STAT3 regulates Nemo-like kinase by mediating its interaction with IL-6-stimulated TGFβ-activated kinase 1 for STAT3 Ser-727 phosphorylation

Hirotada Kojima, Takanori Sasaki, Tohru Ishitani, Shun Ichiro Iemura, Hong Zhao, Shuhei Kaneko, Hiroyuki Kunimoto, Tohru Natsume, Kunihiro Matsumoto, Koichi Nakajima

研究成果: Contribution to journalArticle査読

65 被引用数 (Scopus)

抄録

Signal transducer and activator of transcription 3 (STAT3) is activated by the IL-6 family of cytokines and growth factors. STAT3 requires phosphorylation on Ser-727, in addition to tyrosine phosphorylation on Tyr-705, to be transcriptionally active. In IL-6 signaling, the two major pathways that derive from the YXXQ and the YSTV motifs of gp130 cause Ser-727 phosphorylation. Here, we show that TGF-β-activated kinase 1 (TAK1) interacts with STAT3, that the TAK1-Nemo-like kinase (NLK) pathway is efficiently activated by IL-6 through the YXXQ motif, and that this is the YXXQ-mediated H7-sensitive pathway that leads to STAT3 Ser-727 phosphorylation. Because NLK was recently shown to interact with STAT3, we explored the role of STAT3 in activating this pathway. Depletion of STAT3 diminished the IL-6-induced NLK activation by >80% without inhibiting IL-6-induced TAK1 activation or its nuclear entry. We found that STAT3 functioned as a scaffold for TAK1 and NLK in vivo through a region in its carboxyl terminus. Furthermore, the expression of the STAT3534-770 region in the nuclei of STAT3-knockdown cells enhanced the IL-6-induced NLK activation in a dose-dependent manner but not the TGFβ-induced NLK activation. TGFβ did not cause STAT3 Ser-727 phosphorylation, even when the carboxyl region of STAT3 was expressed in the nuclei. Together, these results indicate that STAT3 enhances the efficiency of its own Ser-727 phosphorylation by acting as a scaffold for the TAK1-NLK kinases, specifically in the YXXQ motif-derived pathway.

本文言語英語
ページ(範囲)4524-4529
ページ数6
ジャーナルProceedings of the National Academy of Sciences of the United States of America
102
12
DOI
出版ステータス出版済み - 3 22 2005
外部発表はい

All Science Journal Classification (ASJC) codes

  • 一般

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