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Suppression of TGF-β/SMAD signaling by an inner nuclear membrane phosphatase complex

Author

Listed:
  • Zhe Ji

    (University of Oxford)

  • Wing-Yan Skyla Siu

    (University of Oxford)

  • Maria Emilia Dueñas

    (Newcastle University
    The Kids Research Institute Australia, Perth Children’s Hospital)

  • Leonie Müller

    (Newcastle University)

  • Matthias Trost

    (Newcastle University)

  • Pedro Carvalho

    (University of Oxford)

Abstract

Cytokines of the TGF-β superfamily control essential cell fate decisions via receptor regulated SMAD (R-SMAD) transcription factors. Ligand-induced R-SMAD phosphorylation in the cytosol triggers their activation and nuclear accumulation. We determine how R-SMADs are inactivated by dephosphorylation in the cell nucleus to counteract signaling by TGF-β superfamily ligands. We show that R-SMAD dephosphorylation is mediated by an inner nuclear membrane associated complex containing the scaffold protein MAN1 and the CTDNEP1-NEP1R1 phosphatase. Structural prediction, domain mapping and mutagenesis reveals that MAN1 binds independently to the CTDNEP1-NEP1R1 phosphatase and R-SMADs to promote their inactivation by dephosphorylation. Disruption of this complex causes nuclear accumulation of R-SMADs and aberrant signaling, even in the absence of TGF-β ligands. These findings establish CTDNEP1-NEP1R1 as the R-SMAD phosphatase, reveal the mechanistic basis for TGF-β signaling inactivation and highlight how this process is disrupted by disease-associated MAN1 mutations.

Suggested Citation

  • Zhe Ji & Wing-Yan Skyla Siu & Maria Emilia Dueñas & Leonie Müller & Matthias Trost & Pedro Carvalho, 2025. "Suppression of TGF-β/SMAD signaling by an inner nuclear membrane phosphatase complex," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58681-x
    DOI: 10.1038/s41467-025-58681-x
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    References listed on IDEAS

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