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bioRxiv · 10.1101/2024.09.23.614427

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

Ji, Z.·Siu, W. S.·Duenas, M. E.·Trost, M.·Carvalho, P.
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Abstract

Cytokines of the TGF-{beta} 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-{beta} 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-{beta} ligands. These findings establish CTDNEP1-NEP1R1 as the elusive R-SMAD phosphatase and reveal the mechanistic basis for TGF-{beta} signaling inactivation and how this process is disrupted by disease-associated MAN1 mutations.

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Ji, Z., Siu, W. S., Duenas, M. E., Trost, M., Carvalho, P.. 2024-09-23. Suppression of TGF-β/SMAD signaling by an inner nuclear membrane phosphatase complex. https://doi.org/10.1101/2024.09.23.614427

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