JAK-STAT signaling pathway

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 the process of 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). Disrupted JAK-STAT signalling may lead to a variety of diseases, such as skin conditions, cancers, and disorders affecting the immune system. Main articles: JAKs and STATs There are four JAK proteins: JAK1, JAK2, JAK3 and TYK2. JAKs contains a FERM domain (approximately 400 residues), an SH2-related domain (approximately 100 residues), a kinase domain (approximately 250 residues) and a pseudokinase domain (approximately 300 residues). The kinase domain is vital for JAK activity, since it allows JAKs to phosphorylate (add phosphate groups to) proteins. There are seven STAT proteins: STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B and STAT6. STAT proteins contain many different domains, each with a different function, of which the most conserved region is the SH2 domain. The SH2 domain is formed of 2 α-helices and a β-sheet and is formed approximately from residues 575–680. STATs also have transcriptional activation domains (TAD), which are less conserved and are located at the C-terminus. In addition, STATs also contain: tyrosine activation, amino-terminal, linker, coiled-coil and DNA-binding domains. The binding of various ligands, usually cytokines, such as interferons and interleukins, to cell-surface receptors, causes the receptors to dimerize, which brings the receptor-associated JAKs into close proximity. The JAKs then phosphorylate each other on tyrosine residues located in regions called activation loops, through a process called transphosphorylation, which increases the activity of their kinase domains.