JAK-STAT signaling pathway
The JAK-STAT signaling pathway transmits information from chemical signals outside the cell, through the cell membrane, and into gene promoters on the DNA in the cell nucleus, which causes DNA transcription and activity in the cell. The JAK-STAT system is a major signaling alternative to the second messenger system.
Many JAK-STAT pathways are expressed in white blood cells, and are therefore involved in regulation of the immune system.
The receptor is activated by a signal from interferon, interleukin, growth factors, or other chemical messengers. This activates the kinase function of JAK, which autophosphorylates itself (phosphate groups act as "on" and "off" switches on proteins). The STAT protein then binds to the phosphorylated receptor, where STAT is phosphorylated by JAK. The phosphorylated STAT protein binds to another phosphorylated STAT protein (dimerizes) and translocates into the cell nucleus. In the nucleus, it binds to DNA and promotes transcription of genes responsive to STAT.
In mammals, there are seven STAT genes, and each one binds to a different DNA sequence. STAT binds to a DNA sequence called a promoter, which controls the expression of other DNA sequences. This affects basic cell functions, like cell growth, differentiation and death.
The JAK-STAT pathway is evolutionarily conserved, from slime molds and worms to mammals (but not fungi or plants). Disrupted or dysregulated JAK-STAT functionality (which is usually by inherited or acquired genetic defects) can result in immune deficiency syndromes and cancers.
JAKs, which have tyrosine kinase activity, bind to some cell surface cytokine receptors. The binding of the ligand to the receptor triggers activation of JAKs. With increased kinase activity, they phosphorylate tyrosine residues on the receptor and create sites for interaction with proteins that contain phosphotyrosine-binding SH2 domains. STATs possessing SH2 domains capable of binding these phosphotyrosine residues are recruited to the receptors, and are themselves tyrosine-phosphorylated by JAKs. These phosphotyrosines then act as binding sites for SH2 domains of other STATs, mediating their dimerization. Different STATs form hetero- or homodimers. Activated STAT dimers accumulate in the cell nucleus and activate transcription of their 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 tyrosine kinases such as c-src.
The pathway is negatively regulated on multiple levels. Protein tyrosine phosphatases remove phosphates from cytokine receptors and activated STATs. More recently identified suppressors of cytokine signalling (SOCS) inhibit STAT phosphorylation by binding and inhibiting JAKs or competing with STATs for phosphotyrosine binding sites on cytokine receptors. STATs are also negatively regulated by protein inhibitors of activated STAT (PIAS), which act in the nucleus through several mechanisms. For example, PIAS1 and PIAS3 inhibit transcriptional activation by STAT1 and STAT3 respectively by binding and blocking access to the DNA sequences they recognize.
- Janus kinase inhibitor, a type of Janus kinases-blocking drugs
- Aaronson DS, Horvath CM (May 2002). "A road map for those who don't know JAK-STAT". Science 296 (5573): 1653–5. doi:10.1126/science.1071545. PMID 12040185.
- Brooks, Andrew (2014). "Mechanism of activation of protein kinase JAK2 by the growth hormone receptor". Science 344 (6185): 1249783. doi:10.1126/science.1249783. PMID 24833397.
- Hebenstreit D, Horejs-Hoeck J and Duschl A (2005). "JAK/STAT-dependent gene regulation by cytokines". Drug News Perspect 18 (4): 243–249. doi:10.1358/dnp.2005.18.4.908658. PMID 16034480. 16034480.
- Krebs DL, Hilton DJ (2001). "SOCS proteins: negative regulators of cytokine signaling". Stem Cells 19 (5): 378–87. doi:10.1634/stemcells.19-5-378. PMID 11553846.
- Shuai K (2006). "Regulation of cytokine signaling pathways by PIAS proteins". Cell Research 16 (2): 196–202. doi:10.1038/sj.cr.7310027. PMID 16474434. 16474434.
- Schroder K, Hertzog PJ, Ravasi T, Hume DA (February 2004). "Interferon-gamma: an overview of signals, mechanisms and functions". J. Leukoc. Biol. 75 (2): 163–89. doi:10.1189/jlb.0603252. PMID 14525967.
- O'Shea JJ, Gadina M, Schreiber RD (April 2002). "Cytokine signaling in 2002: new surprises in the Jak/Stat pathway". Cell 109 (Suppl): S121–31. doi:10.1016/S0092-8674(02)00701-8. PMID 11983158.