Abstract
Phosphorylation of Tyr(705) and Ser(727) of signal transducer and activator of transcription 3 (STAT3) are known to be required for maximal activation by diverse stimuli. Tyr(705) phosphorylation is generally accepted to be mediated by the Janus kinase family. But the mechanism for STAT3 (Ser(727)) phosphorylation is not well understood. Here, we provide evidence that UVA-induced phosphorylation of STAT3 at Ser(727) is inhibited by pretreatment of JB6 cells with PD98059 or SB202190. Phosphorylation of STAT3 (Ser(727)) 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 (Ser(727)) 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 (Ser(727)). Additionally, the role of MAPKs in mediating UVA-stimulated DNA binding activity of STAT3 was investigated. Overall, these results suggest that UVA-induced Ser(727) phosphorylation of STAT3 may occur through MSK1 and JNKs.
Highlights
Kinase [9] or the extracellular signal-regulated kinases (ERKs) [10]
We provide evidence that UVA-induced Ser727 phosphorylation of signal transducer and activator of transcription 3 (STAT3) may occur through Jun N-terminal kinases (JNKs) and mitogen- and stress-activated protein kinase 1 (MSK1), a downstream kinase of both ERKs and p38 kinase
UVA-induced Ser727 phosphorylation was inhibited by pretreatment of JB6 cells with either AG1478 or PD153035 (Fig. 2B), but total levels of STAT3 were unchanged in EgfrϪ/Ϫ cells or after pretreatment with EGFR inhibitors (Fig. 2)
Summary
Kinase [9] or the extracellular signal-regulated kinases (ERKs) [10]. Later, a serine phosphorylation of STAT3, as well as STAT1, 4 and 5, was found to be induced in a stimulus-related manner [4]. STAT3 signaling activation by environmental stresses, such as heat and osmotic shock, short wave UV light, free radicals, or hypoxia, was shown to involve induction of multiple signaling pathways [15,16,17] These findings, indicate that STAT3 may be a convergent point for integrating signals from multiple pathways [18]. In the UVB/UVC response, activation of STAT3 signaling was triggered by phosphorylation at Ser727 but not at Tyr705 [16, 17, 23]. To facilitate an understanding of the role for the STAT3 signaling pathway in UVA-induced skin carcinogenesis, the serine/threonine kinase pathways through which Ser727 in STAT3 is phosphorylated in UVA-irradiated epidermal JB6 cells were investigated. We provide evidence that UVA-induced Ser727 phosphorylation of STAT3 may occur through JNKs and mitogen- and stress-activated protein kinase 1 (MSK1), a downstream kinase of both ERKs and p38 kinase
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