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Turning Pathways Off with a Second Switch

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Science  07 Jan 2000:
Vol. 287, Issue 5450, pp. 13
DOI: 10.1126/science.287.5450.13g

The SMAD family protein messengers carries signals from the cell membrane into the nucleus. When ligand binds to the membrane receptor on the cell surface, SMADs are phosphorylated and translocated into the nucleus where they activate transcription of specific genes. The messenger in the transforming growth factor-beta pathway is Smad2 (see also Wu et al., Research Article, this issue, p. 92), while for the bone morphogenetic protein pathway, they are Smad1 and Smad5.

Although it seemed plausible that SMADs would be inactivated by dephosphorylation, new evidence points instead to a role for ubiquitin-dependent degradation. Lo and Massagué found that phosphorylated and translocated Smad2 becomes covalently tagged with the small protein ubiquitin, and thus targeted for destruction via the proteasome, and that the essential event that provokes ubiquitination of Smad2 appears to be its translocation to the nucleus. This mode of regulation is distinct from that recently described by Zhu et al. for Smad1 and Smad5, in which the ubiquitination is catalyzed by Smurf1 and occurs in the cytoplasm.—LBR

Nature Cell Biol.1, 472 (1999); Nature400, 687 (1999).

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