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 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Hela Cell

SUBMITTER: Pedro Carvalho  

LAB HEAD: Pedro Carvalho

PROVIDER: PXD051056 | Pride | 2025-01-28

REPOSITORIES: Pride