Figure 2.

The canonical transforming growth factor (TGF)-β/Smad signaling pathway. Members of the TGF-β family of growth factors (TGF-βs, activins, nodals) interact sequentially with two membrane receptors. TGF binds first to the constitutively active type II receptor (R) and then the ligand-recepor complex associates with type I TGF-R. TGF-IIR (TβIIR) phosphorylates TGF-IR (TβIR) on a cluster of serine threonine residues. Activated TGF-RI propogates the signal downstream by directly phosphorylating Smad2 and Smad3. These form heterodimeric or trimeric complexes with Smad 4 and translocate into the nucleus where, in combination with LEF-1/T cell factor (TCF) family transcription factors, they down-regulate E-cadherin genes and initiate epithelial-mesenchymal transition. Complexes of Smad7 and Smurf1 or Smurf2 promote ubiquination and degradation of activated receptors limiting the intensity and duration of signaling. P, phosphorylation sites; SARA, small anchor for receptor activity. (Adapted from [61].)