Fig. 1. Modulation of Smad signaling. TGFß/Smad superfamily signal strength is regulated and modulated at several different levels, both intrinsically and through cross-talk with other signaling pathways. R-Smads and co-Smads continuously shuttle between cytoplasm and nucleus. Following TGFß ligand-mediated engagement of the type II/type I receptor complex and R-Smad activation, C-terminally phosphorylated R-Smads are preferentially retained in the nucleus, where they initiate a specific transcription program. Signal termination at the level of receptors results in rapid dephosphorylation of activated R-Smads in the nucleus by the nuclear phosphatase, PPM1A. In addition, cells adapt to their persistent exposure to TGFß ligands by eliminating activated R-Smads by proteasomal degradation. This adaptive response may be mediated by TGFß-initiated non-Smad-dependent activation of MAP kinase pathways, which phosphorylate specific tyrosine residues in the Smad linker regions. These phosphorylation events appear to trigger proteasomal degradation and prevent nuclear transport of activated R-Smads, and are turned off by SCP-type phosphatases. Similar mechanisms centered on R-Smad linker regions appear to be utilized by mitogenic and stress stimuli to counterbalance the effects of TGFß signals. Conversely, MAP kinase-mediated N-terminal phosphorylation of p53 enables its interaction with activated R-Smads, thereby enhancing their cytostatic functions. This pathway may serve as a negative feed-forward loop to counterbalance excessive mitogenic signaling.