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. Structure of JAKs and STATs 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. Mechanism 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. The activated JAKs then phosphorylate tyrosine residues on the receptor, creating binding sites for proteins possessing SH2 domains. STATs then bind to the phosphorylated tyrosines on the receptor using their SH2 domains, and then they are tyrosine-phosphorylated by JAKs, causing the STATs to dissociate from the receptor. At least STAT5 requires glycosylation at threonine 92 for strong STAT5 tyrosine phosphorylation. These activated STATs form hetero- or homodimers, where the SH2 domain of each STAT binds the phosphorylated tyrosine of the opposite STAT, and the dimer then translocates to the cell nucleus to induce transcription of target genes. STATs may also be tyrosine-phosphorylated directly by receptor tyrosine kinases - but since most receptors lack built-in kinase activity, JAKs are usually required for signalling. Movement of STATs from the cytosol to the nucleus To move from the cytosol to the nucleus, STAT dimers have to pass through nuclear pore complexes (NPCs), which are protein complexes present along the nuclear envelope that control the flow of substances in and out of the nucleus. To enable STATs to move into the nucleus, an amino acid sequence on STATs, called the nuclear localization signal (NLS), is bound by