Figure 2. Regulation of Smad signaling.

Thick gray lines illustrate Smad signaling, whereas nucleocytoplasmic shuttling and degradation of Smads are indicated by solid and dashed light-blue lines, respectively. Activation of R-Smads by TβRI facilitates the formation of trimeric R-Smad/Smad4 complexes, which are imported into the nucleus to regulate transcription of target genes. R-Smad phosphorylation at various sites besides the C-terminus prevents nuclear import of the complexes, or favors degradation of the complexes, resulting in termination of signaling. Diverse regulators modulate the activated Smad complexes inside the nucleus, and control the balance between complex formation and dissociation, thus determining the overall signaling outcome in a context-dependent manner. Inhibitory mechanisms are listed in a red box with blunt-headed lines, and those that promote the indicated processes are listed in a green box with arrows.