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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.
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