Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFκB

TLDR

IL‑6 and related gp130 cytokines trigger tyrosine‑phosphorylated STAT3, which activates numerous genes including STAT3 itself. Unphosphorylated STAT3 accumulates after IL‑6 stimulation, binds unphosphorylated NFκB to form a nuclear complex that activates κB‑dependent genes, and also regulates other genes via NFκB‑independent pathways, providing a distinct late‑phase signaling mechanism. Elevated U‑STAT3 levels are likely crucial for gene regulation in response to gp130 cytokines and in cancers with constitutively active STAT3.

Abstract

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 κB elements that are activated by a novel transcription factor complex formed when U-STAT3 binds to unphosphorylated NFκB (U-NFκB), in competition with IκB. The U-STAT3/U-NFκB complex accumulates in the nucleus with help from the nuclear localization signal of STAT3, activating a subset of κB-dependent genes. Additional genes respond to U-STAT3 through an NFκB-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.