Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NF kappa B

gp130-linked cytokines such as interleukin- 6 (IL-6) stimulate the formation of tyrosine-phosphorylated signal transducer and activator of transcription 3 (P- STAT3), which activates many genes, including the STAT3 gene itself. The resulting increase in the concentration of unphosphorylated STAT3 (U- STAT3) drives a second wave of expression of genes such as RANTES, IL6, IL8, MET, and MRAS that do not respond directly to P- STAT3. Thus, U- STAT3 sustains cytokine- dependent signaling at late times through a mechanism completely distinct from that used by P- STAT3. Many U- STAT3- responsive genes have kappa B elements that are activated by a novel transcription factor complex formed when U- STAT3 binds to unphosphorylated NF kappa B (U-NF kappa B), in competition with I kappa B. The U-STAT3/U-NF kappa B complex accumulates in the nucleus with help from the nuclear localization signal of STAT3, activating a subset of kappa B-dependent genes. Additional genes respond to U- STAT3 through an NF kappa B- independent mechanism. The role of signal- dependent increases in U- STAT3 expression in regulating gene expression is likely to be important in physiological responses to gp130-linked cytokines and growth factors that activate STAT3, and in cancers that have constitutively active P- STAT3.