The type II receptors phosphorylate the type I receptors; the type I receptors are then enabled to phosphorylate cytoplasmic R-Smads, which then act as transcriptional regulators. Signaling is initiated by the binding of TGF-β to its serine/threonine receptors. The serene/threonine receptors are the type II and type I receptors on the cell membrane. Binding of a TGF-β members induces assembly of a heterotetrameric complex of two type I and two type II receptors at the plasma membrane. Individual members of the TGF-β family bind to a certain set of characteristic combination of these type I and type II receptors. The type I receptors can be divided into two groups, which depends on the cytoplasmic R-Smads that they bind and phosphorylate. The first group of type I receptors (Alk1/2/3/6) bind and activate the R-Smads, Smad1/5/8. The second group of type I reactors (Alk4/5/7) act on the R-Smads, Smad2/3. The phosphorylated R-Smads then form complexes and the signals are funneled through two regulatory Smad (R-Smad) channels (Smad1/5/8 or Smad2/3). After the ligand-receptor complexes phosphorylate the cytoplasmic R-Smads, the signal is then sent through Smad 1/5/8 or Smad 2/3. This leads to the downstream signal cascade and cellular gene targeting.