an be subdivided into several sub-groups. The transforming growth factor-beta (Tgf-b) Smad-dependent pathway is one of the best characterized modules of the Tgf-b superfamily signaling. In mammals, there are three Tgf-beta isoforms. Tgf-b dimer binding to type II receptor leads to the recruitment and phosphorylation of type I receptor within the GS (glycine and serine rich) domain. Activated type I receptor phosphorylates selected members of the receptor-regulated Smad family, R-Smad. Canonical Tgf-b signaling through Tgfbr2 - Tgfbr1 (known as Alk5) receptors employs the Smad2 and 3 proteins. In certain cell types Tgf-b signaling can activate Smad1, 5 and 8 via Acvrl1 type 1 receptor (known as Alk1). Phosphorylated R-Smad(s) associate with the common Smad4 and translocate into the nucleus. The expression of target genes is regulated through the interaction with repressors and activators; among targets, there are the inhibitory Smad(s) thus providing a regulatory feedback loop. Tgfbr3 co-receptor and scaffolds such as Zfyve9 (known as SARA), aid in the formation of ligand-receptor and receptor-Smad complexes. Ligand binding and trapping by decorin or alpha-2-macroglobulin, the inhibitory Smad7 (binds activated type I receptor and competes with R-Smad(s); can also recruit the E3 Smurf ubiquitin ligases), Fkbp1a (known as Fkbp12, keeps type I receptor in an inactive state), or regulation of DNA-binding partners (phosphorylation of FoxO factors leads to their exclusion from the nucleus), are examples of negative regulation. The MH1 (Mad-homology 1) DNA-binding domain of Smads does not confer high affinity upon the interaction; the exquisite modulation of target gene expression is achieved through the interaction of Smads with co-repressors and co-activators. The MH2 (Mad homology 2) domain is critical for protein-protein interactions. Alterations in Tgf-b signaling have been linked to cardiovascular conditions and cancer. To see the ontology report for annotations, GViewer and download, click here....(less)