ArticleScience signaling2013
Inhibition of TGF-β signaling at the nuclear envelope: characterization of interactions between MAN1, Smad2 and Smad3, and PPM1A.
Article in Science signaling, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 52 citations in OpenAlex.
- LEM-Domain-Containing Inner Nuclear Membrane Proteins: Emerging Regulators of Intranuclear Signaling.International journal of molecular sciences · 2026Review
- Mechanical Signaling: Molecular Mechanisms, Biological Functions, Diseases, and Therapeutic Targets.MedComm · 2025Review
- Acetylation-regulated DUSP1 deficiency contributes to renal fibrosis progression.Theranostics · 2025Article
- The stability of the myelinating oligodendrocyte transcriptome is regulated by the nuclear lamina.Cell reports · 2023Article
- Molecular Pathology of Laminopathies.Annual review of pathology · 2022Review
- Review
- Actin Cytoskeleton and Regulation of TGFβ Signaling: Exploring Their Links.Biomolecules · 2021Review
- The Sky's the LEMit: New insights into nuclear structure regulation of transcription factor activity.Current opinion in cell biology · 2021Review
- TGFβ-Directed Therapeutics: 2020.Pharmacology & therapeutics · 2021Review
- Diversity of Nuclear Lamin A/C Action as a Key to Tissue-Specific Regulation of Cellular Identity in Health and Disease.Frontiers in cell and developmental biology · 2021Review
- The molecular basis for the prothrombotic state in sickle cell disease.Haematologica · 2020Article
- Review
- LncRNA GAS5 attenuates fibroblast activation through inhibiting Smad3 signaling.American journal of physiology. Cell physiology · 2020Article
- Somatic SMAD3-activating mutations cause melorheostosis by up-regulating the TGF-β/SMAD pathway.The Journal of experimental medicine · 2020Article
- Nucleoskeletal regulation of transcription: Actin on MRTF.Experimental biology and medicine (Maywood, N.J.) · 2019Review
- Structural basis for receptor-regulated SMAD recognition by MAN1.Nucleic acids research · 2018Article
- LEM domain-containing protein 3 antagonizes TGFβ-SMAD2/3 signaling in a stiffness-dependent manner in both the nucleus and cytosol.The Journal of biological chemistry · 2018Article
- Linker of nucleoskeleton and cytoskeleton complex proteins in cardiomyopathy.Biophysical reviews · 2018Review
- Messages from the voices within: regulation of signaling by proteins of the nuclear lamina.Current opinion in cell biology · 2018Review
- Lamins and bone disorders: current understanding and perspectives.Oncotarget · 2018Review
Corrections and comments
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Authors and funding
10 authors at 4 institutions in 1 country.
Funding
Abstract
Signaling by transforming growth factor-β (TGF-β) is critical for various developmental processes and culminates in the activation of the transcription factors Smad2 and Smad3. MAN1, an integral protein of the inner nuclear membrane, inhibits TGF-β signaling by binding to Smad2 and Smad3. Depletion of the gene LEMD3 encoding MAN1 leads to developmental anomalies in mice, and heterozygous loss-of-function mutations in LEMD3 in humans cause sclerosing bone dysplasia. We modeled the three-dimensional structure of the MAN1-Smad2 complex from nuclear magnetic resonance and small-angle x-ray scattering data. As predicted by this model, we found that MAN1 competed in vitro and in cells with the transcription factor FAST1 (forkhead activin signal transducer 1) for binding to Smad2. The model further predicted that MAN1 bound to activated Smad2-Smad4 or Smad3-Smad4 complexes, which was confirmed by in vitro experiments; however, in cells, MAN1 bound only to Smad2 and Smad3 and not to the Smad4-containing complexes. Overexpression of MAN1 led to dephosphorylation of Smad2 and Smad3, thus hindering their recognition by Smad4, and MAN1 bound directly in vitro to the phosphatase PPM1A, which catalyzes the dephosphorylation of Smad2/3. These results demonstrate a nuclear envelope-localized mechanism of inactivating TGF-β signaling in which MAN1 competes with transcription factors for binding to Smad2 and Smad3 and facilitates their dephosphorylation by PPM1A.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.