Research ArticleBiochemistry

Inhibition of TGF-β Signaling at the Nuclear Envelope: Characterization of Interactions Between MAN1, Smad2 and Smad3, and PPM1A

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Science Signaling  18 Jun 2013:
Vol. 6, Issue 280, pp. ra49
DOI: 10.1126/scisignal.2003411

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Stopping the Signal from Going Nuclear

Activation of cell surface receptors for transforming growth factor–β (TGF-β) results in changes in gene expression mediated by the transcription factors Smad2 and Smad3. Bourgeois et al. examined how the nuclear membrane protein MAN1 inhibits TGF-β signaling. Modeling, biochemical assays, and cellular assays revealed that MAN1 prevented Smad2 and Smad3 from binding to purified and cellular transcription factor FAST1 (forkhead activin signal transducer 1) and to cellular Smad4, the latter of which promotes transcription regulation by Smad2 and Smad3. In addition, in vitro assays indicated that MAN1 could facilitate the dephosphorylation and inactivation of Smad2 and Smad3 by the phosphatase PPM1A. These results may help to explain why individuals deficient in the gene encoding MAN1 have developmental defects suggestive of aberrant TGF-β signaling.

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