Journal article
Suppression of TGF-β/SMAD signaling by an inner nuclear membrane phosphatase complex
- 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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 1.9MB, Terms of use)
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(Preview, Supplementary materials, pdf, 2.4MB, Terms of use)
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- Publisher copy:
- 10.1038/s41467-025-58681-x
Authors
+ Wellcome Trust
More from this funder
- Funder identifier:
- https://ror.org/029chgv08
- Funding agency for:
- Carvalho, P
- Trost, M
- Grant:
- 223153/Z/21/Z
- 215542/Z/19/Z
- 212947/Z/18/Z
+ European Research Council
More from this funder
- Funder identifier:
- https://ror.org/0472cxd90
- Funding agency for:
- Carvalho, P
- Grant:
- 817708
- Publisher:
- Nature Research
- Journal:
- Nature Communications More from this journal
- Volume:
- 16
- Issue:
- 1
- Article number:
- 3474
- Publication date:
- 2025-04-11
- Acceptance date:
- 2025-03-28
- DOI:
- EISSN:
-
2041-1723
- Language:
-
English
- Pubs id:
-
2106288
- Local pid:
-
pubs:2106288
- Deposit date:
-
2025-04-07
- ARK identifier:
Terms of use
- Copyright holder:
- Ji et al.
- Copyright date:
- 2025
- Rights statement:
- © The Author(s) 2025. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/ licenses/by/4.0/.
- Licence:
- CC Attribution (CC BY)
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