Identification of Smad7, a TGFbeta-inducible Antagonist of TGF-beta Signalling

Nature. 1997 Oct 9;389(6651):631-5. doi: 10.1038/39369.

Abstract

TGF-beta signals from the membrane to the nucleus through serine/threonine kinase receptors and their downstream effectors, termed SMAD proteins. The activated TGF-beta receptor induces phosphorylation of two such proteins, Smad2 and Smad3, which form hetero-oligomeric complex(es) with Smad4/DPC4 that translocate to the nucleus, where they then regulate transcriptional responses. However, the mechanisms by which the intracellular signals of TGF-beta are switched off are unclear. Here we report the identification of Smad7, which is related to Smad6. Transfection of Smad7 blocks responses mediated by TGF-beta in mammalian cells, and injection of Smad7 RNA into Xenopus embryos blocks activin/TGF-beta signalling. Smad7 associates stably with the TGF-beta receptor complex, but is not phosphorylated upon TGF-beta stimulation. TGFbeta-mediated phosphorylation of Smad2 and Smad3 is inhibited by Smad7, indicating that the antagonistic effect of Smad7 is exerted at this important regulatory step. TGF-beta rapidly induces expression of Smad7 mRNA, suggesting that Smad7 may participate in a negative feedback loop to control TGF-beta responses.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • COS Cells
  • Cell Line
  • Culture Techniques
  • DNA-Binding Proteins / analysis
  • DNA-Binding Proteins / physiology*
  • Feedback
  • Gene Expression Regulation
  • Genes, Reporter
  • Humans
  • Mice
  • Molecular Sequence Data
  • Phosphorylation
  • Signal Transduction*
  • Smad7 Protein
  • Trans-Activators*
  • Transfection
  • Transforming Growth Factor beta / antagonists & inhibitors
  • Transforming Growth Factor beta / biosynthesis
  • Transforming Growth Factor beta / physiology*
  • Xenopus
  • Xenopus Proteins

Substances

  • DNA-Binding Proteins
  • SMAD7 protein, human
  • Smad7 Protein
  • Smad7 protein, Xenopus
  • Smad7 protein, mouse
  • Trans-Activators
  • Transforming Growth Factor beta
  • Xenopus Proteins

Associated data

  • GENBANK/AF015260
  • GENBANK/AF015261