Figure 1

Smads as key mediators of transforming growth factor-beta (TGF-β) signaling. TGF-β family ligands induce heteromeric complex formation of type II (TβRII) and type I (TβRI) TGF-β receptors in the cell membrane. RII subsequently phosphorylates RI, which in turn recruits, phosphorylates, and activates R-Smads. Phosphorylated R-Smads subsequently form a complex with the co-Smad (Smad4) and then translocate into the nucleus. In the nucleus, the Smad complexes bind to other DNA-binding transcription factors, co-activators, and co-repressors to regulate the expression of a wide variety of target genes. The inhibitory Smads (Smad6/7) can reduce signaling by preventing phosphorylation of R-Smads. The strength of the signal is also regulated by the continuously shuttling of Smad complexes between the nucleus and the cytoplasm. Besides Smad-mediated signaling, TGF-β family members can activate the indicated non-Smad pathways, several of which can influence the activity of Smad complexes and Smad target genes directly or indirectly or both. Co-Smad, common-partner Smad; I-Smad, inhibitory Smad; P, phosphate; R-Smad, receptor-regulated Smad; TF, transcription factor.