The STAT transcription factors transmit type I/II cytokine signals downstream of the JAKs.There are seven members of the mammalian STAT family: STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6. STAT proteins contain an amino terminal, a coiled coil, a DNA-binding domain (DBD), a linker, a Src-homology2 (SH2), and a transcriptional activation domain (TAD). Inactive cytoplasmic STATs exist primarily as monomers or preformed dimers; upon activation, STAT dimers form a nutcracker-like structure. The highly conserved SH2 domain forms the hinge of this structure and is the target of most patented STAT inhibitors. The linker region and DBD surround the centrally located chromatin like the jaws of the nutcracker, whereas the TAD is located at the C terminus and undergoes serine phosphorylation to recruit additional transcriptional activators and enhance transcriptional activity. These areas display the lowest sequence conservation. Given the involvement of STATs in signaling events downstream of cytokine receptors as well as growth factors, STATs have long been considered as potential therapeutic targets for cancer and autoimmune disease.


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