JAK-STAT signaling

What is JAK/STAT signaling?

The JAK (Janus kinase) /STAT (signal transducers and activators of transcription) signaling pathway is a cell's central communication node, activated by growth factors and cytokines, including hormones, interferons (IFNs), interleukins (ILs), and colony-stimulating factors. It consists of ligand-receptor complexes, JAKs, and STATs (1). JAKS are nonreceptor protein tyrosine kinases composed of JAK1, JAK2, JAK3, and TYK2. STATs have seven members, including STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6 (2). 

The JAK/STAT pathway transmits extracellular signals from cell-membrane receptors to the nucleus, which results in the transcription of genes involved in hematopoiesis, inflammation, immune system development, adipogenesis, tissue repair, apoptosis, and other biological processes (3, 4, 1).

Activation of JAK/STAT signaling pathway

JAK/STAT signaling pathway may be canonical and noncanonical. The canonical JAK/STAT signaling pathway is a conventional pathway in which JAKs become activated by the binding of receptors to an extracellular ligand (4). Upon activation, JAKs phosphorylate each other and the intracellular tail of their receptors (5). This, in turn, results in the formation of docking sites for STATs. JAKs phosphorylate STATs at the docking site, which then detach from the receptor (1). These STATs then dimerize, move to the nucleus, bind DNA, and regulate gene expression (1).

In the atypical or noncanonical JAK/STAT pathway, unphosphorylated STAT is found on heterochromatin (a repressive chromatin state) interacting with HP1 or heterochromatin protein-1 (a protein involved in heterochromatin formation and maintenance) in the nucleus (1, 6, 7). The noncanonical JAK/STAT signaling pathway is beneficial for maintaining HP1 localization and heterochromatin stability. In noncanonical JAK/STAT signaling, STAT phosphorylation leads to HP1 detachment from heterochromatin, leading to heterochromatin instability, which may promote tumor growth (4). 

JAK/STAT signaling may be regulated by various proteins, including N-myc & STAT Interactor (NMI), suppressor of cytokine signaling (SOCS), protein inhibitor of activated STAT (PIAS), and protein tyrosine phosphatase (PTP) to ensure equilibrium and stability for normal physiological functions (1, 4). 

Role of JAK/STAT in normal physiology and disease development

JAK/STAT is a pivotal signal transduction pathway driving cellular responses such as proliferation, migration, differentiation, angiogenesis, and apoptosis. This pathway is central to homeostasis and development, and its dysregulation from mutations or loss of JAK/STAT genes occurs in many diseases (5). 

In particular, it has been shown that the JAK/STAT pathways are involved in immune system responses, including fighting infections (8). For instance, JAK/STAT mediates the innate immune response, the first line of host defense against viral infection; its activation leads to the expression of IFN-stimulated genes and proinflammatory cytokines, initiating the antiviral state (9). 

Aberrant activation of the pathway results in proinflammatory cytokine signaling that interferes with immune function, which in turn, contributes to the pathogenesis of immune-mediated disease and cancer (10). Mutations in JAK1 have been tied to acute myeloid leukemia (AML) development. JAK2 mutations are often found in myeloproliferative neoplasms (MPN) and polycythemia vera. JAK3 mutations have been linked with lymphoma and leukemia (11, 1). 

Due to its relevance in human health and disease, this pathway is a recognized target in mainstay, novel, and emerging therapies for conditions including rheumatoid arthritis (RA), psoriasis, and systemic lupus erythematosus (SLE). For instance, Ruxolitinib is an FDA-approved JAK inhibitor for treating intermediate and high-risk primary myelofibrosis and is promising for treating rheumatoid arthritis and psoriasis. Tofacitinib is another FDA-approved JAK inhibitor recommended for treating rheumatoid arthritis (4). 

Researchers suggest that specifically targeting signaling pathways such as JAK/STAT is beneficial in developing more effective treatments that limit potential side effects and don’t interfere with related pathways.

References 

1. Hu X, Li J, Fu M, Zhao X, Wang W. The JAK/STAT signaling pathway: from bench to clinic. Signal Transduct Target Ther. 2021;6(1):402. Published 2021 Nov 26.
2. Ghoreschi K, Laurence A, O'Shea JJ. Janus kinases in immune cell signaling. Immunol Rev. 2009;228(1):273-287.
3. Moresi V, Adamo S, Berghella L. The JAK/STAT Pathway in Skeletal Muscle Pathophysiology. Front Physiol. 2019;10:500. Published 2019 Apr 30.
4. Seif F, Khoshmirsafa M, Aazami H, Mohsenzadegan M, Sedighi G, Bahar M. The role of JAK-STAT signaling pathway and its regulators in the fate of T helper cells. Cell Commun Signal. 2017;15(1):23. Published 2017 Jun 21.
5. Harrison DA. The Jak/STAT pathway. Cold Spring Harb Perspect Biol. 2012;4(3):a011205. Published 2012 Mar 1.
6. Hahn M, Dambacher S, Schotta G. Heterochromatin dysregulation in human diseases. J Appl Physiol (1985). 2010;109(1):232-242.
7. Jeon YH, Kim GW, Kim SY, et al. Heterochromatin Protein 1: A Multiplayer in Cancer Progression. Cancers (Basel). 2022;14(3):763. Published 2022 Feb 1.
8. Hu Q, Bian Q, Rong D, et al. JAK/STAT pathway: Extracellular signals, diseases, immunity, and therapeutic regimens. Front Bioeng Biotechnol. 2023;11:1110765. Published 2023 Feb 23.
9. Ezeonwumelu IJ, Garcia-Vidal E, Ballana E. JAK-STAT Pathway: A Novel Target to Tackle Viral Infections. Viruses. 2021;13(12):2379. Published 2021 Nov 27.
10. Tzeng HT, Chyuan IT, Lai JH. Targeting the JAK-STAT pathway in autoimmune diseases and cancers: A focus on molecular mechanisms and therapeutic potential. Biochem Pharmacol. 2021;193:114760.
11. O'Shea JJ, Schwartz DM, Villarino AV, Gadina M, McInnes IB, Laurence A. The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annu Rev Med. 2015;66:311-28.