Figure 1. The transforming growth factor (TGF) superfamily. Representative members identified in mouse and humans are shown, except for Drosophila Dpp (decapentaplegic) in brackets. Lines represent the percentage amino acid identity of each member when compared with BMP-2. BMP, bone morphogenetic protein; GDF, growth and differentiation factor; CDMP, cartilage derived matrix protein and OP, osteogenic protein.

Figure 2. TGF structure. Transforming growth factor (TGF) is synthesized as a large precursor protein with a signal sequence, prodomain and mature peptide. Two TGF molecules are held together to form a dimer by intermolecular disulfide bonds from the conserved cysteine residues. When TGF is secreted the signal sequence is removed by proteolytic cleavage. The prodomain, also referred to as the latency-associated peptide (LAP), remains associated with the dimer resulting in a latent protein complex. Bioactive TGF is released when the prodomain is released.

Figure 3. Model for TGF receptor signalling. (1) TGF ligand first binds to the type II receptor, a constitutively active serine/threonine kinase. The type II receptor is then able to form a heteromeric complex with the type I receptor. (2) The type II receptor phosphorylates the GS domain of the type I receptor, activating the serine/threonine kinase activity of the type I receptor. The type I receptor then phosphorylates downstream signalling molecules. (3) Smad1, -2, -3, -5 and -8 are directly phosphorylated by the type I receptor. Smad2 and -3 mediate signalling for TGF and activin. Smad1, -5 and -8 mediate BMP signalling and are therefore not shown here. (4) Phosphorylated Smads form a heteromeric complex with Smad4 and are translocated to the nucleus. (5) Smads act as transcription factors and can either bind to DNA directly or bind in combination with a large array of diverse transcriptional regulators. TGF has also been shown to regulate expression of a large number of diverse genes. Changes in gene expression mediate the biological effects of TGF. (6) Inhibitory Smads have also been identified. Smad7 competes with other Smads for binding to the type I receptor, preventing phosphorylation and blocking signal propagation. (7) Smurf ubiquitin ligases target Smad for degradation, thereby antagonizing the signal.