This invention provides unique members of the Hect family of
ubiquitin ligases that specifically target BMP and TGF beta / activin pathway-specific Smads. The novel ligases have been named Smurf1 and Smurf2. They directly interact with Smads1 and 5 and
Smad7, respectively, and regulate the ubiquitination, turnover and activity of Smads and other proteins of these pathways. Smurf1 interferes with biological responses to BMP, but not activin signalling. In
amphibian embryos Smurf1 inhibits endogenous BMP signals, resulting in altered
pattern formation and
cell fate specification in the
mesoderm and
ectoderm. The present invention provides a unique regulatory link between the ubiquitination pathway and the control of
cell fate determination by the TGF beta superfamily during embryonic development. Thus, Smurf1 is a
negative regulator of
Smad1
signal transduction, by targeting
Smad1, Smurf1 blocks BMP signalling. In mammalian cells, Smurf2 suppresses TGF beta signalling, and in
Xenopus, blocks formation of dorsal
mesoderm and causes anterior truncation of the embryos. Smurf2 forms a stable complex with Smad7, which induces degradation and downregulation of TGF beta / activin signalling.