Ubiquitin-dependent degradation of TGF-beta-activated Smad2

SMAD proteins are phosphorylated by transforming growth factor-beta (TGF-be ta) receptors and translocate to the nucleus, where they control transcript ion. Here we investigate the fate of activated Smad2. We show that receptor -mediated activation leads to multi-ubiquitination and subsequent degradati on of Smad2 by the proteasome. Ubiquitination of Smad2 is a consequence of its accumulation in the nucleus. If degradation is averted, the phosphoryla ted Smad2 remains in the nucleus in an active state. By targeting Smad2 for destruction, TGF-beta ensures the irreversible termination of its own sign alling function.