A SINGLE MISSENSE MUTANT OF SMAD3 INHIBITS ACTIVATION OF BOTH SMAD2 AND SMAD3, AND HAS A DOMINANT-NEGATIVE EFFECT ON TGF-BETA SIGNALS

A missense mutation of Smad2 identified in cancer cells was reconstruc ted on the corresponding residue of Smad3, This mutant, Smad3D407E, wa s not phosphorylated by the constitutively active form of type I recep tor 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 b y the constitutively active form of the bone morphogenetic protein typ e IA receptor. These findings showed that a single missense mutation i n Smad3 could specifically block TGF-beta signals by preventing activa tion of both Smad2 and Smad3, (C) 1998 Federation of European Biochemi cal Societies.