Figure 1.

Basics of transforming growth factor β (TGFβ) signaling. Binding of TGFβ ligands to their receptors initiates the signal, through the phosphorylation of TβRI by TβRII. Then, TβRI transmits the signal to SMAD2 and SMAD3 by phosphorylating their MH2 domains. This phosphorylation enables SMAD2 and SMAD3 activation and the formation of a complex with SMAD4, which, in turn, enters into the nucleus through nuclear pores with the assistance of importins. In the nucleus, the activated SMAD complex regulates the expression of target genes, in a positive or negative manner, depending on its association with transcriptional coactivators or corepressors. The signaling is subjected to negative regulation by SMAD7, which prevents SMAD2/3 activation and induces degradation of TβRI, and by Ski/SnoN, which interferes with the formation of active SMAD2/3/4 complex. MH1: MAD homology 1 domain, L: Linker domain, MH2: MAD homology 2 domain, TβRI: type I TGFβ receptor, TβRII: type II TGFβ receptor.