A single missense mutant of Smad3 inhibits activation of both Smad2 and Smad3, and has a dominant negative effect on TGF-beta signals

FEBS Lett. 1998 Jul 3;430(3):201-4. doi: 10.1016/s0014-5793(98)00658-9.

Abstract

A missense mutation of Smad2 identified in cancer cells was reconstructed on the corresponding residue of Smad3. This mutant, Smad3D407E, was not phosphorylated by the constitutively active form of type I receptor for transforming growth factor-beta (TGF-beta), and inhibited the phosphorylation of co-expressed wild-type Smad2 and Smad3. This mutant also had a dominant negative effect on the growth inhibition of HaCaT cells and on the expression of p3TP-lux reporter gene induced by TGF-beta. However, it did not alter the phosphorylation of Smad1 induced by the constitutively active form of the bone morphogenetic protein type IA receptor. These findings showed that a single missense mutation in Smad3 could specifically block TGF-beta signals by preventing activation of both Smad2 and Smad3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Bone Morphogenetic Protein Receptors, Type I
  • COS Cells
  • Cell Line
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Keratinocytes
  • Molecular Sequence Data
  • Mutation
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / chemistry
  • Receptors, Growth Factor / chemistry
  • Recombinant Fusion Proteins
  • Signal Transduction / physiology*
  • Smad2 Protein
  • Smad3 Protein
  • Trans-Activators*
  • Transcriptional Activation
  • Transfection
  • Transforming Growth Factor beta / pharmacology*

Substances

  • DNA-Binding Proteins
  • Receptors, Growth Factor
  • Recombinant Fusion Proteins
  • Smad2 Protein
  • Smad3 Protein
  • Trans-Activators
  • Transforming Growth Factor beta
  • Protein-Serine-Threonine Kinases
  • Bone Morphogenetic Protein Receptors, Type I