STAT3

STAT3, or signal transducer and activator of transcription 3, is a transcription factor in the STAT family that relays signals from cytokine and growth factor receptors to the nucleus. It is activated by phosphorylation on tyrosine 705 by JAK kinases following receptor engagement, leading to dimerization, nuclear translocation, and binding to DNA at gamma-activated sequences to regulate gene transcription. Serine 727 phosphorylation can further modulate transcriptional activity. Structurally, STAT3 contains an N-terminal domain, a coiled-coil region, a central DNA-binding domain, an SH2 domain, and a C-terminal transcriptional activation domain, all contributing to dimerization, DNA binding, and transcriptional activation.

STAT3 is activated by a broad range of cytokines and growth factors, most prominently the IL-6 family through the gp130 receptor, as well as IL-10, IL-11, oncostatin M, and LIF. Upstream kinases such as JAK1, JAK2, and TYK2 phosphorylate STAT3, which then induces transcription of target genes involved in cell survival (BCL2, BCLXL, MCL1), proliferation (Cyclin D1, c-Myc), and angiogenesis (VEGF), among others. It also induces SOCS3 as part of a negative feedback loop. In the immune system, STAT3 promotes differentiation of Th17 cells and modulates regulatory T cell function, influencing inflammatory responses and host defense.

Dysregulated or constitutive STAT3 signaling is linked to cancer and inflammatory diseases, where it supports tumor cell survival, immune evasion, and metastasis. Negative regulation includes SOCS proteins and PIAS family members; aberrant activation can result from upstream mutations, autocrine cytokine signaling, or persistent inflammatory stimuli. Therapeutic strategies aim to inhibit STAT3 directly (for example, SH2-domain antagonists or decoy oligonucleotides) or indirectly by blocking upstream JAKs or IL-6 signaling; several agents are under investigation, though achieving selective and safe inhibition remains challenging.