JAK-STAT signaling pathway

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The JAK-STAT 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 tumour formation. The pathway communicates information from chemical signals outside of a cell to the cell nucleus, resulting in the activation of genes through a process called transcription. There are three key parts of JAK-STAT signalling: Janus kinases (JAKs), signal transducer and activator of transcription proteins (STATs), and receptors (which bind the chemical signals).

Janus kinase

Janus kinase or tyrosine-protein kinase JAK (JAK) are nonreceptor tyrosine kinases which transduces cytokine-mediated signals via the JAK-STAT pathway. The JAK-STAT pathway transmits signals through the cell membrane to DNA promoters thus causing transcription. The name JAK is derived from Just Another Kinase. JAK proteins contain 2 phosphate-transfer domains, one with kinase activity using a phosphotyrosine (PTyr) and the other a pseudokinase domain which negatively regulates the kinase domain. JAK contains seven Janus homology domains named JH1-7. JAK family members are JAK1, JAK2, JAK3 and TYK2[1].
JAK1 and TYK2 are involved in signaling by members of type I and type II cytokine receptors.
JAK2 is involved in signaling by members of the interferon receptors (type II cytokines).
JAK3 is predominantly active in immune cells. JAK3 is activated by cytokines whose receptors contain the common γ chain subunit (interleukin 2,4,7,9,15,21).
TYK2 is a component of type I and type III interferon signaling pathways. See Tyrosine kinase.

Jak3 inhibitors are tested in treatment of autoimmune diseases and transplant rejection[2].

Mutations in Jak2 are associated with chronic myeloproliferative neoplasms, polycythemia vera, essential thrombocytosis and primary myelofibrosis[3]. Mutations in Jak3 are associated with immune deficiency.

Jak2 containing phosphotyrosine binds the thienopyridine potent inhibitor in the ATP-binding pocket[4]. Water molecules shown as red spheres.

Signal transducer and activator of transcription proteins (STATs)


JAK2 kinase domain complex with inhibitor thienopyridine 3tjc

Drag the structure with the mouse to rotate

References

  1. ↑ Liu KD, Gaffen SL, Goldsmith MA, Greene WC. Janus kinases in interleukin-2-mediated signaling: JAK1 and JAK3 are differentially regulated by tyrosine phosphorylation. Curr Biol. 1997 Nov 1;7(11):817-26. PMID:9382798
  2. ↑ O'Shea JJ, Kontzias A, Yamaoka K, Tanaka Y, Laurence A. Janus kinase inhibitors in autoimmune diseases. Ann Rheum Dis. 2013 Apr;72 Suppl 2:ii111-5. doi: 10.1136/annrheumdis-2012-202576. PMID:23532440 doi:http://dx.doi.org/10.1136/annrheumdis-2012-202576
  3. ↑ Levine RL. Janus kinase mutations. Semin Oncol. 2009 Apr;36(2 Suppl 1):S6-11. doi: 10.1053/j.seminoncol.2009.02.005. PMID:19393837 doi:http://dx.doi.org/10.1053/j.seminoncol.2009.02.005
  4. ↑ Schenkel LB, Huang X, Cheng A, Deak HL, Doherty E, Emkey R, Gu Y, Gunaydin H, Kim JL, Lee J, Loberg R, Olivieri P, Pistillo J, Tang J, Wan Q, Wang HL, Wang SW, Wells MC, Wu B, Yu V, Liu L, Geuns-Meyer S. Discovery of Potent and Highly Selective Thienopyridine Janus Kinase 2 Inhibitors. J Med Chem. 2011 Nov 16. PMID:22087750 doi:10.1021/jm200911r

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