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The JAK-STAT Signaling Pathway

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The discovery of the JAK-STAT signal transduction pathway began in the 1950s with attempts to understand the mechanism of gene induction by interferon signaling11. The JAK-STAT signaling mechanism is the most common signaling mechanism used by cytokine receptors, especially hematopoietic cytokine receptors, to transmit a signal from an external cytokine to the nucleus resulting in activation of transcription. It is estimated that over 50 cytokine receptors signal via the JAK-STAT pathway4,9,12 .

Janus Kinases (JAKs) are non-receptor tyrosine kinases that are non-covalently associated with the cytoplasmic domains of cytokine receptors. To date, four JAKs have been identified, JAK 1, 2, and 3, and TYK21-13. STATs (Signal Transducer and Activator of Transcription) are transcription factors that are activated by tyrosine phosphorylation by JAKs. Once activated STATs translocate to the nucleus where they bind to regulatory elements in cytokine responsive genes. Seven STATs have been identified so far: STAT1, 2, 3, 4, 5A, 5B, and 61-13.

JAKs are large tyrosine kinases of more than 1,100 amino acids13. Structurally, JAKs are composed of seven Janus Homology Domains (JHDs) which can be further organized into four functional domains: an N-terminal FERM domain that mediates receptor binding, an SH2 domain, a pseudokinase domain that attenuates kinase activity, and a C-terminal tyrosine kinase domain4,5,8,12.

STATs are transcription factors of 750-850 amino acids3. They are composed of seven domains: an N-terminal domain, a coiled coil domain, a DNA binding domain, a linker domain, an SH2 domain, a transactivation domain, and a C-terminal domain8,12.

Cytokine receptors lack intrinsic signaling ability. When activated by cytokine binding, oligomerization and conformational changes in the cytoplasmic domains of the receptors activate the associated JAKs, bringing them into close proximity with one another resulting in auto- and trans-tyrosine phosphorylation4,10,12. These phosphorylation events provide a scaffold for the recruitment of STATs which are then phosphorylated by the associated JAKs. The activated STATs then move into the nucleus where they dimerize and bind to DNA regulatory sequences, activating transcription4,10,12.

JAKs bind preferentially to certain cytokine receptor chains by virtue of their FERM and SH2 domains7, and thus have very distinct physiological effects. Many of these effects are most obvious in hematopoiesis and immune regulation2,10,13. For example, deletion of JAK1, JAK3, and TYK2 result in defects in lymphopoiesis, while loss of JAK2 results in embryonic lethality due to a profound defect in erythropoiesis2. JAK1 and JAK3 are vital for signaling through receptors that utilize the common gamma chain (γc) such as Il-2, IL-4, IL-7, and IL-15. Thus loss of JAK 1 and/or 3 results in profound immunodeficiency10. Similarly, JAK2 is critical for signaling through the erythropoietin receptor (EPOR)10 and thus for production of red blood cells. STATs also demonstrate a degree of specificity for certain receptors but they have a greater ability to complement one another in case of a loss10.

JAKs and STATs have been shown to play significant roles in the development of cancers and autoimmune diseases, as well as immunodeficiency1,2,4-7,9,10,12. Hyperactivation of JAK-STAT signaling is a common finding in both cancer and autoimmune diseases. As such, this pathway represents an attractive therapeutic target. A number of JAK inhibitors (aka jacinibs) are currently being evaluated in the clinic, and STAT inhibitors are being developed2,9,10,12. Because of the wide pleiotropic effects of JAK-STAT signaling, the effects of these inhibitors on the immune system must be closely monitored.

JAK-STAT diagram

 

Below is the entire list of targets involved in JAK-STAT Signaling research. Can’t find what you are looking for? Bethyl offers a custom antibody service.

 

References

1. Casanova JL, Holland SM, Notarangelo LD. 2012. Inborn errors of human JAKs and STATs. Immunity 36(4):515-28. PMID: 22520845.

2. Chen E, Staudt LM, Green AR. 2012. Janus kinase deregulation in leukemia and lymphoma. Immunity 36(4):529-41. PMID: 22520846.

3. Darnell JE Jr. 1997. STATs and gene regulation. Science 277(5332):1630-5. PMID: 9287210.

4. Hammarén HM, Virtanen AT, Raivola J, Silvennoinen O. 2018. The regulation of JAKs in cytokine signaling and its breakdown in disease. Cytokine Apr 20. pii: S1043-4666(18)30127-3. PMID: 29685781.

5. Hubbard SR. 2018. Mechanistic Insights into Regulation of JAK2 Tyrosine Kinase. Front Endocrinol (Lausanne). PMID: 29379470.

6. Johnson DE, O'Keefe RA, Grandis JR. 2018. Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat Rev Clin Oncol. 15(4):234-248. PMID: 29405201.

7. Leroy E, Constantinescu SN. 2017. Rethinking JAK2 inhibition: towards novel strategies of more specific and versatile Janus kinase inhibition. Leukemia 31(5):1023-1038. PMID: 28119526.

8. Nan Y, Wu C, Zhang YJ. 2017. Interplay between Janus Kinase/Signal Transducer and Activator of Transcription Signaling Activated by Type I Interferons and Viral Antagonism. Front Immunol. 8:1758. PMID: 29312301.

9. O'Shea JJ, Plenge R. 2012. JAK and STAT signaling molecules in immunoregulation and immune-mediated disease. Immunity 36(4):542-50. PMID: 22520847.

10. Schwartz DM, Bonelli M, Gadina M, O'Shea JJ. 2016. Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases. Nat Rev Rheumatol. 12(1):25-36. PMID: 26633291.

11. Stark GR, Darnell JE Jr. 2012. The JAK-STAT pathway at twenty. Immunity 36(4):503-14. PMID: 22520844

12. Villarino AV, Kanno Y, O'Shea JJ. 2017. Mechanisms and consequences of Jak-STAT signaling in the immune system. Nat Immunol. 18(4):374-384. PMID: 28323260.

13. Yamaoka K, Saharinen P, Pesu M, Holt VE 3rd, Silvennoinen O, O'Shea JJ. 2004. The Janus kinases (Jaks). Genome Biol. 5(12):253. PMID: 15575979.