Schematic of the TGF-β signaling pathway, showing the activation cascade and points of inhibition (??). Active TGF-β, released from the latent complex by the action of thrombospondin, binds to the type II receptor, resulting in the formation of an active receptor-signaling complex. This binding is enhanced by accessory receptors, whereas the receptor dimerization can be inhibited by membrane-bound inhibitors such as bone morphogenic protein and activin membrane bound inhibitor (BAMBI). After ligand binding, the receptor SMADs are phosphorylated, dimerize with SMAD-4, and translocate to the nucleus where they recruit appropriate cofactors and coactivators to stimulate transcription of target genes. TGF-β signaling can be blocked by the inhibitory SMADs, SMAD-6 and SMAD-7, which prevent receptor-SMAD activation; and by the ras pathway, which can lead to inhibition of nuclear translocation of the dimeric SMAD complex. Receptor SMADs can also be degraded following ubiquinylation by the ubiquitin ligase SMURF1. Figure adapted from Massagué .