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

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 Weinstein; Isao Matsumoto; Takayuki Sumida; Mizuko Mamura

doi:10.1038/ncomms8600

Phosphorylation status determines the opposing functions of Smad2/Smad3 as STAT3 cofactors in T_H17 differentiation

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 Weinstein, Isao Matsumoto, Takayuki Sumida, Mizuko Mamura

Department of Pharmaceutical Sciences

Research output: Contribution to journal › Article › peer-review

84 Scopus citations

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 (T_H17); 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 T_H17 differentiation.

Original language	English
Article number	7600
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms8600
State	Published - 21 Jul 2015

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© 2015 Macmillan Publishers Limited. All rights reserved.

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Yoon, J. H., Sudo, K., Kuroda, M., Kato, M., Lee, I. K., Han, J. S., Nakae, S., Imamura, T., Kim, J., Ju, J. H., Kim, D. K., Matsuzaki, K., Weinstein, M., Matsumoto, I., Sumida, T., & Mamura, M. (2015). Phosphorylation status determines the opposing functions of Smad2/Smad3 as STAT3 cofactors in T_H17 differentiation. Nature Communications, 6, Article 7600. https://doi.org/10.1038/ncomms8600

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

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.",

author = "Yoon, {Jeong Hwan} and Katsuko Sudo and Masahiko Kuroda and Mitsuyasu Kato and Lee, {In Kyu} and Han, {Jin Soo} and Susumu Nakae and Takeshi Imamura and Juryun Kim and Ju, {Ji Hyeon} and Kim, {Dae Kee} and Koichi Matsuzaki and Michael Weinstein and Isao Matsumoto and Takayuki Sumida and Mizuko Mamura",

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AU - Yoon, Jeong Hwan

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AU - Kuroda, Masahiko

AU - Kato, Mitsuyasu

AU - Lee, In Kyu

AU - Han, Jin Soo

AU - Nakae, Susumu

AU - Imamura, Takeshi

AU - Kim, Juryun

AU - Ju, Ji Hyeon

AU - Kim, Dae Kee

AU - Matsuzaki, Koichi

AU - Weinstein, Michael

AU - Matsumoto, Isao

AU - Sumida, Takayuki

AU - Mamura, Mizuko

PY - 2015/7/21

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N2 - 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.

AB - 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.

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