A simple model of TGF- β signaling with I-Smad mediated negative feedback. The ligand TGF-β reversibly binds to the TGF-β receptor (reactions 1 and 2), which is then phosphorylated to become fully active (3 and 4). The active receptor induces phosphorylation of R-Smad (denoted simply Smad)(7), which in turn can reversibly dimerize or form a complex with Co-Smad (10 and 11). Those two reactions can take place either in the cytoplasm or in the nucleus and the five species Smad, phosphorylated Smad, Co-Smad, homodimers and heterodimers can shuttle from the cytoplasm to the nucleus and back (8, 9 and 12). Nuclear Smad/Co-Smadf complexes act as transcription factors and trigger the transcription of I-Smad mRNA in the nucleus (14 and 15). The I-Smad mRNA then shuttles to the cytoplasm (16), where it can be degraded (17) or translated into I-Smad (18). I-Smad mediates a negative feedback by sequestering the active receptor (5 and 6) and can be degraded (19).