MSK1 and JNKs Mediate Phosphorylation of STAT3 in UVA-irradiated Mouse Epidermal JB6 Cells

Phosphorylation of Tyr⁷⁰⁵ and Ser⁷²⁷ of signal transducer and activator of transcription 3 (STAT3) are known to be required for maximal activation by diverse stimuli. Tyr⁷⁰⁵ phosphorylation is generally accepted to be mediated by the Janus kinase family. But the mechanism for STAT3 (Ser⁷²⁷) phosphorylation is not well understood. Here, we provide evidence that UVA-induced phosphorylation of STAT3 at Ser⁷²⁷ is inhibited by pretreatment of JB6 cells with PD98059 or SB202190. Phosphorylation of STAT3 (Ser⁷²⁷) is also markedly prevented by a dominant negative mutant of ERK2, c-Jun N-terminal kinase 1 (JNK1), or p38 kinase and in knockout Jnk1^-/- or Jnk2^-/- cells. Furthermore, STAT3 (Ser⁷²⁷) phosphorylation is suppressed by C- or N-terminal "kinase-dead" mutants of mitogen- and stress-activated protein kinase 1 (MSK1), a downstream kinase of ERKs and p38 kinase, and H89, a potential MSK1 inhibitor. In vitro experiments showed that active MSK1 and JNKs, but not ERKs or p38 kinase, phosphorylate STAT3 (Ser⁷²⁷). Additionally, the role of MAPKs in mediating UVA-stimulated DNA binding activity of STAT3 was investigated. Overall, these results suggest that UVA-induced Ser⁷²⁷ phosphorylation of STAT3 may occur through MSK1 and JNKs.