactive. GH and two Growth Hormone Receptors(GHRs) form a ternary complex that induces association and autophosphorylation of JAK2 and of docking sites on the cytoplasmic tail of GHRs. JAK2 phosphorylates cytoplasmic proteins that activate downstream signaling pathways, including STAT5 and mediators upstream of MAPK, once activated, STAT forms dimers that are translocated to the cell nucleus. The STAT dimers in the nucleus are capable of binding to IGF-I ( Insulin-like growth factor 1 ) promoter, which ultimately modulate gene expression.

14. Pegvisomant is GH analog with amino acid substitution that disrupt site 2. It binds the receptor and cause its internalization but cannot trigger the conformational changes that stimulate downstream event in the transduction pathway.

15. Activation of JAK/STAT pathway mediated by Prolactin Prolactin exerts its effects via prolactin receptors (PLR). The binding of prolactin to PLR activates the JAK family of kinases which in turn phosphorylate and activate STAT5. This enables STAT5 to translocate to the nucleus and bind to respective STAT response elements on DNA leading to transcription of DNA sequence motif, GAS [milk protein genes]. STAT5 is also activated by cytokines such as IL-2. CR (cytokines receptor) can form a complex with activated STAT5. This complex enhances STAT5-dependent transcription and would diminish the levels free intracellular CS(corticosteroids)/CR complexes leading to reduced GRE(Glucocorticoid Receptor)-mediated effects. The net effect would be increased levels of expression of activated NF-B and STAT5.

16. Brunton L.L., & Hilal-Dandan R, & Knollmann B.C.(Eds.), (2017).  Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e . McGraw Hill. 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 References

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