The Smads

The Smads are a family of intracellular signalling molecules that act downstream of receptors for the transforming growth factor (TGF)-beta family of ligands. Three classes of Smads have been identified. The receptor-regulated Smads are direct substrates for the type I receptors, which are serine/threonine kinases. Once phosphorylated and activated, these Smads form hetero-oligomeric complexes with a second class of Smad, the common mediator Smads. These Smad complexes translocate to the nucleus, where they are recruited to DNA primarily by site-specific DNA binding transcription factors, and participate in regulating the transcription of target genes. Inhibitory Smads are the third identified class which antagonise the activity of the receptor-regulated Smads. Aberrant TGF-beta signalling has been associated with several human diseases such as cancer and fibrosis. The identification of the Smads as primary transducers of TGF-beta signals raises the possibility that agents directed at modulating Smad activity would have therapeutic applications.