Cytokines and STAT Signaling

https://doi.org/10.1016/S1054-3589(08)60111-8Get rights and content
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Signal transducers and activators of transcription (STATs) represent a family of conserved proteins, seven of which have been identified in mammals. STATs are now known to play a significant role in signal transduction for most cytokines. Homologues of STATs have also been identified in lower eukaryotes. Janus kinases (JAKs) are receptor-associated tyrosine kinases that mediate the ligand dependent activation of STATs. These two protein families are the defining components of the JAK-STAT pathway. The JAK-STAT signaling paradigm has been well characterized for many ligands. This enables receptor-associated JAKs to become activated that, in turn, phosphorylate tyrosine motifs in the cytoplasmic tail of the receptor. These receptor tyrosine motifs are recognized by the src homology (SH)2 domains of STATs, thereby mediating the recruitment of the appropriate STAT to the receptor complex. Once at the receptor, JAKs phosphorylate STATs on a conserved tyrosine activated STATs are released from the receptor and dimerize through the interaction of the SH2 domain of one STAT with the phosphotyrosine of the other STAT. These dimers translocate to the nucleus, where they bind to the members of the GAS (IFN-gamma activation site) family of enhancers, culminating in the transcription of genes. Thus, STATs transduce high-fidelity signals directly from the cell surface to the target genes. In recent times, significant progress has been made in the characterization of the JAK-STAT signaling cascade. Important developments have included the establishment of murine “knockout” models and the resolution of the crystal structure of two STATs. Another exciting area of progress has been in the identification of molecules that modify signaling through the STAT pathway.

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