JAK-STAT signaling pathway

JAK -STAT signaling pathway is a specific signaling mechanism in several multi-cellular organisms. It contributes to the regulation of cell development, growth control, and homeostasis. JAK = Janus kinase, STAT = signal transducer and Activator of Transcription ( STAT proteins ).

JAK -STAT pathway provides for eukaryotic cells is a possibility that information of extracellular signal peptide of the cell membrane, intracellular forward to the promoters of the target genes in the nucleus. It was originally discovered in the treatment of cells with interferons, which are secreted by white blood cells, particularly in response to viral infections. From the group of cytokines are interferons and interleukins next, as well as typical of the group of hormones erythropoietin, prolactin and growth hormone ligands for the cytokine receptors involved. The JAK -STAT signaling pathway is represented in slime molds, worms, flies and vertebrates, but not in fungi and plants.

JAKs are the tyrosine kinase activity of the activated cytokine ready

In general, extracellular signal peptides such as growth factors on target cells of specific transmembrane receptors with intrinsic (own ) tyrosine kinase are bound. In contrast, most of the cytokine receptors of the JAK -STAT pathway not have intrinsic tyrosine kinase activity. Instead of these receptor-associated cytoplasmic proteins of the Janus kinase ( JAK, formerly Just Another Kinase ) family is provided. JAKs are evolutionarily conserved, with four different variants are found in mammalian cells ( JAK1, JAK2, JAK3 and TYK2 ). The importance of JAKs, particularly in the immune system is underscored by hereditary Immunodefizienzen in which the receptor - kinase association or the kinase activity is disrupted by mutations. JAKs bind to specific sites of intracellular receptor domains and catalyze their mutual ligand-induced tyrosine phosphorylation, which increases its kinase activity. Then it comes to the phosphorylation of tyrosine residues of the receptor.

JAKs phosphorylate and activate STATs

The newly created phosphotyrosines at the receptor are critical for the transmission of the signal. They provide binding sites for Src homology 2 (SH2 ) domains represent the part of all signal transducer and activator of transcription ( STATs ), and are near the carboxy terminus. After binding of STATs through its SH2 domain to the phosphorylated receptor also they ( Y701 in STAT1 ) is phosphorylated by the JAKs on a tyrosine, so that also occur on their surface binding sites for SH2 domains. This tyrosine is located carboxy terminal, some amino acid residues away from the SH2 domain. After dissociation from the receptor, the STATs are detected Phosphotyrosine two reciprocally, with the SH2 domain of a STAT phosphotyrosine respectively and the other binds an activated dimer is formed.

Also STATs are as JAKs evolutionarily conserved. In mammals Their family consists of seven members ( STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6 ). Upon activation of the receptor, and depending on receptor and ligand for the homo - or heterodimerization of certain STATs. Similarly, ligand- and receptor-specific JAKs are involved. Thus, interferon γ leads JAK1 and JAK2 with the participation of the homodimerization of STAT1 and interferon α / β with the participation of JAK1 and TYK2 for heterodimerization of STAT1 and STAT2.

Activated STATs act in the nucleus as transcription factors

The exposed by the activated dimers nuclear localization signal ( NLS) leading directly to their translocation into the nucleus, where they carry out their duties as transcription factors. The JAK -STAT signaling pathway therefore represents a direct route into the nucleus and does not constitute a second messenger from. The activated at the plasma membrane latent transcription factors are directly involved in other events in the nucleus. For the recognition of specific promoter sequences, the DNA binding domain (DBD ) is responsible. It is of the SH2 domain N-terminal of view and is connected thereto via a so-called linker domain. Most dimers recognize a 8-10 base pair palindromic DNA element with the consensus sequence 5'- TT (N4 -6) AA -3 '. Typically, these will be referred to as a gas - sequence, which is recognized by STAT1 homodimers their initial characterization as γ - interferon- activation sequence, reflecting. After binding of the STAT dimer at the promoter whose transcription rate increases sharply, the ability of STATs is to recruit other coactivators that mediate chromatin and communication with general transcription factors.