The TGFβ/Smad canonical signaling pathway. TGFβ belongs to a superfamily of growth factors that also includes the activins and BMPs. The active TGFβ ligand is a dimeric molecule composed of two monomers linked by a disulfide bridge and hydrophobic interactions. Each TGFβ subunit is synthesized as a large inactive precursor molecule bound to accessory proteins (LAP and LTBP). This precursor is stored in the extracellular matrix (ECM) and can be rapidly cleaved and activated by several proteolytic mechanisms to become bioavailable. Signal transduction starts with ligand binding to a complex of specific serine/threonine kinase receptors (type I, type II). The type II receptor is constitutively autophosphorylated and, upon ligand binding, transphosphorylates the juxtamembrane region of the type I receptor. This is followed by phosphorylation and recruitment of the R-Smads to the type I receptor and phospho-R-Smad complex formation with common partner Smad4 in the cytoplasm. The Smad complex is then translocated to the nucleus where it interacts with various transcription factors, coactivators, or corepressors to regulate target gene expression. The table lists the different ligands from the superfamily and their interactions with specific receptors and R-Smad proteins.