JAK-STAT signaling pathway

The JAK-STAT signaling pathway transmits information from extracellular chemical signals to the nucleus resulting in DNA transcription and expression of genes involved in immunity, proliferation, differentiation, apoptosis and oncogenesis. The JAK-STAT signalling cascade consists of three main components: a cell surface receptor, a Janus kinase (JAK) and two Signal Transducer and Activator of Transcription (STAT) proteins. Disrupted or dysregulated JAK-STAT functionality can result in immune deficiency syndromes and cancers.

Janus kinase (JAK) is a family of intracellular, nonreceptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. They were initially named "just another kinase" 1 and 2 (since they were just two of a large number of discoveries in a PCR-based screen of kinases) but were ultimately published as "Janus kinase". The name is taken from the two-faced Roman god of beginnings and endings, Janus, because the JAKs possess two near-identical phosphate-transferring domains. One domain exhibits the kinase activity, while the other negatively regulates the kinase activity of the first.

Members of the signal transducer and activator of transcription (STAT) protein family are intracellular transcription factors that mediate many aspects of cellular immunity, proliferation, apoptosis and differentiation. They are primarily activated by membrane receptor-associated Janus kinases (JAK). Dysregulation of this pathway is frequently observed in primary tumors and leads to increased angiogenesis, enhanced survival of tumors and immunosuppression. Gene knockout studies have provided evidence that STAT proteins are involved in the development and function of the immune system and play a role in maintaining immune tolerance and tumor surveillance. There are seven mammalian STAT family members that have been identified: STAT1, STAT2, STAT3, STAT4, STAT5 (STAT5A and STAT5B), and STAT6.

The binding of various ligands, usually cytokines, such as interferon, interleukin, and growth factors to cell surface receptors, activate associated JAKs, increasing their kinase activity. Activated JAKs then phosphorylate tyrosine residues on the receptor, creating binding sites for proteins possessing SH2 domains. SH2 domain containing STATs are recruited to the receptor where they are also tyrosine-phosphorylated by JAKs. These activated STATs form hetero- or homodimers and translocate to the cell nucleus where they induce transcription of target genes. STATs may also be tyrosine-phosphorylated directly by receptor tyrosine kinases, such as the epidermal growth factor receptor, as well as by non-receptor (cytoplasmic) tyrosi/ne kinases such as c-src.

In the past decades, studies of the Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) signaling have uncovered highly conserved programs linking cytokine signaling to the regulation of essential cellular mechanisms such as proliferation, invasion, survival, inflammation and immunity.

Targeting of JAK/STAT pathway in cancer is currently one of the most promising therapeutic strategies in prostate cancer (PCa), hematopoietic malignancies and sarcomas.

Readings and References

The JAK-STAT Signaling Pathway: Input and Output Integration -- Journal of Immunology

JAK-STAT signaling in cancer: From cytokines to non-coding genome.

The JAK/STAT Pathway -- Cold Spring Harbor Perspectives in Biology

Targeting the STAT3 signaling pathway in cancer: Role of synthetic and natural inhibitors

Revisiting STAT3 signalling in cancer: new and unexpected biological functions