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Phosphorylation status determines the opposing functions of Smad2/Smad3 as STAT3 cofactors in TH17 differentiation

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  • Jeong-Hwan Yoon

    (Graduate School of Comprehensive Human Sciences and Faculty of Medicine, University of Tsukuba
    Tokyo Medical University
    Kyungpook National University School of Medicine)

  • Katsuko Sudo

    (Animal Research Center, Tokyo Medical University)

  • Masahiko Kuroda

    (Tokyo Medical University)

  • Mitsuyasu Kato

    (Graduate School of Comprehensive Human Sciences and Faculty of Medicine, University of Tsukuba)

  • In-Kyu Lee

    (Kyungpook National University School of Medicine)

  • Jin Soo Han

    (Institute for the 3Rs, College of Veterinary Medicine, Konkuk University)

  • Susumu Nakae

    (Laboratory of Systems Biology, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, University of Tokyo)

  • Takeshi Imamura

    (Graduate School of Medicine, Ehime University, Shitsukawa)

  • Juryun Kim

    (Catholic University of Korea)

  • Ji Hyeon Ju

    (Catholic University of Korea)

  • Dae-Kee Kim

    (College of Pharmacy, Ewha Womans University)

  • Koichi Matsuzaki

    (Kansai Medical University)

  • Michael Weinstein

    (Ohio State University)

  • Isao Matsumoto

    (University of Tsukuba)

  • Takayuki Sumida

    (University of Tsukuba)

  • Mizuko Mamura

    (Tokyo Medical University
    Kyungpook National University School of Medicine)

Abstract

Transforming growth factor-β (TGF-β) and interleukin-6 (IL-6) are the pivotal cytokines to induce IL-17-producing CD4+ T helper cells (TH17); yet their signalling network remains largely unknown. Here we show that the highly homologous TGF-β receptor-regulated Smads (R-Smads): Smad2 and Smad3 oppositely modify STAT3-induced transcription of IL-17A and retinoic acid receptor-related orphan nuclear receptor, RORγt encoded by Rorc, by acting as a co-activator and co-repressor of STAT3, respectively. Smad2 linker phosphorylated by extracellular signal-regulated kinase (ERK) at the serine 255 residue interacts with STAT3 and p300 to transactivate, whereas carboxy-terminal unphosphorylated Smad3 interacts with STAT3 and protein inhibitor of activated STAT3 (PIAS3) to repress the Rorc and Il17a genes. Our work uncovers carboxy-terminal phosphorylation-independent noncanonical R-Smad–STAT3 signalling network in TH17 differentiation.

Suggested Citation

  • Jeong-Hwan Yoon & Katsuko Sudo & Masahiko Kuroda & Mitsuyasu Kato & In-Kyu Lee & Jin Soo Han & Susumu Nakae & Takeshi Imamura & Juryun Kim & Ji Hyeon Ju & Dae-Kee Kim & Koichi Matsuzaki & Michael Wein, 2015. "Phosphorylation status determines the opposing functions of Smad2/Smad3 as STAT3 cofactors in TH17 differentiation," Nature Communications, Nature, vol. 6(1), pages 1-14, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8600
    DOI: 10.1038/ncomms8600
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