PXD051056

PXD051056 is an original dataset announced via ProteomeXchange.

Title	Suppression of TGF-β/SMAD signaling by an inner nuclear membrane phosphatase complex
Description	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 determined how R-SMADs are inactivated by dephosphorylation in the cell nucleus to counteract signaling by TGF-β superfamily ligands. We showed 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 revealed that MAN1 binds independently to the CTDNEP1/NEP1R1 phosphatase and R-SMADs to promote their inactivation by dephosphorylation. Disruption of this complex led to nuclear accumulation of R-SMADs and aberrant signaling, even in the absence of TGF-β ligands. These findings establish CTDNEP1/NEP1R1 as the elusive R-SMAD phosphatase and reveal the mechanistic basis for TGF-β signaling inactivation and how this process is disrupted by disease-associated MAN1 mutations.
HostingRepository	PRIDE
AnnounceDate	2025-01-28
AnnouncementXML	Submission_2025-01-28_07:26:27.757.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Pedro Carvalho
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2024-03-28 07:07:34	ID requested
⏵ 1	2025-01-28 07:26:28	announced

Dataset with its publication pending

submitter keyword: MAN1,CTDNEP, TGFbeta, SMAD, nuclear envelope

Pedro Carvalho
contact affiliation	Sir William Dunn School of Pathology, University of Oxford, UK
contact email	pedro.carvalho@path.ox.ac.uk
lab head
Pedro Carvalho
contact affiliation	University of Oxford
contact email	pedro.carvalho@path.ox.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD051056
     1. Label: PRIDE project
     2. Name: Suppression of TGF-β/SMAD signaling by an inner nuclear membrane phosphatase complex