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Jak stat pathway
- 1. TOPIC- JAK STAT PATHWAY SUBMITTEDBY- TANUSHREE AND MUSKAN
- 2. JAK STAT PATHWAY (JANUSKINAS SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION) • Also known as CYTOKINE SIGNALLING PATHWAY • Chain of interactions between proteins in a cell, involved in processes • This pathway communicates information from • Resulting in activation of genes through a process known as TRANSCRIPTION • This pathway stimulates cytokine which regulates many biological processes Cell Cell nucleus Via, chemical signals Cell proliferation Cell differentiation Apoptosis Immune regulation
- 3. 3 KEY COMPONENTS JANUSKINASE (JAK) RECEPTOR TYROSINE KINASE (RTK) SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION (STAT)
- 4. STRUCTURE OF JAK JAKProteins JAK 1 JAK 2 JAK 3 TYK 2 4 DOMAINS FERM domain SH2 domain PSEUDOKINASE domain KINASE domain FERM domain – mediates binding of CYTOKINE RECEPTORS FERM + PSEUDOKINASE domain- regulate CATALYTIC ACTIVITY & appear to INTERACT with the KINASE domain KINASE domain- to phosphorylate proteins (vital for activity)
- 5. JAKs auto phosphorylateat ' MULTIPLE SITES ' Including TWO in the ACTIVATION LOOP of the KINASE DOMAIN.
- 6. STRUCTURE OF STAT STATPROTEINS STAT DOMAINS • STAT 1 • STAT 2 • STAT 3 • STAT 4 • STAT 5A • STAT 5B • STAT 6 1. N- TERMINAL domain 2. COILED COIL domain 3. DNA BINDING domain 4. LINKER domain 5. SH2 domain 6. TRANS- ACTIVATION domain N- TERMINAL DOMAIN- dimerization COILED COIL DOMAIN- nuclear receptor binding co-repressor SMRT binding DNA BINDING DOMAIN- importin binding LINKER DOMAIN- DNA binding SH2 DOMAIN- receptor binding dimerization TRANS ACTIVATION DOMAIN
- 7. JAK- STAT SIGNALLINGPATHWAY SIGNALLING MOLECULE- CYTOKINE RECEPTOR- CYTOKINE RECEPTOR CELLULAR ACTIVATORS / SECOND MESSENGERS- JAK STAT CROSS PHOSPHORYLATION TRANSCRIPTION FACTORS- STAT DIMER CELLULAR EFFECTS- Lymphocyte development Gamma signalling NK Cell activation WBC Formation OVERVIEW
- 8. MECHANISM OF JAKSTAT SIGNALLING PATHWAY ACTIVATED BY CYTOKINES
- 9. CYTOKINES binds totheir receptors DIMERISATION ACTIVATES JAK proteins associated with the receptors & come closer This phosphorylation ATTRACTS INACTIVE STATS JAK KINASES phosphorylates STATS DIMERISE using SH2 DOMAINS STAT DIMER travels to the NUCLEUS STAT DIMER binds DNA & activates GENE TRANSCRIPTION ( dimerization of separate cytokine subunit) (kinase then PHOSPHORLATES parts of the receptor subunits/ tyrosine residues) (new dimer undergoes conformational changes during phosphorylation)
- 10. JAK STAT PATHWAYACTIVATED BY ALPHA- INTERFERON Alpha Interferon is a Cytokine produced by the INNATE IMMUNITY in response to environmental exposures including viral infections This has been developed as therapy of several forms of cancer & viral infections BUT major use has been as therapy of CHRONIC HEPATITIS C.
- 11. MECHANISM SIGNALLING MOLECULE- alpha interferon RECEPTOR-TYK2 & JAK2 STAT ACTIVATED- STAT1 & STAT2 RESPONSE- increase cell response to viral infection BINDING of interferon CROSS LINKS adjacent receptors JAKs CROSS PHOSPHORYLATE eachother ON TRYOSINE ACTIVATED JAKs PHOSPHORYLATES RECEPTORS STATs DOCK on specific phosphotryosines JAKs phosphorylates them STATs DISSOCIATES from RECEPTORS DIMERISES by SH2 domain STATs migrates to NUCLEUS BIND to DNA & other gene regulation TARGET GENE TRANSCRIPTION
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