JAK-STAT signal path
The JAK-STAT signaling pathway is a special signal transmission mechanism in some multicellular organisms. It contributes to the regulation of cell development, growth control and homeostasis . JAK = Janus kinase , STAT = Signal Transducers and Activators of Transcription ( STAT proteins ).
The JAK-STAT signaling pathway offers eukaryotic cells a possibility to transmit the information of extracellular signal peptides from the cell membrane intracellularly to the promoters of the target genes in the cell nucleus. It was originally discovered in the treatment of cells with interferons , which are particularly secreted by white blood cells in response to viral infections. In addition to interferons, interleukins from the group of cytokines and from the group of hormones erythropoietin , prolactin and growth hormone are typical ligands for the cytokine receptors involved. The JAK-STAT signaling pathway is found in slime molds, worms, flies and vertebrates , but not in fungi and plants.
JAKs provide tyrosine kinase activity on the activated cytokine receptor
In general, extracellular signal peptides such as growth factors are bound to target cells by specific transmembrane receptors with intrinsic (own) tyrosine kinase activity. In contrast to this, most of the cytokine receptors of the JAK-STAT pathway have no intrinsic tyrosine kinase activity. Instead, this is provided by receptor-associated cytoplasmic proteins of the Janus kinase (JAK, formerly Just Another Kinase) family. JAKs are evolutionarily conserved, with four different variants being found in mammalian cells (JAK1, JAK2, JAK3 and TYK2). The importance of JAKs, especially in the immune system , is underlined by hereditary immunodeficiencies in which the receptor-kinase association or kinase activity is disrupted by mutations . JAKs bind to specific sites on intracellular receptor domains and catalyze their mutual ligand-induced tyrosine phosphorylation, which increases their kinase activity. Then it comes to the phosphorylation of tyrosines of the receptor.
JAKs phosphorylate and activate STATs
The newly created phosphotyrosines on the receptor are crucial for the transmission of the signal. They represent binding sites for Src-homology 2 (SH2) domains , which are part of all signal transducers and activators of transcription (STATs) and are located near the carboxy terminus. After the STATs bind to the phosphorylated receptor via their SH2 domain, they are also phosphorylated by the JAKs on a tyrosine (Y701 in STAT1), so that binding sites for SH2 domains also arise on their surface. This tyrosine is carboxy-terminal, a few amino acid residues away from the SH2 domain. After dissociation from the receptor, the phosphotyrosines of two STATs are recognized reciprocally, whereby the SH2 domain of one STAT binds the phosphotyrosine of the other and an activated dimer is formed.
Like JAKs, STATs are also evolutionarily conserved. In mammals, their family has seven members (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6). Upon activation of the receptor, depending on the receptor and ligand, homo- or heterodimerization of certain STATs occurs. Ligand- and receptor-specific JAKs are also involved. Interferon γ with the participation of JAK1 and JAK2 leads to the homodimerization of STAT1 and interferon α / β with the participation of JAK1 and TYK2 leads to the heterodimerization of STAT1 and STAT2.
Activated STATs act in the core as transcription factors
The nuclear localization signal ( NLS ) exposed by the activated dimers leads directly to their translocation into the nucleus, where they perform their task as transcription factors . The JAK-STAT signal path therefore represents a direct route into the core and does not require a second messenger . The latent transcription factors activated on the plasma membrane are directly involved in other events in the nucleus . The DNA binding domain (DBD) is responsible for the recognition of specific promoter sequences. Seen from the SH2 domain, it lies N-terminally and is connected to it via a so-called linker domain. Most dimers recognize an 8-10 base pair long palindromic DNA element with the consensus sequence 5'-TT (N4-6) AA-3 '. This is usually referred to as the GAS sequence, which reflects its original characterization as a γ-interferon activation sequence, which is recognized by STAT1 homodimers. After the STAT dimer binds to the promoter, its transcription rate increases sharply, which proves the ability of the STATs to recruit additional coactivators that mediate chromatin modifications and communication with general transcription factors.
literature
- JE Darnell Jr. , Proc. Natl. Acad. Sci. USA 94, 11767 (1997)
- WJ Leonard, Int. J. Hematol. 73, 271 (2001)
- T. Decker, DJ Lew, J. Mirkovitch, JE Darnell Jr., EMBO J. 10, 927 (1991)