Protein kinase C delta associates with and phosphorylates Stat3 in an interleukin-6-dependent manner

Stat3 is activated by phosphorylation on Tyr-705, which leads to dimer form ation, nuclear translocation, and regulation of gene expression. Serine pho sphorylation of Stat3 by mitogen-activated protein kinase has also been obs erved in cells responding to epidermal growth factor and shown to affect it s tyrosine phosphorylation and transcriptional activity. Serine phosphoryla tion of Stat3 is also induced by interleukin-6 (IL-6) stimulation, which is shown to be independent of mitogen activated protein kinase and sensitive to the Ser/ Thr kinase inhibitor H7. In this study, we investigated whether protein kinase C (PKC) is the kinase that is induced and responsible for S tat3 serine phosphorylation by IL-6 stimulation and which isoform of PKCs i s likely to be involved. Here, we report that Stat3 was specifically associ ated with PKC delta in vivo in an IL-6-dependent manner in several cell typ es. Furthermore, Stat3 was phosphorylated by PKC delta in vivo on Ser-727, which could be inhibited either by a specific PKC delta inhibitor or by a d ominant-negative mutant of PKC delta. Finally, we showed that the phosphory lation of Stat3 by PKC delta led to a negative regulation of Stat3 DNA bind ing and transcriptional activity. These results indicate that PKC delta is likely to be the kinase that phosphorylates Stat3 in response to IL-6 stimu lation and suggest a possible regulatory role of PKC delta on Stats functio n.