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Cited by 81Cytokine Signaling Pathways and InteractionsNF-κB Signaling PathwaysTGF-β signaling in diseases

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

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Kojima, Hirotada, Sasaki, Takanori, Ishitani, Tohru, Iemura, Shun-ichiro, Zhao, Hong, Kaneko, Shuhei, Kunimoto, Hiroyuki, Natsume, Tohru +2 more·2005·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0500679102PMC PMC555521
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Abstract

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 STAT3 534–770 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.

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  • Direct binding of NLK to STAT3 results in phosphorylation of STAT3 at Ser727, requiring activity of the TAK1-NLK cascade.

    “Direct binding of NLK to STAT3 resulted in phosphorylation of STAT3 at Ser727, which requires the activity of the TAK1-NLK cascade [22,23].”

    From Nemo-Like Kinase in Development and Diseases: Insights from Mouse Studies (2020) · cites this paper as [23]

    The Results show that STAT3 and NLK interact in a complex and that the TAK1–NLK pathway contributes to STAT3 Ser-727 phosphorylation in IL-6 signaling. The interaction experiments do not establish direct binding, and the paper reports that TGFβ-activated NLK did not phosphorylate STAT3 at Ser-727. The claim omits that signaling-specific qualification. (LLM, conf=0.86)

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Cited by

Sorted by citations

Authors
Kojima, H., Sasaki, T., Ishitani, T., Iemura, S.-I., Zhao, H., Kaneko, S., Kunimoto, H., Natsume, T., Matsumoto, K., & Nakajima, K.
Affiliations
Osaka City University (JP)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2005-03-11
Volume
102
Issue
12
Pages
4524-4529
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0500679102
PMC
PMC555521
OpenAlex
W1983370748
Cited by
81
References
1
Citations by year
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FWCI
2.50
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
Boehringer Ingelheim Japan
Topics
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
Keywords
STAT3, Nemo-like kinase, TAK1, IL-6 signaling, gp130, TGF-beta signaling, IL-6 family cytokines, signal transduction
MeSH terms
MAP Kinase Kinase Kinase 7, Amino Acid Sequence, Base Sequence, Binding Sites, Carrier Proteins, Cell Line, DNA, DNA-Binding Proteins, Enzyme Activation, Humans, Phosphorylation, Recombinant Fusion Proteins, Recombinant Proteins, Serine, Signal Transduction, Trans-Activators, Interleukin-6, Amino Acid Motifs, MAP Kinase Kinase Kinases, RNA Interference, Multiprotein Complexes, STAT3 Transcription Factor, I-kappa B Kinase

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