title: Smad7 Protein Interacts with Receptor-regulated Smads (R-Smads) to Inhibit Transforming Growth Factor-β (TGF-β)/Smad Signaling.
abstract: TGF-β is a pleiotropic cytokine that regulates a wide range of cellular actions and pathophysiological processes. TGF-β signaling is spatiotemporally fine-tuned. As a key negative regulator of TGF-β signaling, Smad7 exerts its inhibitory effects by blocking receptor activity, inducing receptor degradation or interfering with Smad-DNA binding. However, the functions and the molecular mechanisms underlying the actions of Smad7 in TGF-β signaling are still not fully understood. In this study we report a novel mechanism whereby Smad7 antagonizes TGF-β signaling at the Smad level. Smad7 oligomerized with R-Smad proteins upon TGF-β signaling and directly inhibited R-Smad activity, as assessed by Gal4-luciferase reporter assays. Mechanistically, Smad7 competes with Smad4 to associate with R-Smads and recruits the E3 ubiquitin ligase NEDD4L to activated R-Smads, leading to their polyubiquitination and proteasomal degradation. Similar to the R-Smad-Smad4 oligomerization, the interaction between R-Smads and Smad7 is mediated by their mad homology 2 (MH2) domains. A positive-charged basic region including the L3/β8 loop-strand module and adjacent amino acids in the MH2 domain of Smad7 is essential for the interaction. These results shed new light on the regulation of TGF-β signaling by Smad7.
authors.affiliation: From the State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084 China, yanxiaohua06@126.com.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Yan
authors.affiliation: From the State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084 China.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Liao
authors.affiliation: From the State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084 China.
authors.forename: Minzhang
authors.initials: M
authors.lastname: Cheng
authors.affiliation: From the State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084 China.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Shi
authors.affiliation: Michael E. DeBakey Department of Surgery and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Xia
authors.initials: X
authors.lastname: Lin
authors.affiliation: Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang, 310058 China, and.
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Feng
authors.affiliation: From the State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084 China, ygchen@tsinghua.edu.cn.
authors.forename: Ye-Guang
authors.initials: YG
authors.lastname: Chen
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008907:Mink; D000075702:Nedd4 Ubiquitin Protein Ligases; D025821:Polyubiquitin / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D054730:Protein Interaction Domains and Motifs; D059748:Proteolysis; D015398:Signal Transduction; D051896:Smad Proteins, Receptor-Regulated / Q000378:metabolism*; D051900:Smad3 Protein / Q000737:chemistry / Q000378:metabolism; D051901:Smad4 Protein / Q000378:metabolism; D051906:Smad7 Protein / Q000737:chemistry / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D000596:Amino Acids; D056827:Endosomal Sorting Complexes Required for Transport; D051896:Smad Proteins, Receptor-Regulated; D051900:Smad3 Protein; D051901:Smad4 Protein; D051906:Smad7 Protein; D016212:Transforming Growth Factor beta; D025821:Polyubiquitin; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618485:Nedd4L protein, human; D044767:Ubiquitin-Protein Ligases
keywords: SMAD transcription factor; Smad7; cell signaling; protein degradation; protein-protein interaction; signaling regulation; transforming growth factor beta (TGF-B); ubiquitylation (ubiquitination)