STAT3 Serine Phosphorylation by ERK-Dependent and -Independent Pathways Negatively Modulates Its Tyrosine Phosphorylation

TLDR

Serine phosphorylation regulates STAT1 and STAT3 activity, yet the kinases involved and its functional impact remain unclear. The study examined growth‑factor‑dependent serine phosphorylation of STAT1 and STAT3. ERK MAP kinases specifically phosphorylate STAT3 at Ser727, a modification that retards its mobility and negatively regulates the tyrosine phosphorylation essential for dimerization, nuclear translocation, and DNA binding; IL‑6 also induces Ser727 phosphorylation through an ERK‑independent pathway, while STAT1 is a poor substrate for MAP kinases.

Abstract

Recent studies have indicated that serine phosphorylation regulates the activities of STAT1 and STAT3. However, the kinase(s) responsible and the role of serine phosphorylation in STAT function remain unresolved. In the present studies, we examined the growth factor-dependent serine phosphorylation of STAT1 and STAT3. We provide in vitro and in vivo evidence that the ERK family of mitogen-activated protein (MAP) kinases, but not JNK or p38, specifically phosphorylate STAT3 at serine 727 in response to growth factors. Evidence for additional mitogen-regulated serine phosphorylation is also provided. STAT1 is a relatively poor substrate for all MAP kinases tested both in vitro and in vivo. STAT3 serine phosphorylation, not its tyrosine phosphorylation, results in retarded mobility of the STAT3 protein on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Importantly, serine 727 phosphorylation negatively modulates STAT3 tyrosine phosphorylation, which is required for dimer formation, nuclear translocation, and the DNA binding activity of this transcriptional regulator. Interestingly, the cytokine interleukin-6 also stimulates STAT3 serine phosphorylation, but in contrast to growth factors, this occurs by an ERK-independent process.