Figure 1. TGF-ß ligand binding to the heteromeric receptor complex induces phosphorylation of the type I receptors by the constitutively active type II receptors. Receptor activation then results in phosphorylation of receptor-associated Smads (Smad2 and Smad3). The phosphorylated Smads may then cooperate with Smad4, which is not associated with the receptor or phosphorylated by it. The cooperativity of receptor-associated Smads with Smad4 may be a general prerequisite for receptor signaling. The activated, heteromeric Smads complex will translocate into the nucleus to function as a transcriptional regulator, which can regulate the expression of transcription factors. Smad7 associates stably with the TGF-ß receptor complex, but is not phosphorylated upon TGF-ß stimulation. TGF-ß-mediated phosphorylation of Smad2 and Smad3 is inhibited by Smad7, indicating the antagonistic effect of Smad7 in regulating the TGF-ß signaling pathway.