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.
authors.affiliation: 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.
authors.forename: Jeong-Hwan
authors.initials: JH
authors.lastname: Yoon
authors.affiliation: Animal Research Center, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan.
authors.forename: Katsuko
authors.initials: K
authors.lastname: Sudo
authors.affiliation: Department of Molecular Pathology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Kuroda
authors.affiliation: 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.
authors.forename: Mitsuyasu
authors.initials: M
authors.lastname: Kato
authors.affiliation: Department of Internal Medicine, Kyungpook National University School of Medicine, 50 SAMDUK-2GA, Jungu, Daegu 700-721, Republic of Korea.
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Jin Soo
authors.identifier: 0000000321361932
authors.initials: JS
authors.lastname: Han
authors.affiliation: 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.
authors.forename: Susumu
authors.initials: S
authors.lastname: Nakae
authors.affiliation: Department of Molecular Medicine for Pathogenesis, Graduate School of Medicine, Ehime University, Shitsukawa, Toon, Ehime 791-0295, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Imamura
authors.affiliation: Department of Rheumatology, Catholic University of Korea, #505, Banpo-Dong, Seocho-Gu, Seoul 137-701, Republic of Korea.
authors.forename: Juryun
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Rheumatology, Catholic University of Korea, #505, Banpo-Dong, Seocho-Gu, Seoul 137-701, Republic of Korea.
authors.forename: Ji Hyeon
authors.initials: JH
authors.lastname: Ju
authors.affiliation: College of Pharmacy, Ewha Womans University, 11-1 Daehyun-dong, Seodaemun-gu, Seoul 120-750, Republic of Korea.
authors.forename: Dae-Kee
authors.identifier: 0000000210184486
authors.initials: DK
authors.lastname: Kim
authors.affiliation: Department of Gastroenterology and Hepatology, Kansai Medical University, 10-15 Fumizonocho, Moriguchi, Osaka 570-8506, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Matsuzaki
authors.affiliation: Department of Molecular Genetics, Ohio State University, 484 West 12th Avenue, Columbus, Ohio 43210, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Weinstein
authors.affiliation: Department of Internal Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Matsumoto
authors.affiliation: Department of Internal Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Sumida
authors.affiliation: 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.
authors.forename: Mizuko
authors.initials: M
authors.lastname: Mamura
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000378:metabolism; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D051899:Smad2 Protein / Q000378:metabolism*; D051900:Smad3 Protein / Q000378:metabolism*; D058504:Th17 Cells
chemical_list: D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539901:Rorc protein, mouse; D050796:STAT3 Transcription Factor; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; C494087:Stat3 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases