SMAD6 INHIBITS SIGNALING BY THE TGF-BETA SUPERFAMILY

SMBD proteins(1) have been identified as signalling mediators of the T GF-beta superfamily, which is involved in a range of biological activi ties including cell growth, morphogenesis, development and immune resp onses(2,3). Smad1, Smad2, Smad3 and Smad5 are ligand-specific Smad1 an d Smad5 transduce signals from bone morphogenetic proteins(4-7), and S mad2 and Smad3 mediate signalling by TGF-beta and activin(8,9), wherea s Smad4 acts as a common signalling component(10). For example, Smad2 is phosphorylated by the TGF-beta type I receptor upon ligand binding, forms a heteromer with Smad4 and then translocates into the nucleus w here it activates transcription(10,11). Here we report the isolation o f Smad6 in the mouse. Smad6 is quite different in structure from the o ther SMAD proteins, and forms stable associations with type I receptor s. Smad6 interferes with the phosphorylation of Smad2 and the subseque nt heteromerization with Smad4, but does not inhibit the activity of S mad3, Smad6 also inhibits the phosphorylation of Smad1 that is induced by the bone morphogenetic protein type IB receptor. These data indica te that signals of the TGF-beta superfamily are regulated both positiv ely and negatively by members of the SMAD family.