Two major Smad pathways in TGF-β superfamily signalling

Authors

  • Keiji Miyazawa,

    1. Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
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  • Masahiko Shinozaki,

    1. Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
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  • Takane Hara,

    1. PharmaDesign Inc., Dai-2 Goseki Building, 4-2-10 Hacchobori, Chuo-ku, Tokyo 104-0032, Japan
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  • Toshio Furuya,

    1. PharmaDesign Inc., Dai-2 Goseki Building, 4-2-10 Hacchobori, Chuo-ku, Tokyo 104-0032, Japan
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  • Kohei Miyazono

    Corresponding author
    1. Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
    2. Department of Biochemistry, The Cancer Institute of the Japanese Foundation for Cancer Research (JFCR), 1-37-1 Kami-ikebukuro, Toshima-ku, Tokyo 170-8455, Japan
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* Correspondence: E-mail: miyazono-ind@umin.ac.jp

Abstract

Members of the transforming growth factor-β (TGF-β) superfamily bind to two different serine/threonine kinase receptors, i.e. type I and type II receptors. Upon ligand binding, type I receptors specifically activate intracellular Smad proteins. R-Smads are direct substrates of type I receptors; Smads 2 and 3 are specifically activated by activin/nodal and TGF-β type I receptors, whereas Smads 1, 5 and 8 are activated by BMP type I receptors. Nearly 30 proteins have been identified as members of the TGF-β superfamily in mammals, and can be classified based on whether they activate activin/TGF-β-specific R-Smads (AR-Smads) or BMP-specific R-Smads (BR-Smads). R-Smads form complexes with Co-Smads and translocate into the nucleus, where they regulate the transcription of target genes. AR-Smads bind to various proteins, including transcription factors and transcriptional co-activators or co-repressors, whereas BR-Smads interact with other proteins less efficiently than AR-Smads. Id proteins are induced by BR-Smads, and play important roles in exhibiting some biological effects of BMPs. Understanding the mechanisms of TGF-β superfamily signalling is thus important for the development of new ways to treat various clinical diseases in which TGF-β superfamily signalling is involved.

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