BLOCK-iT™ RNAi Express

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JAK/STAT Pathway

Cytokines regulate many different biological processes including haematopoiesis, inflammation, and immune responses. Many cytokines are recognized by members of the hematopoietin family of receptors that oligomerize in response to ligand binding and activate trans-phosphorylation of associated Janus kinases (JAKs). These tyrosine kinases subsequently phosphorylate the cytoplasmic tail of the cytokine receptor allowing recruitment and binding of SH2 domain containing proteins including members of the family of signal transducers and activators of transcription (STATs). STAT proteins are directly phosphorylated by receptor associated JAKs allowing dimerization, nuclear translocation, and activation of gene expression.

Cytokine signaling is tightly controlled within the cell through the action of multiple different negative regulators. Members of the supressors of cytokine signaling (SOCS) family specifically interfere with cytokine signaling by several different mechanisms including direct binding and inhibition of JAK proteins, competition with STAT for binding sites on the cytokine receptor, and activation of proteosomal degradation of signaling components through the recruitment of ubiquitin ligases. Additionally, JAK activity can be directly attenuated by specific tyrosine phosphatases and STATs can be negatively regulated by members of the PIAS protein family.

JAK/STAT Pathway Validated Stealth RNAi™ siRNA

JAK

STAT

Supressors of cytokine signaling (SOCS)

JAK phosphatases

Protein inhibitors of activated STATs (PIAS)

References

1.	Alexander, W.S. & Hilton, D.J. The role of supressors of cytokine signaling (SOCS) proteins in regulation of the immune response. Annu. Rev. Immunol. 22, 503-529 (2004).
2.	O'Shea, J.J. et al. A new modality for immunosupression: targeting the JAK/STAT pathway. Nat. Rev. Drug Discov. 3, 555-564 (2004).
3.	O'Shea, J.J. et al. Cytokine signaling in 2002: New surprises in the JAK/Stat pathway. Cell 109, S121-S131 (2002).
4.	Schindler, C.W. JAK-STAT signaling in human disease. J. Clin. Invest. 109, 1133-1137 (2002).
5.	Shua, K. & Liu, B. Regulation of JAK-STAT signaling in the immune system. Nat. Rev. Immunol. 3, 900-911 (2003).
6.	Wormald, S. & Hilton, D.J. Inhibitors of cytokine signal transduction. J. Biol. Chem. 279, 821-824 (2004).