STAT-Dependent Gene Expression without Tyrosine Phosphorylation

The initial discovery that Stats 1 and 2 are activated in response to IFNs through the phosphorylation of specific tyrosine residues, followed by dimerization through phosphotyrosine-SH2 interactions (Figure 1A) (1) led quickly to an appreciation that the same mechanism held true for ligand-dependent activation of all of the other Stats. However, more recently, it has been found that Stats 1 and 3 (and probably other Stats) also play important roles in mediating gene expression without tyrosine phosphorylation. When expressed at normal levels, Stats 1 and 3 support the ligand-independent constitutive transcription of certain genes, and abnormally high levels of Stat3, found in many tumors, drive the overexpression of these genes. Furthermore, ligand-dependent transcription, resulting from the phosphorylation on a specific serine residue in the transactivation domain of Stat 1 or 3, can also drive gene expression without tyrosine phosphorylation. Stat1 mediates constitutive expression of the LMP2 gene (Figure 1B) by collaborating with IRF1 (2), and this mechanism is likely to serve as a paradigm in general for how Stats mediate gene expression without tyrosine phosphorylation. Stats are sticky and can interact with many different proteins. Stat1 and IRF1 bind to each other even in the absence of DNA, and this heterodimer binds to a composite element in the LMP2 promoter that recognizes each monomeric component separately. The ternary complex is stable enough to drive the constitutive expression of LMP2 but can be displaced by the more potent Stat1 dimer in IFNγ-treated cells.