JAK/STAT signaling


The JAK-STAT signaling pathway enables extracellular chemical signals to cross the cell membrane and transmit information to gene promoters on DNA in the nucleus, ultimately causing changes in the level of DNA transcription and activity in the cell. The JAK-STAT system is the most important signaling pathway besides the second messenger system.

The JAK-STAT system consists of three main parts: (1)receptors, (2)Janus Kinases (JAKs), (3) signal transducers and activators of transcription (STATs).

Numerous JAK-STAT pathways are expressed in leukocytes and thus participate in the regulation of the immune system. Signals from interferons, interleukins, growth factors, or other chemical messengers can activate this receptor; this activates the kinase function of JAK, resulting in its phosphorylation (the phosphate group acts as a switch on the protein); next, STAT protein binds to a phosphorylated receptor, where STAT is phosphorylated by JAK; a phosphorylated STAT protein binds to another phosphorylated STAT protein (dimerization) and translocates into the nucleus; in In the nucleus, it binds to DNA and initiates transcription of genes that respond to STAT.

There are seven STAT genes in mammals, each of which binds to a different DNA sequence. STATs bind to DNA sequences called promoters, which control the expression of other DNA sequences. This affects basic cellular functions such as cell growth, differentiation and death. The JAK-STAT pathway is evolutionarily conserved, from slime molds and worms to mammals (but not fungi or plants). If the function of JAK-STAT is disrupted or dysregulated (usually inherited or acquired gene defects), it will lead to immunodeficiency syndrome and cancer



JAKs with tyrosine kinase activity bind to cytokine receptors on the surface of some cells; binding of ligand to the receptor triggers activation of the JAKs; As kinase activity increases, JAK can phosphorylate some tyrosine residues on the receptor and create sites that can interact with proteins containing the bound phosphotyrosine SH2 domain. The STATs containing the SH2 domain, which can bind these phosphotyrosine residues, is recruited to the receptor and phosphorylated by the JAKs tyrosine; These phosphotyrosines then act as binding sites for other STAT-like SH2 domains, mediating their dimerization; All types of STAT can form xor homodimer; Activated STAT dimers accumulate in the nucleus and activate the transcription of their target genes. Receptor tyrosine kinases, such as epidermal growth factor receptors, may directly phosphorylate STAT tyrosines; The STATs is also phosphorylated by non-receptor tyrosine kinases such as c-src.


This pathway is negatively regulated at several levels. Protein tyrosine phosphatases remove phosphate groups from cytokine receptors and activated STATs. Recently identified inhibitors of cytokine signaling (SOCS) inhibit the phosphorylation of STAT by binding to and inhibiting the phosphotyrosine sites of JAKs or competing with STATs on cytokine receptors. STATs are also negatively regulated by activated STAT protein inhibitors (PIAS), which play a role in the nucleus through various mechanisms. For example, PIAS1 and PIAS3 inhibit transcriptional activation caused by STAT1 and STAT3, respectively, by binding to and preventing them from entering the DNA sequence they recognize.

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