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Nat Commun. 2015 Jul 21;6:7600. doi: 10.1038/ncomms8600.

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

Author information

1
1] Department of Experimental Pathology, Graduate School of Comprehensive Human Sciences and Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan [2] Department of Molecular Pathology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan [3] Department of Internal Medicine, Kyungpook National University School of Medicine, 50 SAMDUK-2GA, Jungu, Daegu 700-721, Republic of Korea.
2
Animal Research Center, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan.
3
Department of Molecular Pathology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan.
4
Department of Experimental Pathology, Graduate School of Comprehensive Human Sciences and Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
5
Department of Internal Medicine, Kyungpook National University School of Medicine, 50 SAMDUK-2GA, Jungu, Daegu 700-721, Republic of Korea.
6
Department of Laboratory Animal Medicine, Institute for the 3Rs, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 143-701, Republic of Korea.
7
Laboratory of Systems Biology, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato, Tokyo 108-8639, Japan.
8
Department of Molecular Medicine for Pathogenesis, Graduate School of Medicine, Ehime University, Shitsukawa, Toon, Ehime 791-0295, Japan.
9
Department of Rheumatology, Catholic University of Korea, #505, Banpo-Dong, Seocho-Gu, Seoul 137-701, Republic of Korea.
10
College of Pharmacy, Ewha Womans University, 11-1 Daehyun-dong, Seodaemun-gu, Seoul 120-750, Republic of Korea.
11
Department of Gastroenterology and Hepatology, Kansai Medical University, 10-15 Fumizonocho, Moriguchi, Osaka 570-8506, Japan.
12
Department of Molecular Genetics, Ohio State University, 484 West 12th Avenue, Columbus, Ohio 43210, USA.
13
Department of Internal Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
14
1] Department of Molecular Pathology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan [2] Department of Internal Medicine, Kyungpook National University School of Medicine, 50 SAMDUK-2GA, Jungu, Daegu 700-721, Republic of Korea.

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.

PMID:
26194464
PMCID:
PMC4518312
DOI:
10.1038/ncomms8600
[Indexed for MEDLINE]
Free PMC Article

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