Cited by 99TGF-β signaling in diseasesHippo pathway signaling and YAP/TAZSignaling Pathways in Disease

Structural Basis for the Versatile Interactions of Smad7 with Regulator WW Domains in TGF-β Pathways

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Aragón, Eric, Goerner, Nina, Xi, Qiaoran, Gomes, Tiago, Gao, Sheng, Massagué, Joan, Macias, Maria J.·2012·Structure

Abstract

Transforming growth factor (TGF)-β and BMP signaling is mediated by Smads 1-5 (R-Smads and Co-Smads) and inhibited by Smad7, a major hub of regulation of TGF-β and BMP receptors by negative feedback and antagonistic signals. The transcription coactivator YAP and the E3 ubiquitin ligases Smurf1/2 and Nedd4L target R-Smads for activation or degradation, respectively. Pairs of WW domain in these regulators bind PY motifs and adjacent CDK/MAPK and GSK3 phosphorylation sites in R-Smads in a selective and regulated manner. In contrast, here we show that Smad7 binds YAP, Smurf1, Smurf2, and Nedd4L constitutively, the binding involving a PY motif in Smad7 and no phosphorylation. We also provide a structural basis for how regulators that use WW domain pairs for selective interactions with R-Smads, resort to one single versatile WW domain for binding Smad7 to centralize regulation in the TGF-β and BMP pathways.

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Crossref · 10.1016/j.str.2012.07.014

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  • Several mechanisms have been proposed for how Yap or Taz interact with Smads, including binding to Smad7, promotion of Smad1 transcriptional action, and effects on Smad2/3 localisation.

    “Several mechanisms have been proposed that can explain how Yap or Taz can interact with Smads. These include the binding of Yap to the inhibitory Smad7 (7, 49), the promotion of Smad1 transcriptional action by Yap binding (3), and an effect of Yap and Taz on Smad2/3 localisation (137).”

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  1. Kuratomi G Komuro A Goto K Shinozaki M Miyazawa K Miyazono K Imamura T 2005 NEDD4–2 negatively regulates TGF-beta signaling by inducing ubiquitin-mediated degradation of Smad2 and TGF-beta type I receptor Biochem J 386 461 470 15496141 PMC1134864

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Authors
Aragón, E., Goerner, N., Xi, Q., Gomes, T., Gao, S., Massagué, J., & Macias, M. J.
Affiliations
  • Institute for Research in Biomedicine (ES)
  • Memorial Sloan Kettering Cancer Center (US)
Corresponding author
Massagué, Joan
Venue
Structure
Publisher
Elsevier BV
Published
2012-10
Volume
20
Issue
10
Pages
1726-1736
ISSN
0969-2126 (ISSN-L)
OpenAlex
W2043685957
Cited by
99
References
46
Citations by year
2026: 1 · 2025: 1 · 2024: 4 · 2023: 5 · 2022: 2 · 2021: 12 · 2020: 10 · 2019: 10 · 2018: 7 · 2017: 10 · 2016: 6 · 2015: 14 · 2014: 13 · 2013: 3 · 2012: 1
FWCI
3.98
Type
journal article
Language
en
Open access
Locations
  • Structure (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Cancer Institute (R37CA034610, P30CA008748)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
Keywords
Smad7, WW domain, TGF-beta signaling, BMP signaling, Smad proteins, YAP, Smurf1, Smurf2, NEDD4L, PY motif, protein-protein interaction, ubiquitination, negative feedback regulation, protein structure
MeSH terms
Nedd4 Ubiquitin Protein Ligases, Calorimetry, Humans, Hydrogen Bonding, Models, Molecular, Magnetic Resonance Spectroscopy, Nuclear Proteins, Phosphorylation, Protein Binding, Protein Processing, Post-Translational, Surface Properties, Transcription Factors, Signal Transduction, Transforming Growth Factor beta, Protein Structure, Secondary, Cell Cycle Proteins, Amino Acid Motifs, Ubiquitin-Protein Ligases, Smad7 Protein, Protein Interaction Domains and Motifs, Endosomal Sorting Complexes Required for Transport

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